Faculty The Role of the Kidney in Cardiometabolic Disease Christian W. Mende, MD, FACP, FACN, FASN, FASH Clinical Professor of Medicine University of California at San Diego San Diego, California Disclosures Learning Objectives Dr. Mende: Scientific Advisor Islet Sciences, Inc.; Speakers Bureau Allergan, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen; Office CSO Islet Sciences, Inc. Analyze each component of cardiometabolic syndrome and the associated risk of CKD Evaluate assessment techniques for CKD risk in patients with cardiometabolic syndrome Examine associated comorbidities in patients with cardiometabolic syndrome Assess pharmacotherapy options and therapeutic goals to treat CKD in patients with cardiometabolic syndrome CKD = chronic kidney disease. Definitions Definitions (cont) CKD (CKD - KDIGO 2013) present 3 months egfr <60 ml/min/1.73 m² or Albuminuria 300 mg or Abnormal histology (biopsy) or transplantation Abnormal structure (polycystic kidney disease) Progression of CKD Loss of GFR >5 ml/y Change of category (ie, from CKD 3 to 4) Loss of >25% GFR from baseline Kidney Disease: Improving Global Outcomes; egfr = estimated glomerular filtration rate; GFR = glomerular filtration rate. KDIGO. Kid Int. 2013;3(1):5-150. CMS Large waist circumference: women, 89 cm and above; men, 102 cm and above High triglyceride levels: 150 mg/dl or higher Reduced HDL: <40 mg/dl for men, <50 mg/dl for women Increased blood pressure: 130/80 mm Hg or higher Elevated fasting blood glucose: 100 mg/dl or higher CMS = cardiometabolic syndrome; HDL = high-density lipoprotein. KDIGO = Kidney Disease Improving Global Outcomes; egfr = epidermal growth factor receptor. KDIGO. Kid Int. 2013;3(1):5-150. Mayo Clinic Medical Staff Publication [online], March 19, 2016. 1
ARIC study Risk of CKD in CMS 10,096 non-diabetic participants with no CKD 21% had CMS (ATP III), followed for 9 years CKD developed in 7% NHANES III (2004) 2.6-fold greater incidence with CMS vs general population Spanish study 1498 patients with CMS with 3 components 6.7-fold greater incidence of CKD CKD Need to differentiate between new-onset CKD vs the progression of CKD Normal loss of egfr (after age 40 years) ~0.7 1.0 ml/y Type 2 diabetes mellitus >2 ml/y CMS (no data) likely >1.0 ml/y ARIC = Atherosclerosis Risk in Communities; ATP III = Third Adult Treatment Panel; NHANES III = Third National Health and Nutrition Examination Survey Kurella M, et al. J Am J Soc Nephrol. 2005;16:2134-2140. Chen J, et al. Ann Intern Med. 2004;140:167-176. Landecho MF, et al. Rev Esp Cardiol. 2011;64(5):373-378. Weir MR. Postgrad Med. 2016;128:290,298. Patient #1 A 55-year-old woman with egfr of 90 ml/min ACR 60 (normal <30) BMI 32 (weight, 188 lb; 5 11 ) BP 145/85 mm Hg (no therapy) FBS 110 mg%, TG 220 mg%, LDL 110, HDL 42 Question What are her risk factors for CKD? ACR = albumin-to-creatinine ratio; BMI = body mass index; BP = blood pressure; FBS = fasting blood sugar; TG = triglyceride; LDL = low-density lipoprotein; HDL = high-density lipoprotein. Kidney International Supplements. 2013;3(1):1-150. Patient #2 A 61-year-old man with egfr of 45 ml/min (CKD stage 3A) BMI 34 kg/m 2 (220 lb, 5 10 ) BP 155/95 on benazepril 40 mg, HCTZ 25 mg FBS 115 mg%, HDL 32, LDL 110, TG 300 Urine Benign sediment ACR 400 mg/g Note: A 5-mL egfr loss in the past 12 months! Questions What tests are needed to evaluate his renal function? What therapies should be started to slow the progression of CKD? HCTZ = hydrochlorothiazide. Mechanisms Contributing to CKD Risk in CMS Insulin resistance (salt sensitivity, water retention) Increased BP and intraglomerular pressure (mean arterial) Upregulation of multiple systems RAAS (angiotensin-ii, aldosterone) Sympathetic nervous system (leptin) Inflammatory cytokines (macrophages invade fat cells and produce multiple cytokines) IL-6 (elevated hcrp),tnf-alpha, PAI-1,TGF-beta ROS RAAS = renin-angiotensin-aldosterone system; ROS = reactive oxygen species; IL-6 = interleukin-6; hcrp = human C-reactive protein; TNF = tumor necrosis factor; PAI-1 = plasminogen activator inhibitor-1; TGF = transforming growth factor-beta. Schelling JR, et al. J Am Soc Nephrol. 2004;15:2773-2774. Lastra G, et al. Curr Diab Rep. 2006;6:207-212. Kurella M, et al. J Am Soc Nephrol. 2005;16:2134-2140. Landecho MF, et al. Rev Esp Cardiol. 2011;64(5):373-378. CKD in CMS No data on DIRECT effect of CMS, per se, causing CKD One needs to analyze EACH component of CMS for its risk of CKD Insulin resistance is not unique in CMS, but seen in many conditions Hypertension: ~50% of patients Obesity Pre-diabetes mellitus Type 1 diabetes mellitus: ~50% Type 2 diabetes mellitus: ~90% Polycystic ovary syndrome Lectures from Drs. DeFronzo, Raven, et al. World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease (WCIRDC). 2011-2015. Los Angeles, CA. 2
Hypertension as a CKD Risk in CMS Microalbuminuria CKD risk of systolic BP >140 mm Hg 2.5 times greater than normotension Mechanisms Upregulation of RAAS and SNS Albuminuria Increased intraglomerular pressure Microvascular injury Renal artery stenosis (bilateral/high grade) Microalbuminuria is NOT a sign of renal disease/ckd, but represents the following: Endothelial dysfunction with its risks for cardiovascular events and mortality Risk of progression of micro-albuminuria to albuminuria SNS = sympathetic nervous system. Schelling JR, et al. J Am Soc Nephrol. 2004;15:2773-2774. Lastra G, et al. Curr Diab Rep. 2006;6:207-212. Kurella M, et al. J Am Soc Nephrol. 2005;16:2134-2140. Landecho MF, et al. Rev Esp Cardiol. 2011;64(5):373-378. Bakris GL, et al. Diabetes Care. 2014;37(3):867-875. Blood Pressure in CKD/CMS CKD Blood Pressure Guidelines Blood pressure control is the most effective intervention in CKD NO albuminuria: BP <140/90 mm Hg Albuminuria (>30 mg/d) BP <130/80 mm Hg Use ACEIs or ARBs if >30 mg/d albuminuria Lifestyle BMI >20-25 kg/m 2 Salt <6 g (2400 mg Na) Exercise 30 minutes 5x/week Couser WG, et al. Kidney Int. 2011;80(12):1258-1270. ACEI = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BMI = body mass index. Kidney International Supplements. 2013;3(1):1-150. Drug Choices for Hypertension in Patients with CKD with CMS RAAS blockade: ACEI or ARB Diuretics: Chlorthalidone preferred over HCTZ Effective to egfr of 30 ml/min Longer duration of action SBP decline of ~7 mm Hg more For egfr <30 ml = need for loop diuretics CCB Aldactone (if egfr >30), observe K! Alpha and beta blockers SBP = systolic blood pressure; CCB = calcium channel blocker; K = potassium. KDIGO Clinical Practice Guidelines for the Management of Blood Pressure in Chronic Kidney Disease. December 2012;2(5). Bed-Time Dosing in Patients with Diabetes Mellitus or CKD (at Least 1 BP Drug at Bedtime) Diabetes mellitus ABPM 48 hours: HTN present, if BP 135/85 or nocturnal BP >120/70 448 patients taking 3 drugs ONE hypertension medication at bedtime follow-up: 5.4 years Each 5-mm Hg nocturnal SBP decline = 12% decline of CV events (CVA, MI, CV death) CKD 695 patients with egfr <60, 7-year follow-up (ABPM 48 hours) ONE hypertension medication at bedtime Each 5-mm Hg nocturnal SBP decline = 14% decline of CV events ABPM = ambulatory blood pressure monitoring; MI = myocardial infarction. Hermida RC, et al. Diabetes Care. 2011;134:1270-1276. J Am Soc Nephrol. 2011;22:2313-2321. 3
Issues Use of Beta Blockers for Hypertension in CMS Weight gain Increased resistance to insulin Risk of development of diabetes mellitus Only non-vasodilating beta blocker approved for post-mi in hypertension Vasodilating beta blocker preferred Patients taking carvedilol or nebivolol have little risk of developing diabetes mellitus and fewer adverse effects Obesity as a CKD Risk in CMS Renal effects of obesity Hormonal: Activation of RAAS angiotensin-ii, aldosterone SNS, leptin, ROS Physical: Compression of renal parenchyma Structural: Glomerulopathy (focal glomerulosclerosis), glomerulomegaly albuminuria Functional: Elevated egfr Afferent vasodilation + efferent vasoconstriction = hyperfiltration Manrique C, et al. J Clin Hypertens (Greenwich). 2009;11(6):309-315. Frishman WH, et al. J Clin Hypertens (Greenwich). 2011;13(9):649-653. Ayers K, et al. Hypertension. 2012;59:893-898. Cockcroft JF, et al. J Clin Hyperts (Greenwich). 2012;l14(2):112-120. Locatelli F, et al. J Am Soc Nephrol. 2006;17:S81-S85. Schelling JR, et al. J Am Soc Nephrol. 2004;15:2773-2774. Thomas G, et al. Clin J Am Soc Nephrol. 2011;6(10):2364-2373. Obesity and CKD Obesity and CKD Risk Obesity is an INDEPENDENT risk factor for CKD CKD RR 1.83 (female > male) Progression of CKD Focal and segmental glomerulosclerosis Micro-albuminuria and macro-albuminuria ESRD (risk for BMI >30 kg/m 2 x 3, BMI >36 kg/m 2 x5) Renal calculi Renal cell carcinoma Obesity = 2.5 times CKD risk Obesity is associated with the following: Albuminuria Insulin resistance Increased RAAS and SNS activation Inflammatory state Hypertension (80%) and risk of increasing BP RR = relative risk. Hsu CY, et al. Ann Intern Med. 2006;144(1):21-28. Thomas G, et al. Clin J Am Soc Nephrol. 2011;6(10:2364-2373. Obesity and CKD CKD Risk in MHO Veteran s Administration study of 3,376,187 US veterans with egfr >60 ml/min Mean age, 60 years BMI, ~29 kg/m 2 Followed for 7 years Results 8.1% (274,764) aged >40 years and BMI >30 kg/m 2 developed progressive egfr loss of >5 ml/min/y Best outcome: BMI >25 kg/m 2 but <30 kg/m 2 8500 Korean patients with BMI 26, ~age 67 years No insulin resistance, dyslipidemia, or hypertension (with egfr >60 ml) compared to non-obese MHO BMI 22 kg/m 2 in a 3-year study ~40% greater CKD risk (egfr <60 ml) HR, 1.38 (CI, 1.01-1.87) Lu JL, et al. Lancet Diabetes Endocrinol. 2015;3(9):704-714. MHO = metabolically healthy obese; HR = hazard ratio; CI = confidence interval. Jung CH, et al. Kidney Int. 2015;88(4):843-850. 4
Hyperglycemia as a CKD Risk in CMS There are NO trials to assess the risk of hyperglycemia, per se, as a CKD risk All trials for CKD and CKD progression are in NON-diabetic patients Sparse data in diabetes mellitus without other comorbidities point to 20 years duration before the development of CKD In CMS, hyperglycemia is often not severe enough to be a renal factor Hyperglycemia and Microalbuminuria/Macroalbuminuria Multiple trials in diabetes mellitus show a reduction in new-onset microalbuminuria/macroalbuminuria with stringent A1C control DCCT (type 1 diabetes mellitus A1C 7.3 vs 9.1) reduction new-onset microalbuminuria 39% and macroalbuminuria 54% UKPDS (newly diagnosed type 2 diabetes mellitus) 10-year follow-up: Risk reduction for microalbuminuria 33% in intensive group (A1C difference 11% between groups) ACCORD intensive A1C group to < followed for 6.5 had reduced ESRD (number needed to treat = 410) but higher mortality (any benefit?) Bakris GL. Lecture at the International Society of Nephrology Meeting. Cape Town, South Africa, 2015. Bakris GL. May Clin Proc. 2011;86(5):444-456. Bloomgarden ZT. Diabetes Care. 2009;32(6):e64-e68. Abdelhafiz AH, et al. Aging Dis. 2015;6(4):262-270. Perkovic V, et al. Kidney Int. 2013;83(3):517-523. Zoungas S, et al. N Engl J Med. 2014;371:1392-1406. Hyperglycemia and Microalbuminuria/Macroalbuminuria (cont) Multiple trials in diabetes mellitus show a reduction in new-onset microalbuminuria/macroalbuminuria with stringent A1C control (cont) ADVANCE (5.4 years of A1C <6.5% vs 7.1%) reduced new-onset microalbuminuria by 9% and macroalbuminuria by 33% ADVANCE ON (followed post-trial 6 more years with same A1CE) showed reduction of ESRD (HR.54) with 29 vs 53 There are no data on hyperglycemia in CMS and effect on microalbuminuria/macroalbuminuria or new-onset of CKD or CKD progression Hyperlipidemia as a CKD Risk in CMS No trials or data exist on the effect of hyperlipidemia as a risk factor for CKD Small studies show a benefit in slowing progression of CKD of 1.9 ml/y (same as RAAS blockade) Recent meta-analysis of 57 trials and 140,000 patients with CKD showed a statin therapy benefit of Reduced egfr decline of 0.4 ml/y Mild reduction of albuminuria The main benefit for therapy of hyperlipidemia in CMS is to prevent cardiovascular events Bakris GL. May Clin Proc. 2011;86(5):444-456. Bloomgarden ZT. Diabetes Care. 2009;32(6):e64-e68. Abdelhafiz AH, et al. Aging Dis. 2015;6(4):262-270. Perkovic V, et al. Kidney Int. 2013;83(3):517-523. Zoungas S, et al. N Engl J Med. 2014;371:1392-1406. Fried L, et al. Kidney Int. 2001;59:260-269. Su X, et al. Am J Kidney Dis. 2016;67(6):881-892. Hyperuricemia and Diabetes Mellitus Nephrolithiasis in CMS 1449 patients with type 2 diabetes mellitus egfr >60 ml/min/1.73 m 2, no albuminuria, divided into uric acid <7.0 and >7.0 mg% followed for 5 years with no therapy for uric acid CKD (egfr <60) developed in 29.5% with uric acid >7.0 mg% 11.4% with uric acid <7.0 mg% The risk of renal calculi formation in CMS is 2x greater than in the general population Predisposing factors Lower urine PH Decreased citrate levels Increased uric acid excretion Increased calciuria (ie, high salt intake) Zoppini G, et al. Diabetes Care. 2012;35:99-104. Jeong IG, et al. Am J Kidney Dis. 2011;58(3):383-388. West B, et al. Am J Kidney Dis. 2008;51(5):741-747. 5
Patient #1 Patient #1 (cont) A 55-year-old woman with an egfr of 90 ml/min ACR 60 (normal <30) BMI 32 (weight, 188 lb; 5 11 ) BP 145/85 mm Hg (no therapy) FBS 110 mg%, TG 220 mg%, LDL 110, HDL 42 What are her risk factors for CKD? Age: Loss of egfr of ~1 ml/y after age 40 years Progression of MICRO to MACRO albuminuria (ie, ACR >300 mg/g) Obesity Cardiovascular events (MI, congestive heart failure) affecting renal function Patient #2 A 61-year-old man with egfr of 45 ml/min (CKD 3a) BMI 34 (220 lb, 5 10 ) BP 155/95 taking benazepril 40 mg, HCTZ 25 mg FBS 115 mg%, HDL 32, LDL 110, TG 300 Urine Benign sediment ACR 400 mg/g Note: A 5-mL egfr loss in the past 12 months! Questions What tests are needed to evaluate his renal function? What therapies should be started to slow the progression of CKD? Patient #2 (cont) What tests and therapy are needed to slow progression of his CKD? Renal ultrasound, A1C, calcium, phosphates, parathyroid hormone, vitamin D, electrolytes, sodium bicarbonate, uric acid Lower SBP <130 mm Hg Change hydrochlorothiazide to chlorthalidone Add calcium channel blocker Consider spironolactone 12.5-25 mg or eplenerone 25-37.5 mg Observe potassium levels Lower LDL to <70 mg/dl Weight loss of at least 10 lbs What s the Take Home? The risk of CKD in CMS is 2.5 times greater than in the general population Hypertension (uncontrolled) and obesity are the two major risk factors of CKD in CMS Avoid non-vasodilating beta blockers in CMS to treat hypertension (unless post-mi) Use bedtime dosing of at least one drug for hypertension in CMS Questions? 6