Chronic Kidney Disease Dr. Rachel Carson Nephrologist With thanks to Dr. Gaylene Hargrove and Dr. Nancy Craven
Disclosures Speaker fees from Sanofi and Bristol- Myers-Squibb for community CME
Mr. Hales Current Age: 57 BP 140/85 Smoking: quit Weight: 203 lbs BMI: 29.1 A1C 6.7 egfr 53, ACR 38
What intervention is most effective in delaying the progression to ESRD? A. Dietary protein restriction (0.6 g/kg/d) B. Optimal BP control (<130/80) C. ACEI/ARB therapy D. Optimal glycemic control E. Weight reduction F. Smoking cessation
Which of the following statements is true of Mr. Hales? A. He has established diabetic nephropathy, so he will need dialysis/transplant in the future, despite optimal intervention. B. His current blood pressure (140/85) is acceptable. C. It is possible to normalize the ACR and stabilize egfr with optimal, multi-faceted intervention. D. He should be referred to a nephrologist urgently.
Mr. Hales is likely to experience a CV event before he requires renal replacement therapy. A. TRUE B. FALSE
The Challenge In Canada 22% of Canadians 18-70 years of age have hypertension 50% of Canadians >65 years of age have hypertension Hypertensive patients who are treated but BP uncontrolled Hypertensive patients who are treated and BP controlled 21% 13% 9% 22% 43% Diabetic patients Who are treated and BP controlled Patients who are aware but remain untreated and BP uncontrolled Hypertensive patients who are unaware Joffres et al. Am J Hyper 2001
Prevalence of Hypertension in Type 2 Diabetes Normoalbuminuria (n = 323) Microalbuminuria (n = 151) Macroalbuminuria (n = 75) Total (n = 549) 100 90 93 80 71 % Prevalence of hypertension (BP 140/90 mm Hg) 50 0 Tarnow L et al. Diabetes Care 1994
Diabetic Nephropathy and Albuminuria Diabetic nephropathy is the #1 cause of ESRD in Canada & Western World Normal range MAU Macroalbuminuria 10 30 300 7 20 200 mg/day µg/min Albumin excretion rate (AER) Maher JF Am Fam Physician 1992 Meltzer et al. CMAJ 1998 ESRD=End Stage Renal Disease
Proteinuria Predicts Stroke and CHD Events in Type 2 Diabetes A: U-Prot <150 mg/l B: U-Prot 150 300 mg/l C: U-Prot >300 mg/l Survival curves for CV mortality 1 0.9 0.8 0.7 0.6 0.5 Overall: p<0.001 A B C Incidence (%) 40 30 20 10 p<0.001 0 0 0 10 20 30 40 50 60 70 80 90 Stroke CHD events Miettinen H et al. Stroke 1996 Months U-Prot = Urinary protein concentration
Relative Importance of Microalbuminuria in Prediction of Mortality 10 10.02 8 6.52 6 Odds ratio 4 2 3.20 2.32 0 Microalbuminuria Smoking Diastolic BP Cholesterol Eastman RC et al. Lancet 1997
ONCE NEPHROPATHY IS PRESENT, PTS ARE MORE LIKELY TO DIE THAN TO PROGRESS Consider annual risk for 100 pts at each stage of DN No nephropathy 2 1.4 D Microalbuminuria 2.8 3 Macroalbuminuria 2.3 4.6 Plasma Cr >175 or RRT 5097 patients in UKPDS: Adler et al Kidney Int 2003;63:225-231 19.2 E A T H
Preserving Renal Function Blood Pressure Control/RAS Blockade Best evidence to support target of <130/80 is UKPDS data (each 10 mmhg reduces risk by 12%) IRMA-2 2 trial (Irbesartan( Irbesartan) 70% RR in progression from MAU to overt nephropathy; normalization of ACR possible IDNT trial (Irbesartan( Irbesartan) Decreased risk of CV death, CHF, doubling of SCr,, and ESRD in DM2 pts with macroalbuminuria RENAAL trial (Losartan( Losartan) Similar composite endpoint reduction in DM2 pts with well-established established CKD (egfr < 60 ml/min)
BP REDUCTION IS WHERE THE MONEY IS UKPDS data, Bakris et al AJKD 2000
Bakris et al, AJKD 2000
IRMA 2: Primary Endpoint Development of Overt Proteinuria 18 16 14 14.9 RRR=70% p<0.001 RRR=39% p=0.08 Subjects (%) 12 10 8 9.7 6 4 5.2 2 0 Usual care (n=201) 150 mg (n=195) 300 mg (n=194) Parving H-H et al. N Engl J Med 2001 Irbesartan
IRMA 2: Normalization of Urinary Albumin Excretion Rate 45 40 p=0.006 35 34 Subjects (%) 30 25 20 21 24 15 10 5 0 Usual care (n=201) 150 mg (n=195) 300 mg (n=194) Parving H-H et al. N Engl J Med 2001 Irbesartan
RENAAL Trial: Post-Hoc Analyses Most significant risk factor for progressive CKD was severity of proteinuria Every 10 mmhg increase in SBP increased risk of ESRD or death by 6.7% 18% decrease in risk of CV event for every 50% decrease in rate of albumin excretion For all levels of achieved BP, larger reduction in albuminuria correlated with lower risk of ESRD
Preserving Renal Function Primary Prevention of Nephropathy ADVANCE trial (Perindopril( Perindopril+ Indapamide) 11,000 DM2 pts fewer developed new onset MAU compared to controls, 19.6% vs 23.6%) BENEDICT trial (Trandolopril( Trandolopril) 1204 DM2 pts significant reduction in new onset MAU in treated vs controls (30 vs 18 events)
Preserving Renal Function Conclusions from ACEI/ARB Trials Blockade of the RAS is renoprotective in pts with DM2 and hypertension (prevents onset of incipient nephropathy) ACEI/ARB Tx stabilizes and can even improve renal fn in pts with established nephropathy The renoprotective effects of RAS blockade are independent of BP control ( Control Group in trials had equivalent BP control)
Preserving Renal Function Dietary Protein Restriction 2 small trials in Diabetes (NEJM 1991, Lancet 1989) 0.6 g/kg/d vs usual protein intake slowed rate of decline in GFR by 60-75% ie.. From 12 ml/min/yr to 3 ml/min/yr MDRD (NEJM 1994) 585 moderate CKD pts (lots of Polycystic Kidneys) 0.6 g/kg/d vs 1.3 g/kg/d showed small benefit only after 4 mos 255 severe CKD pts 0.3 g/kg/d vs 0.6 g/kg/d showed marginally slower decline Potential problems: Compliance Increased risk of protein malnutrition normal protein intake is 1.5 g/kg/day Moderate reduction is 1 g/kg/day (recommended)
Preserving Renal Function STENO 2 Trial Combined Therapy 160 pts randomized to standard vs intensive multifactorial Tx Diet, exercise, smoking cessation ACEI Tx (independent of BP) ASA Tx in pts with CAD, PVD BP goal < 140/85 HbA1c < 6.5% Tchol < 5.0; TG<1.65
Preserving Renal Function STENO 2 Trial Combined Therapy Mean F/U 7.8 yrs Primary end point progression to overt nephropathy at 4 yrs; composite CV endpoint at 8 yrs Significant improvement in albuminuria (-20 vs +30 mg/d) Reduced progression to overt nephropathy (20% vs 39%)
What about the very elderly? Beckett et al (NEJM 2008) RCT of 3,845 pts from Europe, China, Australasia aged >80 yrs with SBP>160, creat < 150 Well (<15% with DM, cardiovascular dz) Indapamide +/- Perindopril vs placebo Target BP <150/80 2 year follow up 21% reduction in all-cause mortality 64% reduction in heart failure
CAUTION: CAUSES OF FALSE POSITIVE Urine ACR Fever Exercise CHF (decompensated( decompensated) Poor glycemic control Urinary tract infection Hematuria
Preserving Renal Function Summary/Recommendations Parameters to monitor Q3monthly: BP (home BP monitoring useful) SCr/eGFR Urine ACR HbA1c Lipids Q6-12 monthly Therapeutic Goals: BP < 130/80; ACEI/ARB first line Tx Normalize urine ACR; use ACEI/ARB even if normotensive Slow decline in egfr LDL chol < 2.0 mmol/l if CAD
Preserving Renal Function Summary/Recommendations Algorithm for treating HTN: ACEI or ARB first line Tx Titrate to maximum dose tolerated Repeat SCr,, K within 1 week Add diuretic (loop diuretic if GFR < 35 ml/min) If BP target not reached, add CCB, or beta-blocker blocker If persistent albuminuria combined ACEI/ARB Tx?
ACEi plus ARB? YES! CALM (2000) 199 DM HTN pts w MAU, candesartan and lisinopril Lower BP, mild additional reduction of albuminuria CHARM-added (2003) 2548 CHF pts candesartan plus ACEi fewer CV death or CHF hospitalizations COOPERATE (2003) 263 Japanese non-dm pts, losartan trandalapril Slowed renal progression and reduced proteinuria Kunz Meta-analysis analysis (Ann Int Med Jan 2008) greater reduction in proteinuria (18-25%) but no renal outcome data NO! ONTARGET (NEJM April 2008) 6365 pts w DM Ramipril telmisartan no outcome benefit, greater risk of renal impairment and adverse effects VALIANT (2003) 14,703 pts w MI and CHF valsartan and captopril no outcome benefit, increased adverse reactions MAYBE! ValHeFT (2001) 5010 pts w CHF, valsartan + ACEi less CHF, better QOL, BUT if pt already on BBL and ACEi,, higher mortality
ACEi / ARB Therapy: SAFE USE / MONITORING Check serum K and creatinine at initiation of therapy or at time of dose change and 1-21 2 wks later Start with low doses ACE/ARB medications should be held in the event of significant systemic illness (fever, vomiting, diarrhea) to avoid a pre-renal renal insult If K 5 5.5, Potassium-restricted diet (Renal Dietician now available in Nanaimo!) consider reducing dose if possible, d/c drugs that interfere with K excretion: NSAIDs, Septra,, potassium salts, potassium-sparing sparing diuretics Prescribe thiazide or loop diuretics If none of these work, THEN discontinue ACEi/ARB
Additional Anti-hypertensive options Look for dual indications Alpha blockers prostatic disease (Terazosin, Prazosin, Doxazosin) Sympatholytics anxiety (Clonidine 0.1 mg BID, caution with discontinuation) Direct Vasodilators - male pattern hair loss (Minoxidil, Hydralazine)
Hidden Factors Salt NSAIDS Etoh Over the counter drugs (decongestants) Tricyclics,, MAO inhibitors Anabolic steroids Oral contraceptives Caffeine (energy drinks) Illegal drugs (cocaine, methamphetamine) Secondary Hypertension? Renal Artery Stenosis (fibromuscular dysplasia or atherosclerotic) Hyperaldosteronism (hypokalemia) Hypercortisolism Pheochromocytoma Coarctation of the aorta (BP in both arms +/- legs) Obstructive sleep apnea
Preserving Renal Function Lifestyle Modification Dietary Sodium restriction 100 mmol/d = 2300 mg/d Consider doing 24h urine collection for Na to assess dietary compliance Weight Loss (can reduce (can reduce albuminuria,, BP, improve glycemic control) Smoking Cessation Regular Exercise Dietary Protein restriction (1.0 Moderation of ETOH (re: BP control) (1.0 g/kg/d)
What intervention is most effective in delaying the progression to ESRD? A. Dietary protein restriction (0.6 g/kg/d) B. Optimal BP control (<130/80) C. ACEI/ARB therapy D. Optimal glycemic control E. Weight reduction F. Smoking cessation
Which of the following statements is true of Mr. Hales? A. He has established diabetic nephropathy, so he will need dialysis/transplant in the future, despite optimal intervention. B. His current blood pressure (140/85) is acceptable. C. It is possible to normalize the ACR and stabilize egfr with optimal, multi-faceted intervention. D. He should be referred to a nephrologist urgently.
Mr. Hales is likely to experience a CV event before he requires renal replacement therapy. A. TRUE B. FALSE
What to tell Mr. Hales? Commend him re: Smoking cessation Good glycemic control (A1c 6.7%) Parameters to treat: BP ACEI/ARB; goal BP < 130/80 Albuminuria ACEI/ARB Weight aim for BMI <= 25 Lipids; goal LDL < 2.0
GRAND OPENING! Early Bird Special! The VIHA Kidney Care Clinic is moving into the Beaufort Centre (old NRGH Foundation office) Opening Day November 3rd RN Renal Dietician Social Worker Early Education for patients with egfr >50 Learning Session #1 (pts with egfr 30-60) Learning Session #2 (pts with egfr <30)
Thank you! Questions Welcome
Reaching Target: Combination Therapy TPR x CO = MAP TPR Reduction ACEi ARB CCB Direct Renin Inhibitors (Aliskiren/Rasilez) Alpha Blockers Other Vasodilators (Hydralazine, Minoxidil) HR/Contractility Reduction BBL CCB Centrally Acting agents (Clonidine) Preload Reduction Thiazide Diuretics Loop Diuretics Potassium Sparing Diuretics Venodilators (NTG) Centrally Acting Agents (Clonidine)
Assessing Alcohol Intake Frequency During the past 12 months, how often, on average, did you drink alcoholic beverages? Everyday 4-66 times/week 2-33 times/week Once per week 1-33 times per month Less than once per month Abstainer/not applicable Quantity On the days when you drank alcohol, how many drinks did you usually have? Rehm J, Int J Epidemiol 1999;28:219-24 24