Case #1. Current Management Strategies in Chronic Kidney Disease. Serum creatinine cont. Pitfalls of Serum Cr

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1 Current Management Strategies in Chronic Kidney Disease Grace Lin, MD Assistant Professor of Medicine, University of California San Francisco Case #1 50 y.o. 70 kg man with long-standing hypertension is found to have a serum creatinine of 1.5mg/dl and a blood pressure of 150/90. Does he have chronic kidney disease? What additional assessment should you undertake? What are treatment goals and options for therapy? Pitfalls of Serum Cr Serum creatinine cont If both of these politicians had a SCr of 1.5 mg/dl, what is their respective estimated CrCl? Age = kg (220 lbs) SCr = 1.5 mg/dl GFR = 77.8 ml/min Age = kg (143 lbs) SCr = 1.5 mg/dl GFR = 31.7 ml/min 1

2 Estimating Renal Function Need serum creatinine, age, sex, and weight (140-agein yrs) Xweightin kg) X 0.85(female) 72 Xserum Crin mg/dl Or serum creatinine, age, sex, and race GFR= 186 X(serum Crin mg/dl) X(agein yrs) X0.742(for female) X1.210 (for African-American) Estimating Renal Function 50y.o man who weighs 70kg and has serum Cr= 1.5 mg/dl for > 3 months (140-50) X70kg) 72 X1.5in mg/dl = 58 ml/min per 1.73 meters 2 Definition of Chronic Kidney Disease Stages of Chronic Kidney Disease Structural or functional abnormalities of the kidneys for 3 months as manifested by either: Kidney damage Pathologic abnormalities, or Markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging test, or GFR <60 ml/min/1.73 m2, with or without kidney damage Stage Description GFR (ml/min per Kidney damage with normal or increased GFR 2 Kidney damage with mild decrease in GFR m 2 ) to 89 3 Moderate decrease in GFR 30 to 59 4 Severe decrease in GFR 15 to 29 5 Kidney failure <15 or dialysis 2

3 Chronic Kidney Disease: An underrecognized epidemic Primary Diagnoses for Patients Who Start Dialysis Kidney failure (ESRD) Decreased GFR Damage (Proteinuria) Endstage Progression Initiation, injury > 300,000 patients GFR ,000 patients GFR million patients 10 million patients Other 10% Glomerulonephritis 13% Hypertension 27% Diabetes 50% Age, DM, HBP, family history At risk 20 million patients CKD increases health care costs by 65% over 10 years Incident CKD increases costs by 38% Baumeister, Am J Nephrol, 2009 United States Renal Data System (USRDS) 2000 Annual Data Report Slide Source Hypertension Online Risk Factors for CKD Screening for Chronic Kidney Disease Diabetes mellitus Hypertension Autoimmune disease Systemic infections Urinary tract infections Nephrolithiasis Lower urinary tract obstruction Neoplasia Family history CKD Recovery from ARF Reduction in kidney mass Nephrotoxic drugs Older age Racial/ethnic minority status Low socioeconomic status Not recommended for general population Consider screening if any of 3 risk factors Diabetes Hypertension Age > 55 years Identifies 93% of cases Number needed to screen = 9 per 1 case 3

4 Evaluation of CKD History (PMH, family/social hx) Medication exposure (NSAIDs, aminoglycosides) Time course of decline in renal function Urinalysis (proteinuria, casts, cells, etc) Checking for complications of CKD (CBC, K +, HCO 3, albumin, Ca +2, PO 4, PTH, uric acid, albumin) Serologies or specialized testing if indicated (ANA, ANCA, Hep B/C, RF, HIV, SPEP/UPEP, anti-gbm, complement levels) Imaging renal ultrasound (RAS, cysts, obstruction) Renal biopsy when uncertain diagnosis and considering immunosuppressive therapy Evaluation of urinary protein excretion Normally very small amount of protein excreted in urine Increased excretion of albumin sensitive marker for CKD due to diabetes, HTN, glomerular disease Spot urine samples (first morning specimen preferred) to evaluate Can calculate spot urine protein/creatinine ratio to assess approximate protein excretion rate (g/24 hrs) < 0.3 (< 300 mg) = normal (300 mg 3000 mg) = non-nephrotic range proteinuria > 3 (> 3 g) = nephrotic range protenuira Risk Factors for Progression of Renal Disease Early intervention in CKD reduces time to progression to ESRD Can be modified Hypertension Albuminuria/Proteinuria Dyslipidemia Cannot be modified Age Ethnicity Gender Hemoglobin A 1C Smoking Anemia Ca P0 4 4

5 Treatment of CKD: Outline Diagnose and treat specific cause of CKD Slow progression of GFR BP control Maximize ACE-I/ARB therapy Reduce cardiovascular disease risk Control BP, lipids Treat comorbidities Glucose control Assess and treat for complications Anemia, bone disease Refer to nephrologist when GFR < 30 ml/min/1.73 m 2 or earlier Reversible Causes of CKD Decreased renal perfusion Hypovolemia Hypotension Infection Nephrotoxic drugs* NSAIDs Aminoglycoside antibiotics Radiographic contrast Urinary tract obstruction *Some drugs cause spurious elevation of creatinine but do not decrease GFR: cimetidine, trimethoprim, cefoxitin, flucytosine Blood Pressure and CKD Most patients with CKD will develop hypertension, regardless of initial cause 10 mmhg reduction of mean arterial pressure is associated with preservation of 3.7 ml/min of glomerular filtration Treatment goal of < 130/80, lower (< 125/75) in patients with > 1 gram/day of proteinuria Anti-Hypertensive Treatment in CKD Recommended therapy: 1 st agent: ACE-I or ARB, particularly in diabetic patients or patients with significant proteinuria 2 nd agent: Diuretic 3 rd agent: Calcium channel blockeror beta-blocker Most patients require 2 agents for adequate BP control In patients with proteinuria, ACE-I appear to offer reno-protective benefits over other anti-hypertensive therapies 5

6 Average Number of Anti-Hypertensive Agents Used to Achieve Target BP Goal BP Achieved BP Avg # of drugs per patient MDRD ABCD HOT UKPDS <92 mmhg MAP* <75 mmhg DBP <80 mmhg DBP <85 mmhg DBP 93 ~ *The goal mean arterial pressure (MAP) of <92 mmhg specified in the MDRD trial corresponds to a systolic/diastolic blood pressure of approximately 125/75 mmhg. Slide Source Hypertension Online Proteinuria in CKD Proteinuria is independent risk factor for renal failure Protein excretion > mg per day increases risk of progression of CKD Reduction in proteinuria is correlated with decreased progression of CKD For each 1 gram/day reduction in proteinuria, rate of GFR decline decreased by mg/min per year (MDRD study) Peterson, Ann Intern Med, 2005 Relative Risk of ESRD on ACE-I By Baseline Proteinuria ACE Inhibitor in Non Diabetic CKD Relative Risk = no ACEI benefit Baseline Urinary Protein Excretion (grams/day) Jafar, Ann Int Med, 2001 Ifserum creatinine >1.5 mg/dl (24hr CrCl <60) and proteinuria > 500 mg -1 gm, ACE-I is first line Most effective agent for decreasing protein excretion Beneficial even in absence of hypertension Effect independent of BP Benefits of ACE-I increase with amount of baseline proteinuria 6

7 Missed Opportunities Only 1/3 of patients with CKD receive ACE-I Non diabetics less likely to receive ACE-I than diabetics Likelihood of being on ACE-I not related to nephrology referral Case #2 65 y.o. man with stage 3 CKD currently on moderate dose of ACE-I with BP of 130/80 Positive urine dipstick; follow-up urine protein/creatinine ratio is 0.7 You increase the dose of his ACE-I and at a follow-up appointment, his BP and proteinuria have improved, but his creatinine increased from 1.4 to 1.7 mg/dl Nissenson, J Am Soc Nephrol, 2001 What do you do next? Case #2 1. Reduce dose of ACE inhibitor 2. Maintain dose of ACE inhibitor 3. Increase dose of ACE inhibitor 4. Stop ACE inhibitor Starting/Increasing ACE Inhibitor Check electrolytes and creatinine at baseline and within 1 week Expected short-term decrease in GFR ( 30%) If rise in creatinine > 30%, reduce dose by 50% and recheck labs in 1 week If rise in creatinine > 50%, exclude hypoperfusion and RAS 7

8 Does ARB = ACE-I? Case #2 > 40 randomized head to head comparisons Similar level of BP control and reduction of proteinuria Similar benefits on mortality, CV disease, progression of CKD, and quality of life Relatively little data on long term outcomes or safety with either drug Less cough and angioedema with ARB ARBs more costly 1. Reduce dose of ACE inhibitor 2. Maintain dose of ACE inhibitor 3. Increase dose of ACE inhibitor 4. Stop ACE inhibitor Case #3 Case # 3 53 y.o. woman with CKD (serum creatinine = 2.2 mg/dl), controlled HTN, and proteinuria (1 gram/24 hrs), on maximum dose ACE-I. What changes, if any, would you make in her treatment? 1. Change the ACE inhibitor to an ARB 2. Combine the ACE inhibitor with an ARB 3. Don t change treatment 8

9 ARB + ACE-I for Proteinuria? Blocking angiotensin II reduces proteinuria Some angiotensin II can form without ACE (ACE-I flaw) ARB s only block one subtype of angiotensin II (ARB flaw) Proteinuria in Monotherapy vs Combined ACE-I and ARB 16 trials Similar blood pressure lowering Combined therapy lowers proteinuria by about 25% more than monotherapy Do not achieve proteinuria lowering effects from either agent alone by simple increasing dose However... Kunz, Ann Intern Med, 2008 ONTARGET RCT of ramipril (ACE-I) vs telmisartan (ARB) vs combination therapy > 8000 patients with high cardiovascular risk or diabetes per arm Single drug arms equivalent outcomes Combination had more adverse effectsincluding more advanced renal disease without clear benefits Case # 3 1. Change the ACE inhibitor to an ARB 2. Combine the ACE inhibitor with an ARB 3. Don t change treatment ONTARGET investigators, New Engl J Med,

10 ACEI/ARB Treatment Timing REIN Follow Up Study Early intervention in non diabetic CKD more likely to preserve renal function and may arrest development of ESRD Treatment of microalbuminuria slows/prevents development of proteinuria in diabetics, more effective if started before proteinuria develops Non-diabetic CKD with proteinuria Placebo group switched to ACE-I Late change to ACE-I offered some benefit Early treatment with ACE-I associated with greater benefit In some patients, ESRD avoided GFR Placebo ACE I ACE I Years Risk of Hyperkalemia in CKD ACE-I underprescribed due to concerns about hyperkalemia Risk increases with decreasing GFR Baseline GFR Event rate per 100 pt-years (95% CI) ( ) > 30 to ( ) > 40 to ( ) > ( ) ACE-I greater risk than beta-blockers or CCB Can frequently be managed with low potassium diet and/or diuretics CKD as Risk Factor CKD is associated with increased mortality Cardiovascular disease is the main cause Weinberg, Arch Intern Med,

11 CV Mortality in General Population & Dialysis Patients Annual % Mortality (Log Scale) GP Black Dialysis Black Age (years) GP White Dialysis White Age-Standardized Rate of Cardiovascular Events (per 100 person-yr) <15 Estimated GFR (ml/min/1.73 m 2 ) Foley RN, Am J Kidney Dis, 1998;32(S ) Slide Source Hypertension Online Go et al. N Eng J Med. 351;13: Case #4 CKD and Cardiac Risk 57 y.o. woman with CKD, HTN, hyperlipidemia, and anemia of chronic disease What are the renal and cardiovascular benefits of treating her hyperlipidemia? 40% of patients have MI or revascularization prior to dialysis Treatment of hyperlipidemia with statins associated with slowing rate of GFR decline Statins associated with decreased risk of CV events/death in patients with mild-moderate CKD Statins not effective in reducing CV events/death in patients on dialysis No large RCTs demonstrating that treating dyslipidemia in CKD patients prevents CV disease 11

12 Case #4 Case # 4 57 y.o. woman with CKD, HTN, hyperlipidemia, and anemia of chronic disease Her Hgb = 8 gm/dl How would treating her anemia affect her risk for cardiovascular disease? 1. Lower risk of cardiovascular events and death 2. Reduce risk of left ventricular hypertrophy 3. Both of the above 4. Neither of the above CKD related anemia and cardiovascular complications Anemia is common About 50% of patients when GFR < 35 Almost 90% of patients when GFR < 25 Associated with CV deaths and LVH in observational studies NKF guidelines recommend use of erythopoietin when Hgb < 9 gm/dl What is the optimal target? Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) >1400 adult patients with GFR ml/min and anemia (Hgb<11.0 mg/dl) randomized to Epo SQ with different treatment targets Compared death, MI, CHF hospitalization and stroke for Hgb 13.5gm/dl versus 11.3gm/dl Study terminated early due to increased events in high hemoglobin group (125 vs 97; hazard 1.34) and no quality of life benefit Singh, NEJM,

13 Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin (CREATE) > 600 adult patients with GFR ml/min and anemia (Hgb mg/dl) randomized to EPO with different treatment targets Compared death, MI, acute heart failure, stroke, TIA, or hospitalization for angina, amputation or arrhythmia for Hgb gm/dl versus gm/dl More cardiovascular events and deaths in higher hemoglobin group but not statistically significant No reduction in LVH in higher Hgb group Correcting Anemia in CKD Complete correction not obviously beneficial and may be harmful Several additional studies in field that should help to determine whether there are benefits to lower treatment targets Current guidelines: goal Hgb = g/dl Maintain adequate iron stores Drueke NEJM, 2006 Secondary hyperparathyroidism Phosphorus: restrict dietary PO4, add binders Add phosphate binders to improve control Ca-P product target < 55 mg 2 /dl 2 Caution with phosphate-containing bowel preparations: risk of acute phosphate nephropathy Calcium: limit supplementation to < 2 g/day Treat vitamin D insufficiency (< 30 ng/ml) Add vitamin D analogs (calcitriol) CKD Stage Target ipth(pg/ml) 3(GFR 30-59) ( ) 4 (GFR 15-29) ( ) Other Complications of CKD Metabolic acidosis Develops when GFR < 60 ml/min/1.73 m 2 Increases loss of calcium from bone Target CO 2 22 meq/l Add oral sodium bicarbonate or Bicitra Risk of acute aluminum or magnesium toxicity Common ingredients in OTC antacids (Maalox, Mylanta) Citrate containing preparations (Mg citrate, calcium citrate, potassium citrate) increase aluminum absorption 5 (< 15 or dialysis) ( ) 13

14 Bottom Line on Preventing Progression of CKD and Mortality Risk Aggressive BP control to reach target < 130/80 Screening for CKD and proteinuria in patients with HTN and DM is cost-effective Intervene with ACE-I or ARB to reduce proteinuria and microalbuminuria (in diabetics) Aggressive treatment of cardiovascular risk factors, especially lipids Treat anemia to moderate level Monitor and treat secondary hyperparathyroidism 14

Case #1. Current Management Strategies in Chronic Kidney Disease. PiRalls of Serum Cr. Grace A. Lin, MD Primary Care Medicine: Update 2011

Case #1. Current Management Strategies in Chronic Kidney Disease. PiRalls of Serum Cr. Grace A. Lin, MD Primary Care Medicine: Update 2011 Current Management Strategies in Chronic Kidney Disease Grace A. Lin, MD Primary Care Medicine: Update 2011 Disclosures: None Case #1 50 y.o. 70 kg man with long- standing hypertension is found to have