New Developments in Management of Chronic Kidney Disease

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1 New Developments in Management of Chronic Kidney Disease Andrew Bindman, MD Professor of Medicine, Epidemiology and Biostatistics University of California San Francisco 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? Work up of Renal Insufficiency Definition of Chronic Kidney Disease Medical history Serum Cr measurements over time Urine analysis - ph, specific gravity, blood, protein, cells, casts Renal ultrasound - kidney size, cysts, obstruction CBC, lipids, uric acid, albumin Na +, K +, Cl -, HCO 3, calcium, phosphorus Consider ANA, Hep B, Hep C, HIV, anca, spep/upep Biopsy when uncertain dx and considering immunosuppressant Rx Structural or functional abnormalities of the kidneys for 3 months as manifested by either: Kidney damage Pathologic abnormalities Markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging test GFR <60 ml/min/1.73 m2, with or without kidney damage 1

2 Stages of Kidney Disease Estimating Renal Function Need serum creatinine, age, sex, and weight Kidney failure (ESRD) Decreased GFR Endstage Progression (140-age in yrs) X weight in kg) X 0.85(female) 72 X serum Cr in mg/dl Damage (Proteinuria) Age, DM, HBP, family history Initiation, injury At risk Chronic Kidney Disease Or serum creatinine, age, sex, and race GFR= 186 X (serum Cr in mg/dl) X (age in yrs) X 0.742(for female) X (for African-American) Estimating Renal Function Chronic Kidney Disease in U.S. Adults 50 y.o man who weighs 70 kg and has serum Cr= 1.5 mg/dl for > 3 months (140-50) X 70 kg) 72 X 1.5 in mg/dl = 58 ml/min per 1.73 meters 2 >7 million (4%) with moderate CKD (30-59 ml/min) ~ 400,000 with severe CKD (15-29 ml/min) > 300,000 patient with kidney failure (<15ml/min) = Stage 3 Chronic Kidney Disease Men have higher rates than women Rates increase substantially with age 2

3 Etiology of Chronic Kidney Disease Screening for Chronic Kidney Disease ~ 45% - Diabetes ~ 25% - HTN ~ 10% - Glomerulonephritis ~ 10% - Other identifiable causes ~ 10% - Idiopathic Not recommended for general population But if any of 3 risk factors Diabetes HTN Age > 55 yrs Identifies 93% of cases Need to screen 9 to find 1 case Goals of Intervention Reverse acute renal failure Address underlying systemic disease Slow progression of chronic kidney disease Lower mortality risk of chronic kidney disease Common Causes of Reversible Renal Insufficiency in Primary Care Dehydration Medications Infection Obstruction 3

4 Blood Pressure and CKD Hypertension can be a primary cause of CKD Hypertension develops in most patients who have CKD regardless of initial cause 10 mmhg reduction of mean arterial pressure associated with preservation of 3.7 ml/min of glomerular filtration Anti-Hypertensive Treatment in CKD Treatment goal <130/80 Most patients require >2 drugs for adequate B/P control ACEI appears to offer reno-protective benefits over other anti-hypertensive treatments JNC 7, JAMA, 2003 Relative Risk of ESRD on ACEI By Baseline Proteinuria Proteinuria: A Sign and a Cause of Kidney Disease = no ACEI benefit Increases in glomerular pressure increase size of pores through which proteins can escape into collecting system Reabsorption of filtered proteins (e.g.albumin) activates inflammatory substances such as endothelin-1 which attract inflammatory cells to interstitium Baseline Urinary Protein Excretion Resulting scarring destroys glomeruli and increases pressure in remaining glomeruli escalating a cycle of destruction Jafar, Ann Int Med,

5 Anti-Hypertensive Treatment in CKD Proteinuria is an independent risk factor for renal failure Calcium channel blocker more effective than ACEI in systemic lowering of blood pressure but ACEI lowers proteinuria while Ca++ channel blocker increases ACE Inhibitor in Non Diabetic CKD If serum creatinine >1.5 mg/dl (24hr CrCl <60) and proteinuria >1 gm offer ACE inhibitor Beneficial even in absence of hypertension Effect independent of B/P Benefits of ACEI increase with amount of baseline proteinuria Missed Opportunities 1/3 of patients with CKD receive ACEI Non diabetics less likely to receive ACEI than diabetics Likelihood of being on ACEI not related to nephrology referral 47 y.o. hypertensive with a B/P of 150/90 Baseline serum creatinine is 1.6 mg/dl. You start patient on a moderate dose of an ACE inhibitor and 2 weeks later blood pressure is 130/80 and serum creatinine is 1.9 mg/d. What do you do next? Nissenson, J Am Soc Nephrol,

6 Case #1 1. Reduce dose of ACE inhibitor 2. Maintain dose of ACE inhibitor 3. Increase dose of ACE inhibitor 4. Stop ACE inhibitor Starting ACE Inhibitor Check electrolytes and creatinine at baseline and within 2-4 weeks of starting Short term decline in GFR is to be expected Less than 30% decline in GFR proceed cautiously More than 50% increase exclude hypoperfusion and renal artery stenosis Bakris, Arch Int Med, y.o. man with renal insufficiency and a history of proteinuria on the maximal dose of an ACE inhibitor. His serum creatinine has slowly risen over several years to 3.2 mg/dl. Case # 2 1. Reduce dose of ACE inhibitor 2. Maintain dose of ACE inhibitor 3. Increase dose of ACE inhibitor 4. Stop ACE inhibitor What change would you make in the ACEI? 6

7 ACE Inhibitor in Advanced CKD Randomized 224 pts with serum Cr3.1 to 5.0 mg/dl Non diabetics with proteinuria Benezapril 20 mg daily vs placebo 5% excluded during run in period for >30% increase in serum Cr or hyperkalemia >5.6 mmol/l 43% reduction in composite 2x serum Cr, ESRD, death Does ARB = ACEI? > 40 randomized head to head comparisons Similar level of B/P control Similar level of reduction of proteinuria Similar benefits on mortality, cardiovascular disease, progression of kidney disease, and quality of life Hou et al. NEJM, 2006 Matchar/Kunz, Annals of Internal Medicine, 2008 Does ARB = ACEI? Relatively little data on long term outcomes or safety with either drug Similar side effect profile except less cough and angioedema with ARB ARBs tend to be more costly 53 y.o. woman with renal insufficiency (serum Cr= 2.2 mg/dl), controlled hypertension and proteinuria (1 gm/ 24 hour) on maximum dose of an ACEI. What if any changes would you make in her treatment? 7

8 Case # 3 ARB and ACEI Together to Lower Protein Change the ACE inhibitor to an ARB Combine the ACE inhibitor with an ARB Blocking angiotensin II reduces proteinuria Some angiotensin II can form without ACE (ACEI flaw) ARB s only block one subtype of angiotensin II (ARB flaw) Don t change treatment Proteinuria in Monotherapy vs Combined ACE and ARB 16 trials Blood pressure lowering similar Combination lowers proteinuria more than either drug alone (about 25%) Do not achieve the proteinuria lowering effects from either agent alone by simply increasing dose Kunz, Annals of Internal Medicine, 2008 ONTARGET Ramipril (ACEI),vs Telmisartan (ARB) vs Combination >8000 high risk cardiovascular or diabetics per arm Single drug arms equivalent Combination had more adverse events including more advanced renal disease without clear benefits ONTARGET investigators, New Engl J Med,

9 Case # 3 ACEI/ARB Treatment Timing 1. Change the ACE inhibitor to an ARB 2. Combine the ACE inhibitor with an ARB 3. Don t change treatment Early intervention in non diabetic CKD more likely to preserve renal function and may arrest development of ESRD Among diabetics treatment more effective if started before proteinuria develops REIN Follow Up Study Treating Diabetics Earlier Non diabetic CKD with proteinuria ACEI group continued Placebo group switched to ACEI Late change to ACEI offered some benefit Early treatment with ACEI associated with greater benefit Some patients benefit to the point that ESRD is avoided GFR Placebo ACE I ACE I YEARS Treatment of microalbuminuria with ACEI slows/prevents development of proteinuria in type I and type II diabetics More cost-effective as a reno-protective strategy than treating all diabetics Treating all diabetics regardless of microalbuminuria with ACEI may prove to be cost-effective in terms of heart disease 9

10 Incipient Nephropathy in Diabetes Managing Microalbuminuria Microalbuminuria predictive of nephropathy/esrd in diabetics Albumin excretion of mg/24 hours = microalbuminuria Urine testing for with Micral, RIA, 24 hour or spot urine (AM best) Variation requires repeat testing to confirm diagnosis Accuracy enhanced by adjusting for urine creatinine urine protein > 200mg/g urine creatinine Persistent microalbuminuria in diabetic patients is an indicator to treat with ACEI or ARB Titrate ACEI or ARB to avoid blood pressure and electrolyte complications Measurement of microalbuminuria over time not accurate enough to titrate dose Glycemic Control and CKD CKD as Risk Factor Intensive control (HgA1c <7%) reduces microvascular CKD associated with increased mortality events However, intensive control not associated with improvements in macrovascular events and may be Cardiovascular disease is the major cause associated with increased risk of death Optimal glycemic control may be 7-8% 10

11 Age-Standardized Rate of Death from Any Cause (per 100 person-yr) Age-Standardized Rate of Cardiovascular Events (per 100 person-yr) < <15 Estimated GFR (ml/min/1.73 m 2 ) Estimated GFR (ml/min/1.73 m 2 ) Go, N Eng J Med. 351;13: Go et al. N Eng J Med. 351;13: y.o. woman with chronic kidney disease, hypertension, hyperlipidemia and anemia of chronic disease What are the renal and cardiovascular benefits of treating her hyperlipidemia? CKD and Cardiac Risk 40% have MI or revascularization prior to dialysis Treatment of hyperlipidemia with statins associated with slowing rate of GFR decline Statins associated with reduced risk of cardiovascular events/death in patients with mild to moderate renal failure Statins not effective in reducing cardiovascular events/death in diabetic patients on dialysis No large randomized trials demonstrating that treating dyslipidemia in CKD prevents cardiovascular disease 11

12 Case # 4 57 y.o. woman with chronic kidney disease, hypertension, hyperlipidemia and anemia of chronic disease Her Hgb is <9 gm/dl How would treating her anemia with erythropoietin affect her risk of cardiac 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 a common complication of CKD Anemia associated with cardiovascular deaths and LVH in observational studies NKF guidelines recommend use of erythropoietin when Hgb <9 gm/dl In 2004 Hgb treatment target increased from 12.0 gm/dl to 13.0 gm/dl to improve quality of life 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 13.5 gm/dl versus 11.3 gm/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 erythropoeitin 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 of hemoglobin g/dl Maintain adequate iron stores Drueke NEJM, 2006 Bottom Line on Preventing Progression of CKD and Mortality Risk Endstage Progression Initiation At risk Chronic Kidney Disease Aggressive blood pressure control (usually 2 or more drugs) to reach target of <130/80 Screening for CKD and proteinuria in hypertensives and diabetics is cost-effective Intervene with ACEI or ARB to reduce proteinuria In diabetics, treat with ACEI or ARB if microalbuminuria is persistently elevated Moderate glycemic control (HgbA1c 7-8%) Statins may be beneficial for those with CKD and dyslipidemia Use caution in treating anemia with erythropoietin 13