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

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Current Management Strategies in Chronic Kidney Disease Grace A.

70 kg man with long- standing hypertension is found to have a serum creaknine of 1.

1 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 a serum creaknine of 1.5mg/dl and a blood pressure of 150/90. Does he have chronic kidney disease? What addikonal assessment should you undertake? What are treatment goals and opkons for therapy? PiRalls of Serum Cr If both of these politicians had a SCr of 1.5 mg/dl, what is their respective estimated GFR? 1

2 Serum creaknine cont 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 EsKmaKng Renal FuncKon Need serum creaknine, age, sex, and weight (140- age in yrs) X (weight in kg) X 0.85(female) 72 X serum Cr in mg/dl Or serum creaknine, 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) EsKmaKng Renal FuncKon 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 2

3 DefiniKon of Chronic Kidney Disease Structural or funckonal abnormalikes of the kidneys for 3 months as manifested by either: Kidney damage Pathologic abnormalikes, or Markers of kidney damage, including abnormalikes in the composikon of the blood or urine or abnormalikes in imaging test, or GFR <60 ml/min/1.73 m2, with or without kidney damage Stages of Chronic Kidney Disease Stage Description GFR (ml/min per 1.73 m 2 ) 1 Kidney damage with normal or increased GFR 2 Kidney damage with mild decrease in GFR to 89 3 Moderate decrease in GFR 30 to 59 4 Severe decrease in GFR 15 to 29 5 Kidney failure <15 or dialysis Chronic Kidney Disease: An underrecognized epidemic Endstage Progression > 300,000 patients GFR ,000 patients GFR million patients Initiation, injury 10 million patients 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,

4 Other 10% Glomerulonephritis 13% Hypertension 27% Diabetes 50% United States Renal Data System (USRDS) 2000 Annual Data Report Slide Source Hypertension Online Risk Factors for CKD Diabetes mellitus Hypertension Autoimmune disease Systemic infeckons Urinary tract infeckons Nephrolithiasis Lower urinary tract obstruckon Neoplasia Family history CKD Recovery from ARF ReducKon in kidney mass Nephrotoxic drugs Older age Racial/ethnic minority status Low socioeconomic status Screening for Chronic Kidney Disease Not recommended for general populakon Consider screening if any of 3 risk factors Diabetes Hypertension Age > 55 years IdenKfies 93% of cases Number needed to screen = 9 per 1 case 4

5 EvaluaKon of CKD History (PMH, family/social hx) MedicaKon exposure (NSAIDs, aminoglycosides) Time course of decline in renal funckon Urinalysis (proteinuria, casts, cells, etc) Checking for complicakons of CKD (CBC, K +, HCO 3, albumin, Ca +2, PO 4, PTH, uric acid, albumin) Serologies or specialized teskng if indicated (ANA, ANCA, Hep B/C, RF, HIV, SPEP/UPEP, ank- GBM, complement levels) Imaging renal ultrasound (RAS, cysts, obstruckon) Renal biopsy when uncertain diagnosis and considering immunosuppressive therapy EvaluaKon of urinary protein excrekon Normally very small amount of protein excreted in urine Increased excrekon of albumin sensikve marker for CKD due to diabetes, HTN, glomerular disease Spot urine samples (first morning specimen preferred) to evaluate Can calculate spot urine protein/creaknine rako to assess approximate protein excrekon rate (g/24 hrs) < 0.3 (< 300 mg) = normal (300 mg 3000 mg) = non- nephrokc range proteinuria > 3 (> 3 g) = nephrokc range protenuira Risk Factors for Progression of Renal Disease Can be modified Hypertension Albuminuria/Proteinuria Dyslipidemia Cannot be modified Age Ethnicity Gender Hemoglobin A 1C Smoking Anemia Ca P0 4 5

6 Early intervenkon in CKD increases Kme to progression to ESRD 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 comorbidikes Glucose control Assess and treat for complicakons 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 InfecKon Nephrotoxic drugs* NSAIDs Aminoglycoside ankbiokcs Radiographic contrast Urinary tract obstruckon *Some drugs cause spurious elevakon of creaknine but do not decrease GFR: cimekdine, trimethoprim, cefoxikn, flucytosine 6

7 Blood Pressure and CKD Most pakents with CKD will develop hypertension, regardless of inikal cause 10 mmhg reduckon of mean arterial pressure is associated with preservakon of 3.7 ml/min of glomerular filtrakon Treatment goal of < 130/80, lower (< 125/75) in pakents with > 1 gram/day of proteinuria AnK- Hypertensive Treatment in CKD Recommended therapy: 1 st agent: ACE- I or ARB, parkcularly in diabekc pakents or pakents with significant proteinuria 2 nd agent: DiureKc 3 rd agent: Calcium channel blocker or beta- blocker In pakents with proteinuria, ACE- I appear to offer reno- proteckve benefits over other ank- hypertensive therapies Average Number of AnK- 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 7

8 Proteinuria in CKD Proteinuria is independent risk factor for renal failure Protein excrekon > mg per day increases risk of progression of CKD ReducKon in proteinuria is correlated with decreased progression of CKD For each 1 gram/day reduckon in proteinuria, rate of GFR decline decreased by mg/min per year (MDRD study) Peterson, Ann Intern Med, 2005 RelaKve Risk of ESRD on ACE- I By Baseline Proteinuria Relative Risk = no ACEI benefit Baseline Urinary Protein ExcreKon (grams/day) Jafar, Ann Int Med, 2001 ACE Inhibitor in Non DiabeKc CKD If serum creaknine >1.5 mg/dl (24hr CrCl <60) and proteinuria > 500 mg - 1 gm, ACE- I is first line Most effeckve agent for decreasing protein excrekon Beneficial even in absence of hypertension Effect independent of BP Benefits of ACE- I increase with amount of baseline proteinuria However, only 1/3 of pakents with CKD receive ACE- I therapy! 8

9 Case #2 65 y.o. man with stage 3 CKD currently on moderate dose of ACE- I with BP of 130/80 PosiKve urine dipskck; follow- up urine protein/ creaknine rako 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 creaknine increased from 1.4 to 1.7 mg/dl 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 StarKng/Increasing ACE Inhibitor Check electrolytes and creaknine at baseline and within 1 week Expected short- term decrease in GFR ( 30%) If rise in creaknine > 30%, reduce dose by 50% and recheck labs in 1 week If rise in creaknine > 50%, exclude hypoperfusion and RAS 9

10 Does ARB = ACE- I? > 40 randomized head to head comparisons Similar level of BP control and reduckon of proteinuria Similar benefits on mortality, CV disease, progression of CKD, and quality of life RelaKvely livle data on long term outcomes or safety with either drug Less cough and angioedema with ARB ARBs more costly Case #2 1. Reduce dose of ACE inhibitor 2. Maintain dose of ACE inhibitor 3. Increase dose of ACE inhibitor 4. Stop ACE inhibitor Case #3 53 y.o. woman with CKD (serum creaknine = 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? 10

11 Case # 3 1. Change the ACE- I to an ARB 2. Combine the ACE- I with an ARB 3. Don t change treatment 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,

12 ONTARGET RCT of ramipril (ACE- I) vs telmisartan (ARB) vs combinakon therapy > 8000 pakents with high cardiovascular risk or diabetes per arm Single drug arms equivalent outcomes CombinaKon had more adverse effects including more advanced renal disease without clear benefits ONTARGET investigators, New Engl J Med, 2008 Case # 3 1. Change the ACE inhibitor to an ARB 2. Combine the ACE inhibitor with an ARB 3. Don t change treatment ACEI/ARB Treatment Timing Early intervenkon in non diabekc CKD more likely to preserve renal funckon and may arrest development of ESRD Treatment of microalbuminuria slows/prevents development of proteinuria in diabekcs, more effeckve if started before proteinuria develops 12

13 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 diurekcs Weinberg, Arch Intern Med, 2009 CKD PaKents are at High Risk of CV Mortality Foley RN, Am J Kidney Dis, 1998;32(S ) Slide Source Hypertension Online Case #4 57 y.o. woman with CKD, HTN, hyperlipidemia, and anemia of chronic disease What are the renal and cardiovascular benefits of treakng her hyperlipidemia? 13

14 CKD and Cardiac Risk 40% of pakents have MI or revascularizakon prior to dialysis Treatment of hyperlipidemia with stakns associated with: Slowing rate of GFR decline Decreased risk of CV events/death in pakents with mild- moderate CKD StaKns not effeckve in reducing CV events/death in pakents on dialysis No large RCTs demonstrakng that treakng dyslipidemia in CKD pakents prevents CV disease Case #4 57 y.o. woman with CKD, HTN, hyperlipidemia, and anemia of chronic disease Her Hgb = 8 gm/dl How would treakng her anemia affect her risk for cardiovascular disease? Case # 4 1. Lower risk of cardiovascular events and death 2. Reduce risk of lex ventricular hypertrophy 3. Both of the above 4. Neither of the above 14

15 CKD related anemia and cardiovascular complicakons Anemia is common About 50% of pakents when GFR < 35 Almost 90% of pakents when GFR < 25 Associated with CV deaths and LVH in observakonal studies NKF guidelines recommend use of erythopoiekn when Hgb < 9 gm/dl What is the opkmal target? CorrecKon of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) >1400 adult pakents with GFR ml/min and anemia (Hgb<11.0 mg/dl) randomized to Epo SQ with different treatment targets Compared death, MI, CHF hospitalizakon 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, 2006 Cardiovascular Risk ReducKon by Early Anemia Treatment with EpoeKn (CREATE) > 600 adult pakents with GFR ml/min and anemia (Hgb mg/dl) randomized to EPO with different treatment targets Compared outcomes for Hgb gm/dl versus gm/dl More cardiovascular events and deaths in higher hemoglobin group but not stakskcally significant No reduckon in LVH in higher Hgb group Drueke NEJM,

16 CorrecKng Anemia in CKD Complete correckon not obviously beneficial and may be harmful Several addikonal 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 Secondary hyperparathyroidism Phosphorus: restrict dietary PO4, add binders Add phosphate binders to improve control Ca- P product target < 55 mg 2 /dl 2 CauKon with phosphate- containing bowel preparakons: risk of acute phosphate nephropathy Calcium: limit supplementakon 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) ( ) 5 (< 15 or dialysis) ( ) TreaKng Ca, Phos, PTH: What does the evidence say? Meta- analysis of 47 cohort studies ObjecKve to assess associakon of levels of calcium, phosphorus, and PTH and risks of death and CV mortality in CKD pakents No significant associakon found between levels of calcium and PTH and outcomes For every 1 mg/dl increase in serum phosphorus, RR of 1.18 (all- cause mortality) and RR 1.10 (CV mortality) Evidence overall was poor (no RCTs) Palmer et al, JAMA 2011;305:

17 Other ComplicaKons 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 preparakons (Mg citrate, calcium citrate, potassium citrate) increase aluminum absorpkon Bovom Line on PrevenKng Progression of CKD and Mortality Risk Aggressive BP control to reach target < 130/80 Screening for CKD and proteinuria in pakents with HTN and DM is cost- effeckve Intervene with ACE- I or ARB to reduce proteinuria and microalbuminuria (in diabekcs) Aggressive treatment of cardiovascular risk factors, especially lipids Treat anemia to moderate level Monitor and treat secondary hyperparathyroidism 17

Missed OpportuniKes Only 1/3 of pakents with CKD receive ACE- I Non diabekcs less likely to receive ACE- I than diabekcs Likelihood of being on ACE- I not related to nephrology referral Nissenson, J

18 Missed OpportuniKes Only 1/3 of pakents with CKD receive ACE- I Non diabekcs less likely to receive ACE- I than diabekcs Likelihood of being on ACE- I not related to nephrology referral Nissenson, J Am Soc Nephrol, 2001 Age- Standardized Rate of Cardiovascular Events (per 100 person- yr) Go et al. N Eng J Med. 351;13: CKD as Risk Factor CKD is associated with increased mortality Cardiovascular disease is the main cause 18

19 REIN Follow Up Study Non- diabekc 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 pakents, ESRD avoided GFR Placebo ACE I ACE I Years 19

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

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