CKD in the United States Management of The Patient With Chronic Kidney Disease Paul J. Scheel, Jr., M.D., FASN Director,Division of Nephrology An estimated 26 million adults have CKD Many are unaware of their condition Prevalence is increasing 1988-1994: 14.5% 1999-2004: 16.8% Persons 60 years: 39.4% Risk factors Diabetes, CV disease, hypertension Mexican Americans, non-hispanic blacks http://www.kidney.org/kidneydisease/ckd/index.cfm#facts. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5608a2.htm CKD Patients Are More Likely to Die Than Progress to ESRD Management Goals Percentage of Patients 100% 90% 80% 70% 60% 50% 40% 5-Year Follow-up 74.8% 63.3% 64.2% 27.8% 6.6% 19.9% Event free Disenrolled RRT Died 1) Diagnose 2) Delay Progression 3) Treat Complications 4) Prepare For Renal Replacement Therapy 30% 20% 10% 0% 16.2% 10.3% 1.2% 1.0% 45.7% 14.9% 19.5% 24.3% 10.2% Stage 1 Stage 2 Stage 3 Stage 4 Adapted from: Keith DS et al. Arch Intern Med. 2004; 164:659-663. RRT = renal replacement therapy What is Chronic Kidney Disease (CKD)? CKD Stages Structural or functional abnormalities of the kidneys > 3 months, as manifested by either Kidney damage, with or without decreased glomerular filtration rate (GFR), defined by Pathologic abnormalities Markers of kidney damage in blood, urine, or imaging tests GFR < 60 ml/min/1.73m 2 Stage 1 2 3 Description Kidney damage with normal GFR Kidney damage with mildly decreased GFR Moderately decreased GFR GFR ml/min/1.73 m 2 Prevalence ( 1000) 90 5900 60-89 5300 30-59 7600 4 Severely decreased GFR 15-29 400 5 Kidney failure <15 or on dialysis 300 http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm Adapted from: Coresh J, et al. Am J Kidney Dis. 2003;41:1-12. 1
Serum Creatinine (mg/dl) Corresponding to GFR of 60 ml/min/1.73m 2 (Stage 3 CKD) Risk Factors for CKD Age (years) European-American African-American Men Women Men Women 40 1.39 1.08 1.65 1.27 50 1.34 1.03 1.58 1.22 60 1.30 1.00 1.53 1.18 70 1.26 0.97 1.49 1.15 80 1.23 0.94 1.46 1.12 Using simplified (4-variable) MDRD equation CLINICAL FACTORS Diabetes mellitus Hypertension Autoimmune diseases Ui Urinary tract tobstruction/ ti infection/stones Family history of CKD/ESRD History of AKI Reduced kidney mass Low birth weight Exposure to certain medications/toxins SOCIOEPIDEMIOLOGIC FACTORS Older age Ethnicity: African American American Indian Hispanic Asian Pacific Islander Low income Lower educational level Determining GFR Serum creatinine is a POOR measure of kidney function Significant kidney disease may be present with nearnormal serum creatinine -- especially in older women Creatinine i clearance CCr = (140-age) x wt (in Kg) (x 0.85 in women) 72 x Cr 24-hour creatinine clearance Mean of 24-hour creatinine and urea clearances Determining GFR, cont d MDRD equation (estimated GFR in ml/min/1.73m 2 ) GFR=186 X (Cr) -1.154 x (Age) -0.203 x (0.742 if female) x (1.210 if African American) Not validated in Hispanic, certain other populations CKD-EPI equation (estimated GFR in ml/min/1.73m 2 ) GFR = 141 X min(scr/κ,1) α X max(scr/κ,1) 1.209 X 0.993 Age X 1.018 [if female] X 1.159 [if black] κ is 0.7 for females and 0.9 for males α is 0.329 for females and 0.411 for males Min indicates the minimum of Scr/κ or 1 Max indicates the maximum of Scr/κ or 1 Levey AS et al. Ann Intern Med. 2009;150:604-612. Available online: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm Calculated egfr is an estimate.. even with the new and improved version CKD-EPI True GFR could be > 55 ml/min.1.73m 2 egfr 45 ml/min/1.73m 2 = true GFR of 25 80 ml/min/1.73m 2 or < 15 ml/min.1.73m 2 Botev R et. al. Clin J Am Soc Nephrol. 2009; 4: 899 906. Available online: http://cjasn.asnjournals.org/cgi/rapidpdf/cjn.05371008v1.pdf Levey AS et al. Ann Intern Med. 2009;150:604-612. 2
Screening for Microalbuminuria, Albuminuria or Proteinuria GFR, Proteinuria, and CKD Progression Standard urine dipsticks detect total protein > 30 mg/dl not sensitive enough for microalbuminuria screening Albumin-specific dipstick is useful for screening Untimed, random spot urine for ACR or protein/creatinine ratio (first morning void preferred) ACR: Normal<30mg/g; Mild 30-300mg/g; Heavy>300mg/g Hemmelgarn BR et al. JAMA. 2010;303(5):423-429. Available online at: http://jama.ama-assn.org/cgi/data/303/5/423/dc1/1 Albuminuria, GFR, and Death GFR and albuminuria: egfr < 60-75 ml/min/1.73m 2 Urine albumin > 10 mg/g creatinine Are INDEPENDENT predictors of all-cause and cardiovascular death Initial Assessment of Patient with Proteinuria and Elevated Creatinine History is the proteinuria and elevated creatinine new? Often old labs that can be helpful Rule out acute kidney injury (AKI) vs. CKD Recent events Diabetic vs. non-diabetic renal disease Is the proteinuria persistent Other urinalysis findings? Quantify proteinuria Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375(9731): 2073 2081. Delay Progression Progression of CKD Can be modified Hypertension Albuminuria/proteinuria Dyslipidemia Hemoglobin A 1C Cannot be modified Age Ethnicity Gender Genes Smoking Dietary protein intake Anemia 3
Renoprotection Goals AASK: Effect of CCB vs ACEI on Renal Outcomes Blood pressure < 125/75 mmhg if proteinuria > 1 g/d < 130/80 mmhg if proteinuria < 1 g/d STILL CONTROVERSIAL!! Proteinuria < 0.5-1 g/d Control lipid and blood glucose levels, stop smoking, lose weight Events per Person-yr 41% 44% 38% Peter son JC et al. Ann Intern Med. 1995;123:754-762. Adapted from: Agodoa LY et al. JAMA. 2001;285:2719-2728. Meta-analysis of the Effects of Dietary Protein Restriction on Rate of Decline in Renal Function Avoiding Acute Renal Injury 13 randomized controlled trials Mean follow-up 21.8 months Mean dietary protein intake (DPI) ~ 0.6-0.7 mg/kg/d g vs. ~1-1.2 mg/kg/d g Protein restriction decreased rate of GFR decline by 0.53 ml/min/yr Volume depletion Iodinated radiographic contrast media Sodium phosphate bowel prep Nephrotoxic antibiotics NSAIDs Kasiske BL et al. Am J Kidney Dis. 1998;31(6):954-961. Lower BP Slows Decline in GFR Multiple Agents are Required to Achieve BP Goals /year) GFR (ml/min/ MAP (mmhg) 95 98 101 104 107 110 113 116 119 0-2 -4-6 -8-10 -12-14 130/85 140/90 Untreated HTN 3.8 3.3 3.6 28 2.8 2.7 3.0 3.1 3.0 Number of Agents Needed Bakris GL et al. Am J Kidney Dis. 2000; 36(3):646-661. Bakris GL, et al. Am J Kidney Dis. 2000; 36(3):646-661. 4
Our RAAS Blockade Tools ACE inhibitors ARBs Aldosterone receptor antagonists Direct renin inhibitors RAAS Blockade in Type II Diabetes Most placebo-controlled studies in type 2 DM have been in patients with either microalbuminuria or established nephropathy treated with ARB ARB and ACEi appear to be equivalent for microalbuminuria and proteinuria reduction No mortality benefit demonstrated RAAS=renin-angiotensin-aldosterone system Parving HH et al. NEJM.2001;345:870-878. Is More RAAS Blockade Better? Supra-high doses ACEi + ARB ACEior ARB + aldosterone receptor antagonist ACEi + ARB + aldosterone receptor antagonist The COOPERATE Trial Double-blind RCT of 336 pts with non-diabetic renal disease treated with ACEi or ARB or both ACEi + ARB resulted in greater reduction in proteinuria and fewer patients with doubling of serum creatinine or ESRD Similar BP control The only study to show improved CKD progression and ESRD outcomes with dual RAAS blockade Retracted by Lancet, October, 2009 Nakao, et al. (Lancet. 2003 Jan 11;361(9352):117-124) Lancet. 2009 Oct 10;374(9697):1226. Combined ACEi + ARB Treatment Summary No long-term studies showing improved renal outcomes (CKD progression, ESRD) Likewise for aldosterone receptor blockade No demonstrated mortality benefit in patients with CKD Risk > benefit, especially in patients at low risk for progression to ESRD In all patients on RAAS blockade, low Na + diet potentiates proteinuria reduction and BP management Use ACEi or ARB as first-line therapy for diabetics and nondiabetics with microalbuminuria or proteinuria Titrate doses to maximally reduce proteinuria Diuretics, low salt diet Consider dual therapy only in patients with high risk of CKD progression and significant proteinuria despite reasonably high doses of single ACEi or ARB ACEi+ ARB ACEi or ARB + spironolactone or eplerenone Add 2 nd agent in lowest doses Carefully monitor BP, egfr, K + 5
Treat Complications Metabolic Acidosis Metabolic Acidosis Secondary Hyperparathyroidism Anemia? Often becomes apparent at GFR < 25-30 ml/min Higher protein diet more acidosis May contribute to bone disease, protein catabolism Maintain serum bicarbonate > 22 mmol/l Start with 0.5-1 meq/kg per day Sodium bicarbonate tablets 325 mg (3.9 meq) or 650 mg (7.8 meq) tablets Sodium citrate solution 1 meq/ml Avoid if patient on aluminum phosphate binders Baking soda 54 meq/level tsp Vitamin D Consequences of PTH Elevation in Patients With CKD Decreased Vitamin D Receptors and Ca-Sensing Receptors PTH PTH PTH Bone Disease Bone Loss Pi Ca ++ 1,25 D Calcitriol Systemic Toxicity Cardiovascular Disease Phosphorous Calcium. Renal Failure 1(25)OH 2 D Decline and PTH Elevation as CKD Progresses Prevalence of Abnormalities of Mineral Metabolism, PTH in CKD 1(25)OH 2 D (ng/ml) 50 40 30 25 20 10 CKD Stage 1 lower limit Stage 2 Stage 3 Stage 4 P<0.01 P<0.01 0 105 95 85 75 65 55 45 35 25 egfr (ml/min/1.73 m 2 ) N = 150. egfr = estimated glomerular filtration rate; ipth = intact parathyroid hormone. Martinez et al. Nephrol Dial Transplant. 1996;11(suppl 3):22-28. upper limit 15 400 300 200 100 65 ipth (p pg/ml) % of Patients 100 90 80 70 60 50 40 30 20 10 0 ipth >65 pg/ml Phosphorus >4.6 mg/dl Calcium <8.4 mg/dl CKD Stage 3 CKD Stages 4 and 5 >80 79 70 69 60 59 50 49 40 39 30 29 20 <20 (n = 61) (n = 117) (n = 230) (n = 396) (n = 355) (n = 358) (n = 204) (n = 93) Adapted from: Levin A et al. Kidney Int. 2007;71:31-38. egfr (ml/min/1.73 m 2 ) ipth = intact parathyroid hormone 6
CKD-MBD and Mortality CKD-Mineral Bone Density Testing All-cause and CV mortality increase 30-60% with each 1 mg/dl higher phosphorus level above normal Mortality impact of calcium and PTH levels in CKD patients not on dialysis is unknown No studies showing benefit of treatment Low phosphorous and calcium levels also associated with higher mortality Likely related to nutritional status CKD Stage Stage 3 Stage 4 Stage 5 Calcium, Phosphorus Every 6-12 months Every 3-6 months Every 1-3 months PTH Once then based on CKD progression Every 6-12 months Every 3-6 months 25(OH)D Once, then based on level and treatments Use CKD progression, presence or absence of abnormalities, treatment response and side effects to guide testing frequency Covic A et al. NDT. 2009;24:1506-1523. KDIGO Guideline. Kidney Int. 2009;76 (113):S1-S130. CKD-MBD Treatment Goals CKD-MBD Treatment Goals Use trends to guide therapy, rather than single level Bone density testing does not predict fracture risk so should not be used routinely for assessing CKD-MBD or guiding therapy Maintain calcium and phosphorus levels in reference ranges Treat 25(OH)D deficiency as in general population Cholecalciferol 1000-2000 IU/d Ergocalciferol 10,000 IU weekly-50,000 IU monthly PTH goal unclear Treat with calcitriol or vitamin D analogue if progressively increasing despite correction of abnormal calcium, phosphorous, vitamin D levels In stage 5, maintain ipth 2-9 times upper reference level Calcimimetics not recommended in stage 3-5 CKD KDIGO Guideline. Kidney Int. 2009;76 (113):S1-S130. Uhlig K et al. Am J Kidney Dis. 2010;55(5):773-799. Phosphorus in Stage 3-5 CKD Dietary restriction to < 600-1000 mg/d Dietary protein intake ~ 1.2 g/kg/d Maintain caloric intake of 30-35 kcal/kg/d Review diet: Food additives/preservatives Meat phosphorus absorption > seeds, nuts, legumes Highest P/protein ratio in many cheeses, milk, nondairy creamer Many soda, iced-tea have high phosphorus content Phosphorus Management in Stage 3-5 CKD Phosphate binders Aluminum hydroxide Least expensive Calcium carbonate Calcium acetate Sevelamer carbonate Lanthanum Most expensive Tolerability, interactions, and patient adherence also key considerations in binder selection 7
Calcium and Vitamin D in Stage 3-4 CKD Anemia Occurs Early in CKD and Worsens as Kidney Function Declines More opinion than evidence Maintain corrected total calcium within the normal range for the laboratory used, preferably toward the lower end (8.4 to 9.5 mg/dl; 2.1-2.37 mmol/l) Supplement vitamin D2 if serum 25-(OH) vitamin D level <30 ng/ml (75 nmol/l) Ergocalciferol 50,000 U weekly-monthly depending on severity Treat with active oral vitamin D if serum 25(OH) vitamin D >30 ng/ml (75 nmol/l) and ipth is above target range Calcitriol: 0.25 mcg 3x/wk-daily ts (%) Patient Hgb 12 g/dl GFR (ml/min/1.73 m 2 ) Adapted from: McClellan et al. Curr Med Res Opin. 2004;20:1501-1510. Pathophysiology of Anemia in CKD Impact of Anemia in CKD Erythropoietin deficiency Iron deficiency Anemia of chronic investigation Vitamin deficiency (folate, B12) Renal osteodystrophy Infection/inflammation Other illness: malignancy, multiple myeloma, HIV, etc Decreased quality of life Increased: Morbidity and mortality risk Cardiovascular disorders LVH, angina, CHF, MI, stroke Physical and psychosocial impairments depression, cognitive impairment Hospitalization and length of hospital stay Rate of progression of CKD McClellan W et al. Curr Med Res Opin. 2004;20:1501-1510. Morreale A et al. Curr Med Res Opin. 2004;20(3):381-395. Kinchen KS et al. Ann Intern Med. 2002;137:479-486. Anemia is Associated with Higher Mortality Rate at each CKD Stage Anemia and Quality of Life ate n years) Mortality Ra (per 100 person Anemia Status GFR ml/min/1.73m2 Adapted from: Culleton, B. F. et al. Blood 2006; 107(10):3841-3846. Lefebvre et al. Curr Med Res Opinion. 2006; 22(10):1929-1937. 8
ESA Options Epoetin alfa Typically every 1-2 weeks, sometimes every 3-4 weeks Darbepoetin alfa Typically every 2-4 weeks Both given subcutaneously in CKD CHOIR Epoetin alfa in CKD Open label, RCT, N= 1432; mean study duration 16 months egfr 15-50 ml/min/1.73m 2 Hgb < 11.0 g/dl High Hgb target: 13.0-13.5 initially; changed 13.5 g/dl Low Hgb target: 10.5-11.0 initially; changed 11.3 g/dl Singh AK et al. N Engl J Med. 2006;355(20):2085-2098. CHOIR Results 34% increased risk of composite outcome of death, MI, hospitalization for CHF, stroke (p = 0.03) No significant difference in % of patients requiring RRT Similar QOL measures TREAT Darbepoetin Alfa in CKD and Diabetes Double-blind placebo-controlled trial, N=4038 egfr 20-60 ml/min/1.73m 2 Hgb < 11.0 g/dl Darbepoetin: adjusted to maintain Hgb ~13.0 g/dl Placebo: Darbepoetin only if/when Hgb < 9.0 g/dl Primary end points: time to composite of death or a CV event and time to composite of death or ESRD Singh AZ et al. N Engl J Med. 2006;355(20):2085-2098. Pfeffer MA et al. N Engl J Med. 2009 ;361(21):2019-2032. TREAT Results No significant difference in cardiovascular composite endpoint Greater risk of stroke (~ 2X) in darbepoetin group No significant difference ESRD composite endpoint Similar QOL measures; some measures slightly better in darbepoetin group More hypertension and deaths due to cancer in patients with history of cancer in darbepoetin group FDA ALERT 2009 The dosing recommendations for anemic patients with chronic renal failure have been revised to recommend maintaining hemoglobin levels within 10-12 g/dl. Quality of life claims in the previous labeling were removed, with the exception of improved exercise tolerance and functional ability for chronic renal failure patients The revised product labeling includes a strengthened Boxed Warning Pfeffer MA et al. N Engl J Med. 2009;361(21):2019-2032. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm110280.htm 9
Cochrane Review 2010 Prepare For Renal Replacement Therapy Targeting higher hemoglobin levels in CKD increases risks for stroke, hypertension, and vascular access thrombosis and probably increases risks for death, serious cardiovascular events, and end stage renal disease. Modality Access Palmer SC et al. Ann Intern Med. 2010;153(1):23-33. When to Refer for Transplant Dialysis Options Pre-emptive transplant is best for many patients avoids dialysis altogether Living donor kidney outcomes are superior to deceased donor kidney outcomes Among living donors except identical twin not much difference among related and nonrelated donors Refer for transplant evaluation as egfr approaches ~ 20 ml/min Home HD Short daily Nocturnal PD Center HD Three times per week Nocturnal Self care Mange KC et al. Am J Transplant. 2003;3:1336-1340. Rao S et al. CJASN 2009;4:1827-1823. Dialysis: Early vs. Late Start RCT of > 800 patients with egfr 10-15 ml/min Start HD (early start) or wait until egfr 5-7 ml/min (late start) 76% of late start group started with higher egfr due to symptoms or other indication Mean age 60 yrs No difference in survival, other outcomes, QOL Conclusion: OK to delay dialysis until GFR < 7.0 ml/min or other specific clinical indicators for the initiation of dialysis are present Cooper BA, et al. NEJM. 2010; Published Online June 27. Managing the Patient with CKD Summary 1. Assess GFR 2. Determine etiology; consider renal biopsy, etc. 3. Identify reversible factors Workup: complete H&P; cbc, electrolytes, bicarbonate, calcium, phosphate, albumin, urinalysis, SPEP/UPEP, assess proteinuria, renal ultrasound Approaching ESRD 1. Patient/family education 2. Chose RRT modality 3. Referral for transplant evaluation 4. Dialysis access Progressive CKD 1. Reduce progression 2. Manage comorbid conditions 3. Manage complications: BP - use ACEI/ARB, screen and treat hyperlipidemia, CA/phos/PTH, anemia; smoking cessation; preserve vessels; patient education 10
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