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Chronic Kidney Disease (CKD): An Update for the Primary Physician. Joshua Augustine, M.D. Wade Park Veterans Administration Hospital 1/28/14. Quiz Questions. 1.Name the two formulas that are best at estimating glomerular filtration rate (GFR) in patients with CKD.
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Chronic Kidney Disease (CKD):An Update for the Primary Physician Joshua Augustine, M.D. Wade Park Veterans Administration Hospital 1/28/14
Quiz Questions 1.Name the two formulas that are best at estimating glomerular filtration rate (GFR) in patients with CKD. 2.At what stage of CKD should all patients be referred to a nephrologist? 3.Name three situations that may warrant a nephrology referral at lower stages of CKD
Chronic Kidney Disease: Definition • Kidney damage for ≥ 3 months, as defined by structural or functional abnormalities • Pathological abnormalities • Markers of kidney damage by blood, urine, or imaging tests • GFR < 60 ml/min/1.73 m2 for > 3 months, with or without kidney damage
Risk Factors for CKD • Diabetes • Hypertension • Autoimmune diseases • Systemic infections • Exposure to drugs associated with acute decline in kidney function • NSAIDs • Contrast agents • Recovery from acute kidney failure • Age > 60 years • Family history of kidney disease • Reduced kidney mass • Smoking National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S17-S31. Pinto-Sietsma SJ, et al. Ann Intern Med. 2000;133:585-591.
Etiology of Chronic Kidney Disease • Diabetic glomerulosclerosis • Type I or II 33% • Glomerular disease (primary or secondary) 19% • Vascular disease and hypertension • Including sickle cell and HUS 21% • Tubulointersitial disease • Pyelonephritis, analgesic, allergic 4% • Cystic disease • Polycystic, medullary cystic 6%
Stage 1: Normal GFR; GFR >90 mL/min/1.73 m2 with other evidence of chronic kidney damage* Stage 2: Mild impairment; GFR 60-89 mL/min/1.73 m2 with other evidence of chronic kidney damage* Stage 3: Moderate impairment; GFR 30-59 mL/min/1.73 m2 Stage 4: Severe impairment: GFR 15-29 mL/min/1.73 m2 Stage 5: Established renal failure: GFR < 15 mL/min/1.73 m2 or on dialysis * “Other evidence” may be one of the following: • Persistent microalbuminuria/proteinuria • Persistent hematuria from a renal origin • Structural abnormalities of the kidneys demonstrated on ultrasound or other radiological tests • Biopsy-proven inflammation or fibrosis Chronic Kidney Disease Stages
Prevalence of CKD in NHANES* 1999-2004 participants *National Health and Nutrition Examination Survey, n=12,785 age ≥ 20 y/o By MDRD formula, USRDS 2010
Kidney Disease in African Americans • African Americans make up about 12% of the population but account for 32% of people with kidney failure • Among new patients whose kidney failure was caused by high blood pressure, more than half (51%) are African American • Among new patients whose kidney failure was caused by diabetes, almost 1/3 (31%) are African American • African-American men ages 20-29 and 30-39 are 10 x and 14 x more likely to develop kidney failure due to high blood pressure than Caucasian men in the same age group
Death ESRD Current CKD Outcomes: Death vs. ESRD n = 40,250 D = diabetes ND = no diabetes Adaptedfrom US Renal Data System. USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health. 2002. Available at: www.usrds.org/atlas.htm.
But ESRD is More Common than Death in Blacks with Hypertensive Kidney Disease AASK Trial, 1/3 of patients were < 50 y/o at enrollment J Am Soc Nephrol 21: 1361-9, 2010
Kidney Disease Improving Global Outcomes (KDIGO) (Kidney Int 2013) • New CKD guidelines from 2013 • New staging concept: GFR and albuminuria categories • GFR categories add “G3a” for GFR 45-59, “G3b” for GFR 30-44 • Albuminuria categories:
Estimating renal function • Abbreviated MDRD equation = • CKD-EPI equation = 186 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if Black)
Estimated GFR • Google: “MDRD Calculator” • http://www.nephron.com/MDRD_GFR.cgi • Save to your favorites! • More recent CKD EPI equation is less likely to underestimate GFR in patients with higher GFR
Cystatin C • A low molecular weight cysteine protease inhibitor- produced by all nucleated cells • Filtered at the glomerulus and not reabsorbed • However, metabolized in the tubules • Inflammation, thyroid disease, and steroids may affect levels • Less dependent on race and body mass • Potetential uses: • Confirming stage 3a CKD (eGFR 45-59 ml/min) • KDIGO: if cystatin C formula > 60, patient should not be labeled as having CKD • Assessing for CKD in malnourished patients
Testing for CKD and Monitoring Progression • Regular testing of patients at risk with: • Diabetes • Hypertension • Family history of kidney failure • Cardiovascular disease • Rapid progression is considered a decline of more than 5 ml/min/1.73m2/yr
Graphing glomerular filtration rate 59 y/o with autosomal dominant polycystic kidney disease 51 y/o with severe acute and chronic interstitial nephritis
Screen for Proteinuria • As part of the initial assessment of patients with: • Diabetes mellitus • Newly discovered GFR < 60 ml/min/1.73 m2 • Newly discovered hematuria • Newly diagnosed hypertension • Unexplained edema • Suspected heart failure • Suspected multisystem disease, e.g. lupus
Screening for Proteinuria: Spot Sample is Recommended • KDIGO recommends albumin:creatinine ratio • Better laboratory precision than protein:creatinine • May also check spot total urine protein to creatinine ratio or 24 hr urine • Test a.m. samples • Avoid testing in febrile patient or after vigorous exercise • Confirm with repeat testing
Treatment of Hypertension: KDIGO • Recommended that all CKD patients with no proteinuria have a target BP ≤ 140/90 • Goal blood pressure for all CKD patients with any degree of proteinuria: ≤ 130/80 (JNC8-140/90) • ARB or ACEI first line for any diabetic with abnormal proteinuria, and for any CKD patient with albumin excretion • ACEI/ARB combination not recommended
Intensive blood pressure control in non-diabetic blacks with CKD: benefit in subgroup with proteinuria N Engl J Med 363: 918-29, 2010
Referral to Nephrology • All patients with GFR <30 mL/min/1.73m2 (Stage 4) should be referred to a nephrologist • Additionally refer stage 3 CKD with: • Younger Age • Poorly controlled blood pressure • Declining kidney function • Hyperkalemia on acei/arb therapy • Proteinuria DeCoster C et al. J Nephrol 23: 399-407, 2010
Late Referral to Nephrology • Often defined as referral at < six months prior to initiation of dialysis therapy • Historically the case for 30-50% of patients • Typically leads to inpatient dialysis (often urgently) with a vascular catheter • Associated with increased one year morbidity and mortality • High rate of infection, line sepsis Nephrol Dial Transplant 20: 490-6, 2006
Late Referral to Nephrology • Causes: • Fulminant renal failure • Lack of access to any medical care • Emergency room presentation • Patient failure to follow through with referral • Older patient with plans for conservative management of uremia • However, most older patients choose dialysis Nephrol Dial Transplant 20: 490-6, 2006
Case #1 • 77 y/o white female with longstanding diabetes and 2+ proteinuria, Cr 2.4 • eGFR = 20 ml/min/1.73m2 • Patient states she is “not interested” in dialysis • Who is? • Cr appears stable, so decision made not to refer • Three months later, patient hospitalized with CHFrequiring diuresis • Cr on f/u testing is 3.3 • eGFR=14 ml/min/1.73m2 • Patient agrees to dialysis if necessary
Survival in the Elderly: Dialysis vs. Conservative Management • UK study of 202 patients > 70 y/o with stage 5 CKD • 173 chose dialysis, 29 chose conservative management • Median survival 37.8 mos (range 0 to 106) for dialysis vs. 13.9 mos (range 2 to 44) for conservative management • But dialysis patients spent more time in the hospital relative to days of survival and were more likely to die in the hospital Clin J Am Soc Nephrol 4:1611-9, 2009
Survival in the Elderly: Dialysis vs. Conservative Management Clin J Am Soc Nephrol 4:1611-9, 2009
Hypertension • Can consider nephrology referral if blood pressure > 150/90 despite usage of three antihypertensive drugs from different classes • ACE inhibitors or ARBs are first line in any patient with proteinuria/albuminuria • Diuretics key to blood pressure control • Thiazide if eGFR >30 • Loop diuretics for lower GFR • May need 4-5 agents, varied timing, bedtime dosing
Ambulatory Blood Pressure Monitoring in CKD • VA study of 217 CKD patients stage III to V (pre-ESRD) with abnormal urinary protein • Clinic BP vs. 24 hr. ambulatory monitoring • Correlated measurements with ESRD and death • Occurred in 34.5% over a median of 3.5 yrs • Systolic blood pressure correlated with primary outcome • But normal home BP more predictive of renal outcomes in patients with high clinic BP Kidney Int. 69: 1175-80, 2006
Predictive value of ambulatory BP in patients with high clinic BP n=95 n=51 Kidney Int. 69: 1175-80, 2006
Correlation of non-dipping with ESRD Kidney Int. 69: 1175-80, 2006
Diabetic Nephropathy • “Microalbuminuria” defines the onset • Urinary albumin excretion of 30-300 mg/day • Spot urinary albumin:creatinine ratio > 30 mg/g Cr • Persistent elevation of urinary protein in the absence of other kidney disease • Consider referral when proteinuria is increasing, even with normal creatinine
Natural history of diabetic nephropathy d Hyperfiltration Microalbuminuria
Type II DM: IDNT (Irbesartan in Diabetic Nephropathy) Trial(NEJM 2001; 345:851-60)
Addition of the Aldosterone Inhibitor Spironolactone to ACE Inhibitor in Diabetic Nephropathy *Potassium level ≥ 6 meq/L occurred in 14/27 (52%) on spironolactone J Am Soc Nephrol 20: 2641-50, 2009
Preventing hyperkalemia with angiotensin blockade • Introduce agents at low dose • Check labs 1 week after initiation/dose change • If adding spironolactone or eplerenone, do not exceed 25 mg/day • Avoid if GFR is < 30 ml/min or potassium >5.0 mmol/L • Diuretics can increase distal sodium delivery and potassium excretion • Loop diuretics if GFR < 30 ml/min • Avoid volume depletion with diuretics, which may worsen hyperkalemia NEJM 2004; 351:585-592
Possible scenarios of change in creatinine after angiotensin blockade Volume depletion, CHF, NSAIDs or RAS Stable CKD Normal kidney function Arch Intern Med 2000 160:685-693
Anemia Treatment in CKD-KDIGO • Intravenous iron usage is encouraged • With TSAT up to 30% and ferritin up to 500 ng/ml • Avoid with acute infection • Based on animal data demonstrating impaired response to infection • Do not initiate ESA therapy unless Hb < 10 g/dl • Goal: to avoid Hb < 9 g/dl and Hb > 11.5 g/dl • Avoid escalation in resistant patients to greater than double the weight-based recommended dosage • Use with great caution in patients with active malignancy or history of CVA
Caveats on Treating Anemia in CKD • TREAT trial • Randomized 4038 patients with DM and CKD • Mean age 68 yrs, median eGFR 33 ml/min/1.72m2 • Median follow-up 29 months • Darbepoetin treatment: • Target Hb of 13 g/dL vs. watchful waiting and rescue Tx for Hb < 9 g/dL • Achieved Hb level: 12.5 vs. 10.6 g/dL • No difference in death, CHF, or time to ESRD New Engl J Med 361: 2019-32, 2009
Caveats on Treating Anemia in CKD • TREAT trial • Slight improvement in fatigue score in treated group • More transfusions in untreated group • 24.5% vs. 14.8% (p<0.001) • Greater stroke risk in treated group • 5% vs. 2.6%, hazards ratio 1.92 (1.38 to 2.68, p<0.001) • Also greater risk of venous and arterial thrombosis New Engl J Med 361: 2019-32, 2009
Lipid Lowering: SHARP trial • Study of Heart and Renal Protection • 9270 patients ≥ 40 y/o with CKD • SCr ≥ 1.7 mg/dl in men, ≥ 1.5 mg/dl in women • 1/3 of patients had ESRD • Randomized to simvastatin 20 mg/d + ezetimibe 10 mg/d vs. placebo • F/U average 4.9 yrs • Analyzed rate to first major atherosclerotic event (MI, coronary death, CVA or arterial revascularization) • 11.3% vs. 13.4% (rr=0.83, 95% CI: 0.74 to 0.94, p=0.002) Lancet 377: 2181-92, 2011
SHARP Trial Lancet 377: 2181-92, 2011
SHARP Trial Lancet 377: 2181-92, 2011
Lipid Lowering: SHARP trial • Subgroup analysis showed statistical difference only in non-dialysis cohort • No affect on mortality • No affect of progression of CKD • Well tolerated, no increase in myopathy or other s.e.’s
Monitoring Markers of Bone Mineralization: When to Refer? • CKD stage III: • Check Serum Ca, Phos, PTH annually • Phos goal: 2.7 to 4.6 mg/dL • PTH goal 35 to 70 pg/mL • If high: check 25 vitamin D • Treat low 25 vitamin D with ergocalciferol • Monitor Ca and Phos on vitamin D therapy • Repeat PTH and 25 vitamin D in six months • If persistent elevation in phos or PTH: • Refer to nephrology for dietician, binders or calcimimetic therapy
Lifestyle and Dietary Goals • BMI 20-25 kg/m2 • < 2 g Sodium/day (<5 g NaCl) • Protein 0.8 gm/kg/day • Exercise: goal 30 minutes 5x/week • EtOH no more than 2/d men, 1/d women
Preparing for Hemodialysis Access • When GFR <45 (CKD stage 3b) the patient should be educated about saving veins in non-dominant arm (avoid needle sticks and BP checks) • When GFR <30 (CKD Stage 4) and patient chooses hemodialysis, nephrologist should refer to surgeon for AV fistula consultation. • Best for AV fistula to be created 6 months to 1 year prior to dialysis start to allow for maturation time • Goal should be to avoid hemodialysis catheter whenever possible.