Implementing an Evidence-Based Stage-Specific Clinical Action Plan Jeffrey S. Berns, MD Steps to CKD Patient Care 1. 2. 3. 4. 5. 6. 7. Does the patient have CKD? Assess GFR, albuminuria Determine etiology Assess for evidence of progression Assess for associated complications Patient education Assess life expectancy and patient wishes for dialysis/transplantation Definition of Chronic Kidney Disease • Kidney damage for > 3 months – Structural or functional abnormalities of the kidneys, with our without decreased GFR, manifest by either • Pathological abnormalities • Markers of kidney damage, including abnormalities in the composition of the blood or urine, or in imaging tests • GFR < 60 ml/min/1.73 m2 for > 3 months, with or without kidney damage as defined above Estimating GFR DO NOT USE SERUM CREATININE ALONE • Creatinine clearance •24 hour urine •Cockcroft-Gault formula • Mean of 24-hour creatinine and urea clearances • MDRD equation (estimated GFR in mL/min/1.73m2) • CKD-EPI equation (estimated GFR in mL/min/1.73m2) • Creatinine-based • Cystatin C-based • Creatinine + Cystatin C-based SCr Age Gender 20 M 20 Race (mg/dL) eGFR (mL/min/1.73 m ) B 1.3 91 M W 1.3 75 55 M W 1.3 61 20 F W 1.3 56 55 F B 1.3 55 50 F W 1.3 46 B = black; W = all ethnic groups other than black; *With evidence of kidney damage. 2 CKD: The Old Way Stage 1 2 3 4 5 Description GFR ml/min/1.73 m2 Kidney damage with normal or increased GFR Kidney damage with mild decreased GFR Moderate decreased GFR 60-89 Severe decreased GFR 15-29 Kidney failure < 15 or on dialysis > 90 30-59 The New CKD Categories The “e” in eGFR Stands for “Estimated”….. True GFR could be > 70 mL/min.1.73m2 or < 15 mL/min.1.73m2 Levey AS et al. Ann Intern Med. 2009;150:604-612. Bias and Accuracy of Estimating Equations Inker, at al. NEJM 2012 Use These Equations Cautiously if at all in …. • Patients who have/are: – – – – – – – Poor nutrition/loss of muscle mass Amputation Chronic illness Not African American or Caucasian Changing serum creatinine Obese Very elderly, young Clinical Evaluation of Patients with CKD • Blood pressure • Serum creatinine – Use a GFR estimating equation or clearance measurement; don’t rely on serum creatinine concentration alone – Be attentive to changes in creatinine over time--even in “normal” range • Urinalysis – Urine sediment – Spot urine for protein/creatinine or albumin/creatinine ratio • Albuminuria/Proteinuria • Electrolytes, blood glucose, CBC Clinical Evaluation of Patients with CKD • Depending on stage: albumin, phosphate, calcium, iPTH • Renal imaging • Depending on age and H&P – Light chain assay, serum or urine protein electrophoresis (SPEP, UPEP) – HIV, HCV, HBV tests – Complements, other serologies—limited role unless specific reason Screening for Microalbuminuria, Albuminuria or Proteinuria • Standard urine dipsticks detect total protein > 30 mg/dL—not sensitive enough for “microalbuminuria” screening • Untimed, random “spot” urine for albumin/creatinine or protein/creatinine ratio (first morning void preferred) Definitions: Albuminuria and Proteinuria • Normal to Moderately Increased Albuminuria – Albumin:creatinine ratio < 30 mg/g creatinine • Moderately Increased Albuminuria – Albumin:creatinine ratio 30-300 mg/g creatinine – 24-hour urine albumin 30-300 mg/d • Severely Increased Albuminuria – Albumin:creatinine ratio > 300 mg albumin/g creatinine – 24-hour urine albumin > 300 mg/d • Proteinuria – (+) urine dipstick at > 30 mg/dl – > 200 mg protein/g creatinine – 24-hour urine protein > 300 mg/d eGFR and Albuminuria Predict CKD Outcomes Slowing Progression of CKD CKD Stage and Progression Risk Potentially Modifiable CKD Progression Risk Factors • • • • • • • • • Hypertension Diabetes/Glycemic control Albuminuria/Proteinuria Metabolic acidosis Obesity ? Hyperuricemia ? Smoking ? Sedentary lifestyle ? Dietary Protein Intake ? Non-Linear GFR Changes are Common Li, et al. AJKD 2012 BP and CKD Progression • Control of BP more important than which agents are used – Avoidance of side-effects is important • With proteinuria: diuretic + ACEi or ARB • No proteinuria: no clear drug preference – ACEi or ARB ok to use Lower BP Slows Decline in GFR MAP (mmHg) GFR (mL/min/year) 95 0 98 101 104 107 110 113 116 119 -2 -4 -6 Untreated HTN -8 -10 -12 130/85 140/90 -14 But newer studies suggest there may be other dangers down here Bakris GL, et al. Am J Kidney Dis. 2000 Goals for Renoprotection • Blood pressure—STILL CONTROVERSIAL – < 130-140/80-90 mmHg if urinary albumin > 30 mg/d – < 140/90 mmHg if normal urinary albumin • Proteinuria – ACEi or ARB in diabetic with Ualb > 30 mg/d – ACEi or ARB in non-diabetic with Ualb > 300 mg/d ARBs and Progression of Diabetic Nephropathy • 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 Parving HH, et al. N Engl J Med. 2001 Renal Outcomes: CCB v. ACEI Multiple Agents are Required to Achieve BP Goals 3.8 3.3 3.6 2.8 2.7 3.0 3.1 3.0 Number of Agents Needed Bakris, G.L. et al, Am J Kid Dis. 2000 Combination RAAS Blockade • ACEi and/or ARBs + spironolactone or eplerenone or aliskerin – More effective than monotherapy in reducing proteinuria • No proven benefit on long-term renal outcomes – Reduces GFR in short term – No demonstrated GFR benefit over time – Increases risk of AKI, hypotension, hyperkalemia – Certainly no role if proteinuria < 1 g/d and even then…. • May be used in setting of severe proteinuria and high CKD progression risk…with caution Other Goals of CKD Management • Target HgbA1C ~ 7%; higher if significant comorbidities or limited life expectancy • Limit sodium intake to < 90 mmol (2 gm; 5 gm salt) per day • CVD management: lipids, ASA (secondary prevention), etc Lipid Disorders in CKD A 32% reduction in LDL17% reduction in primary outcome (nonfatal MI, coronary death, nonhemorrhagic stroke, arterial revascularization) No reduction in CKD progression, overall or CAD mortality, other individual CAD end-points Lancet 2011 Lipid Disorders in CKD • Use statin alone or statin + ezetimibe in adults > 50 yrs with CKD 3-5(ND) • Use statin alone in adults > 50 yrs with CKD 1-2 • In adults < 50 yrs use statin alone if history of known CAD, MI, DM, stroke • Treat according to a “fire and forget” rather than “treat to target” strategy Meta-Analysis of the Effects of Dietary Protein Restriction on Rate of Decline in Renal Function Kasiske, et al AJKD 1998 • 13 randomized controlled trials • Mean follow-up 21.8 months • Mean DPI ~ 0.6-0.7 mg/kg/d vs. ~1-1.2 mg/kg/d • Protein restriction decreased rate of GFR decline by 0.53 ml/min/yr • Recommendation: Avoid high protein intake (> 1.3 g/kg/d) if at risk for CKD progression Avoid Adding Insult to Injury • • • • • • • Volume depletion ACEI/ARB if not needed Iodinated radiographic contrast media Sodium phosphate bowel prep Nephrotoxic antibiotics NSAID’s Herbal preparations • Caution with PPIs Treating Complications of CKD Patients (%) Anemia Becomes More Common as Kidney Function Declines Hgb ≤12 g/dL CKD Stages Adapted from: McClellan et al. Curr Med Res Opin. 2004;20:1501-1510. Erythropoieses Stimulating Agent (ESA) Treatment • Epoetin alfa, darbepoetin alfa • Recent studies in CKD patients show little improvement in quality of life measures, moderate reduction in need for transfusion, no overall mortality or morbidity benefit, increased risk of stroke, increased cancer-related mortality • Evaluate and treat iron deficiency • ESA therapy must be individualized—typically starting when Hgb 9-10 g/dl, maintaining Hgb < 11.5-12 g/dl, avoiding Hgb > 13 g/dl % of Patients Prevalence of Abnormalities of Mineral Metabolism, PTH in CKD 100 90 80 70 60 50 40 30 20 10 0 iPTH >65 pg/mL CKD Stages 4 and 5 Phosphorus >4.6 mg/dL Calcium <8.4 mg/dL CKD Stage 3 >80 79-70 69-60 59-50 49-40 39-30 29-20 <20 eGFR (mL/min/1.73 m2) iPTH = intact parathyroid hormone Adapted from: Levin A et al. Kidney Int. 2007;71:31-38. CKD-MBD and Mortality • 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 mortality benefit of treatment of phosphorus or PTH CKD-MBD Testing CKD Stage Calcium, Phosphorus Stage 3 Every 6-12 months PTH 25(OH)D Once then based on CKD progression Stage 4 Every 3-6 months Every 6-12 months Stage 5 Every 1-3 months Every 3-6 months Once, then based on level and treatments • Use CKD progression, presence or absence of abnormalities, treatment response and side effects to guide testing frequency CKD-MBD Treatment • Treat 25(OH)D deficiency as in general population • Maintain serum phosphate in normal range • Dietary restriction to < 600-1000 mg/d • Food additives/preservatives • Meat phosphorus absorption > seeds, nuts, legumes • High P/protein ratio in many cheeses, milk, nondairy creamer • Many sodas, iced-tea have high phosphorus content Phosphate Binders – Aluminum hydroxide Least Expensive – Calcium carbonate – Calcium acetate – Sevelamer carbonate – Lanthanum Most Expensive Other CKD-MBD Items • Goal PTH not clear • Don’t use calcimimetics • Unclear role of DEXA scans with eGFR < 45 ml/min/1.73m2 • Use bisphosphonates as in general population if eGFR > 30 ml/min/1.73m2 – Avoid in most patients with lower eGFR Metabolic Acidosis • Often becomes apparent at GFR < 25-30 ml/min – More severe with higher protein intake • May contribute to bone disease, protein catabolism, and progression of CKD Adults with CKD (eGFR 15-30 ml/min/1.73m2) with bicarbonate 16-20 mmol/L; treated with sodium bicarbonate for 2 years to normalize serum bicarbonate concentration Brito-Ashurst, et al. JASN 2009 Metabolic Acidosis • Maintain serum bicarbonate > 22 mmol/L – Start with 0.5-1 mEq/kg per day – Sodium bicarbonate tablets • 325mg, 625 mg tablets; 1 g = 12 mEq – Sodium citrate solution • 1 mEq/ml • Avoid if on aluminum phosphate binders – Baking soda • 54 mmol/level tsp Managing the Patient with CKD Approaching ESRD 1. Patient/family education 2. Chose RRT modality 1. Assess GFR 3. Referral for transplant evaluation 2. Determine etiology; consider renal biopsy, etc. 4. Dialysis access 3. Identify reversible factors Workup: complete H&P; cbc, electrolytes, bicarbonate, calcium, phosphate, albumin, urinalysis, SPEP/UPEP, assess proteinuria, renal ultrasound Progressive CKD 1. Reduce progression 2. Manage comorbid conditions 3. Manage complications of CKD Treat BP, use ACEI/ARB, evaluate and treat hyperlipidemia, calcium/phosphate/iPTH, anemia; smoking cessation; preserve vessels; patient education Frequency of Monitoring When to Refer to a Nephrologis • CKD stages 3-5 • Progression of disease – declining eGFR, increasing proteinuria • Degree of proteinuria: nephrotic syndrome, > 0.5-1.0 g/d on ACEi or ARB therapy • Etiology of CKD not certain • Need help with disease management • Indications for kidney biopsy How the Nephrologist Helps • 20-50% lower mortality • More likely to have AV fistula • Fewer dialysis catheters • Better control of BP, anemia, Ca-phos-PTH • Shorter hospital LOS if admitted to start dialysis • Lower costs of care When to Refer Dialysis Options • In-Center HD • 3 times per week • Nocturnal WORST • Home Dialysis – HD • Short daily • Nocturnal – PD BEST Is Earlier HD Start Better? • RCT of > 800 patients with eGFR 10-15 mL/min – Start HD early or wait until eGFR 5-7 mL/min – 76% of late start group started with higher eGFR due to symptoms or other indication • No difference in survival, other outcomes, QOL • Conclusion: OK to delay dialysis until GFR < 7 mL/min or other specific clinical indicators for the initiation of dialysis are present such as uremic symptoms, declining nutritional status Cooper BA, et al. NEJM. 2010. Kidney Function Declines with Age Per decade decline: • 19 mL/min in men • 15 mL/min in women ClCr 140 (ml/min) 120 100 80 • Many elderly have low GFR without albuminuria and are at very low progression risk 60 40 20 0 60 70 80 Age (years) 90 100 Threshold eGFR Risk of ESRD vs. Death Risk of ESRD > Risk of Death Adapted from: O'Hare AM et al. J Am Soc Nephrol. 2007; 18(10):2758-2765. Starting Dialysis in the Elderly…Or Not? • Among patients > 75 yrs with stage 5 CKD who chose to NOT start dialysis: – Overall, more likely to die over next 1-2 years – But if they had ischemic heart disease or other significant comorbidity NO DIFFERENCE in survival • Active disease management and supportive care may be appropriate without starting dialysis in the ill elderly – Palliative care does not mean “no care” • Must have end-of-life discussions! Murtagh, et al. Nephrol Dial Transplant. 2007;22(7):1955-62. Conclusions • • • • Use GFR estimating equations Stage CKD with eGFR and albminuria and consider cause Control BP…but not too tightly Not everyone with CKD need RAAS blockade – Avoid ARB + ACEi • • • • Manage DM, lipids, acidosis Avoid nephrotoxins Not everyone with ESRD needs to start dialysis Think transplant over dialysis, home dialysis over in-center hemodialysis • Nephrologists are your friends…we can help you and your patients. Thank You. Any Questions?