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 Risk factors for CKD include the following: Diabetes Hypertension Autoimmune diseases Systemic infections Exposure to drugs associated with acute decline in kidney function Recovery from kidney failure Age >60 years Family history of kidney disease Reduced kidney mass (includes kidney donors and transplant recipients)1,2 Smoking3. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S17-S31. Bolton WK, Kliger AS. Am J Kidney Dis. 2000;36(suppl 3):S4-S12. Pinto-Sietsma SJ, et al. Ann Intern Med. 2000;133:585-591. 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%

Chronic Kidney Disease Stages 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

Prevalence of CKD in NHANES* 1999-2004 participants Demographic Stage I Stage 2 Stage 3 Stage 4/5 All 5.7 5.4 0.4 Age 20-39 5.9 2.2 0.3 0.1 Age 40-59 5.8 4.4 2.1 0.2 Age 60+ 5.0 12.8 20.3 1.3 Black race 9.4 4.8 4.7 1.1 Diabetic 19.5 11.4 8.2 1.0 Cardiovasc Dz 4.5 10.8 10.5 2.4 *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

Progressive CKD is Associated with Cardiovascular Risk A cardiovascular event was defined as hospitalization for coronary disease, heart failure, stroke, or peripheral arterial disease

Current CKD Outcomes: Death vs. ESRD The impact of CKD on morbidity, mortality, and health-care resources is considerable. Data from the USRDS indicate that patients with CKD are far more likely to die from complications of their disease than to survive long enough to reach ESRD.1 This slide shows the likelihood of death or progression to ESRD among general Medicare patients for the years 1996–1997 combined who were continuously enrolled in Medicare part A and part B and alive on December 31, 1997. A total of 40,250 patients with CKD were included in this analysis. Patients who were enrolled in an HMO or already in ESRD were excluded from these numbers.1 Expected lifetimes for patients after they begin dialysis are only 16% to 37% as long as those of the US population when matched for age, gender, and race.2 Obrador and colleagues suggest that improving the care of patients in the early stages of kidney disease, particularly by aggressively treating anemia, could significantly improve patients’ physical function, cardiac function, and QOL. Should RRT later be required for these patients, they will enter that stage with better opportunities for survival.2 This might alleviate some of the social and economic burdens of the disease. In 1994, although patients with ESRD constituted only six out of every 1,000 patients in the Medicare population, they accounted for 5.1% of all program expenditures.3 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. Obrador GT, et al. J Am Soc Nephrol. 1999;10:1793-1800. National Institutes of Health. Healthy People 2010. Available at: www.health.gov/healthypeople/document/HTML/volume1/04CKD.htm. Accessed 08/27/02. Death ESRD D = diabetes ND = no diabetes Adapted from 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.

AASK Trial, 1/3 of patients were < 50 y/o at enrollment But ESRD is More Common than Death in Blacks with Hypertensive Kidney Disease African American individuals with hypertensive nephrosclerosis (diastolic BP ≥95 mmHg with a GFR 20 to 65 ml/min per 1.73 m2). Participants with a history of a CVD event within 6 months, New York Heart Association class 3 or 4 heart failure, diabetes, malignant or accelerated hypertension within 6 months of enrollment, UP/Cr >2.5, or evidence of renal disease other than hypertensive nephrosclerosis were excluded at trial baseline. 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: Category AER (24 hr) mg/mmol mg/g Terms A1 <30 <3 Normal A2 30-300 3-30 Moderate A3 >300 >30 Severe

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

MDRD vs. CKD-EPI Equation NHANES data 2003-2006 Stage 3 CKD % Stage 4/5 CKD % Stage 4/5 CKD All Adults 7.8 0.5 6.3 0.6 Male 6 5.2 Female 9.4 7.4 White 9.2 Black 4.8 1.1 4.9 1.2 USRDS 2010

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 During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. 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 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 Hyperfiltration Microalbuminuria

Type II DM: IDNT (Irbesartan in Diabetic Nephropathy) Trial (NEJM 2001; 345:851-60) 1715 patients with type 2 DM, HTN, urinary protein > 900 mg/d, Cr 1-3 mg/dl Randomized to irbesartan vs amlodipine or placebo Significant reduction in risk of doubling creatinine in irbesartan vs placebo and vs amlodipine at mean follow-up of 2.5 years rr = 0.71, 95% CI: 0.54 to 0.92 vs placebo rr = 0.61, 95% CI: 0.48 to 0.79 vs amlodipine

Addition of the Aldosterone Inhibitor Spironolactone to ACE Inhibitor in Diabetic Nephropathy A double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). Randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily). Blood pressure did not differ between groups. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. 48 wk. **Potassium > 6 in 14/27 (52%) in spironolactone group *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.

Mortality in First 90 Days of Dialysis Related to Vascular Access Am J Kidney Dis 54: 912-21,2009

Coordinating Care between the PCP and the Nephrologist Nephrologist needs to maintain a relationship with the primary physician Care for the CKD patient should not transfer entirely to the nephrologist Primary doctor should maintain active role in monitoring of CKD, treating cardiovascular risk and addressing other comorbidities The nephrologist may see patient once for counseling or follow annually if renal function is stable and CKD is stage 3 or lower Nephrol Dial Transplant 20: 490-6, 2006

Case 2 85 y/o black female with longstanding hypertension, serum creatinine of 1.7, eGFR = 35 ml/min/1.73m2, minimal proteinuria This patient could be monitored initially by the PCP Blood pressure management and cardiovascular risk reduction is the first goal May need nephrology referral for blood pressure management Discussion about end of life appropriate at this age If Cr trends up and eGFR falls below 30, referal to nephrologist is appropriate

Case 3 42 y/o white male with hypertension and Cr of 1.6, eGFR of 48 ml/min/1.73m2, urinary albumin:cr ratio of 3400 mg/g This patient is at significant risk of progressing to ESRD over years Refer to nephrologist early Patient would require biopsy to evaluate for underlying glomerular disease May require aggressive therapy with angiotensin blockade and/or immunosuppressive therapy depending on diagnosis

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 would warrant a nephrology referral at lower stages of CKD

Summary Monitor eGFR and spot protein in high risk patients Refer all patients with CKD stage 4 or with albuminuria/proteinuria > 600-1000 mg/g creatinine Reasonable to refer early with stage 3 CKD particularly with: A younger patient Kidney function worsening quickly Urinary protein not decreasing with acei/arb Difficulty managing acei/arb due to rise in potassium serum creatinine Refractory hypertension

PCP Should be Part of the Team One quarter of patients > age 60 have been identified as having CKD stage 3 Approximately 8 million patients Not enough nephrologists to staff all patients Most will not progress to ESRD, but require careful monitoring, blood pressure control, and cardiac risk assessment and treatment Older, Caucasian, diabetic more likely to die than progress to ESRD The PCP is essential in the care of CKD patients