Chronic Kidney Disease (CKD):An Update for the Primary Physician

Joshua Augustine, M.D.Wade Park Veterans Administration

Hospital

1/28/14

Quiz Questions1.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

By MDRD formula, USRDS 2010

Demographic Stage I Stage 2 Stage 3 Stage 4/5

All 5.7 5.4 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

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

Current CKD Outcomes: Death vs. ESRD

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.

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But ESRD is More Common than Death in Blacks with Hypertensive

Kidney Disease

AASK Trial, 1/3 of patients were < 50 y/o at enrollmentJ 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 <30 Normal

A2 30-300 3-30 30-300 Moderate

A3 >300 >30 >300 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 EquationNHANES data 2003-2006

MDRD CKD-EPI

Stage 3 CKD%

Stage 4/5 CKD %

Stage 3 CKD%

Stage 4/5 CKD%

All Adults 7.8 0.5 6.3 0.6

Male 6 0.5 5.2 0.6

Female 9.4 0.5 7.4 0.6

White 9.2 0.5 7.4 0.6

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

59 y/o with autosomal dominant polycystic kidney disease

51 y/o with severe acute and chronic interstitial nephritis

Graphing glomerular filtration rate

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

Kidney Int. 69: 1175-80, 2006

n=95

n=51

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

d

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

J Am Soc Nephrol 20: 2641-50, 2009

*Potassium level ≥ 6 meq/L occurred in 14/27 (52%) on spironolactone

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

blockadeVolume 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 Questions1.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