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
– Recovery from acute
kidney failure
– Age > 60 years
– Family history of kidney
disease
– Reduced kidney mass
– Smoking
• NSAIDs
• Contrast agents
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* 19992004 participants
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
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
Annual Likelihood of Event
Current CKD Outcomes: Death vs.
ESRD
35
30
<65
25
65+
20
n = 40,250
15
10
5
0
D
D = diabetes
ND = no diabetes
ND
Death
D
ND
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.
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:
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 =
186 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if Black)
• CKD-EPI equation =
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
MDRD
CKD-EPI
Stage 3 CKD
%
Stage 4/5 CKD
%
Stage 3 CKD
%
Stage 4/5 CKD
%
7.8
0.5
6.3
0.6
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
All Adults
Male
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 (JNC8140/90)
• 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 nondiabetic 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 (preESRD) 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.
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