Case #1
Current Management Strategies in
Chronic Kidney Disease
Grace Lin, MD
Assistant Professor of Medicine,
University of California San Francisco
Pitfalls of Serum Cr
If both of these politicians had a SCr of 1.5 mg/dl,
what is their respective estimated CrCl?
50 y.o. 70 kg man with long-standing hypertension is
found to have a serum creatinine of 1.5mg/dl and a
blood pressure of 150/90.
• Does he have chronic kidney disease?
• What additional assessment should you undertake?
• What are treatment goals and options for therapy?
Serum creatinine cont…
Age = 56
100 kg (220 lbs)
SCr = 1.5 mg/dl
Age = 78
65 kg (143 lbs)
SCr = 1.5 mg/dl
GFR = 77.8 mL/min
GFR = 31.7 mL/min
1
Estimating Renal Function
• Need serum creatinine, age, sex, and weight
(140-age in yrs) X weight in kg) X 0.85(female)
72 X serum Cr in mg/dl
Estimating Renal Function
50 y.o man who weighs 70 kg and has serum Cr= 1.5
mg/dl
for > 3 months
(140-50) X 70 kg)
72 X 1.5 in mg/dl
• Or serum creatinine, age, sex, and race
GFR= 186 X (serum Cr in mg/dl) -1.54 X (age in yrs) -0.203
= 58 ml/min per 1.73 meters2
X 0.742(for female) X 1.210 (for African-American)
Definition of Chronic Kidney Disease
• Structural or functional abnormalities of the kidneys
for 3 months as manifested by either:
• Kidney damage
• Pathologic abnormalities, or
• Markers of kidney damage, including
abnormalities in the composition of the blood or
urine or abnormalities in imaging test, or
• GFR <60 mL/min/1.73 m2, with or without kidney
damage
Stages of Chronic Kidney Disease
Stage
Description
GFR (ml/min per 1.73
m2)
1
Kidney damage with normal or
increased GFR
≥90
2
Kidney damage with mild decrease
in GFR
60 to 89
3
Moderate decrease in GFR
30 to 59
4
Severe decrease in GFR
15 to 29
5
Kidney failure
<15 or dialysis
2
Chronic Kidney Disease:
An underrecognized epidemic
Kidney failure
(ESRD)
Decreased
GFR
Damage
(Proteinuria)
Age, DM, HBP,
family history
> 300,000 patients
Endstage
Progression
Initiation, injury
GFR 15-29 360,000 patients
GFR 30-59 7.6 million patients
10 million patients
Baumeister, Am J Nephrol, 2009
Risk Factors for CKD
Diabetes mellitus
Hypertension
Autoimmune disease
Systemic infections
Urinary tract infections
Nephrolithiasis
Lower urinary tract
obstruction
• Neoplasia
Other
10%
Glomerulonephritis
13%
Diabetes
50%
Hypertension
27%
20 million patients
At risk
• CKD increases health care costs by 65% over 10 years
• Incident CKD increases costs by 38%
•
•
•
•
•
•
•
Primary Diagnoses for
Patients Who Start Dialysis
• Family history CKD
• Recovery from ARF
• Reduction in kidney
mass
• Nephrotoxic drugs
• Older age
• Racial/ethnic minority
status
• Low socioeconomic
status
United States Renal Data System (USRDS) 2000
Annual Data Report • WWW.USRDS.ORG
Slide Source
Hypertension Online
www.hypertensiononline.org
Screening for Chronic Kidney Disease
• Not recommended for general population
• Consider screening if any of 3 risk factors
– Diabetes
– Hypertension
– Age > 55 years
• Identifies 93% of cases
• Number needed to screen = 9 per 1 case
3
Evaluation of CKD
Evaluation of urinary protein excretion
•
•
•
•
•
History (PMH, family/social hx)
Medication exposure (NSAIDs, aminoglycosides)
Time course of decline in renal function
Urinalysis (proteinuria, casts, cells, etc)
Checking for complications of CKD (CBC, K+, HCO3, albumin,
Ca+2, PO4, PTH, uric acid, albumin)
• Serologies or specialized testing if indicated (ANA, ANCA,
Hep B/C, RF, HIV, SPEP/UPEP, anti-GBM, complement
levels)
• Imaging – renal ultrasound (RAS, cysts, obstruction)
• Renal biopsy when uncertain diagnosis and considering
immunosuppressive therapy
Risk Factors for
Progression of Renal Disease
Can be modified
Cannot be modified
Hypertension
Age
Albuminuria/Proteinuria
Ethnicity
Dyslipidemia
Gender
• Normally very small amount of protein excreted in
urine
• Increased excretion of albumin sensitive marker for
CKD due to diabetes, HTN, glomerular disease
• Spot urine samples (first morning specimen
preferred) to evaluate
• Can calculate spot urine protein/creatinine ratio to
assess approximate protein excretion rate (g/24 hrs)
< 0.3 (< 300 mg) = normal
0.3 – 3 (300 mg – 3000 mg) = non-nephrotic range proteinuria
> 3 (> 3 g) = nephrotic range protenuira
Early intervention in CKD reduces time to
progression to ESRD
Hemoglobin A1C
Smoking
Anemia
Ca•P04
4
Treatment of CKD: Outline
• Diagnose and treat specific cause of CKD
• Slow progression of GFR
– BP control
– Maximize ACE-I/ARB therapy
• Reduce cardiovascular disease risk
– Control BP, lipids
• Treat comorbidities
– Glucose control
• Assess and treat for complications
Reversible Causes of CKD
• Decreased renal perfusion
– Hypovolemia
– Hypotension
– Infection
• Nephrotoxic drugs*
– NSAIDs
– Aminoglycoside antibiotics
– Radiographic contrast
• Urinary tract obstruction
– Anemia, bone disease
• Refer to nephrologist when GFR < 30 mL/min/1.73
m2 or earlier
Blood Pressure and CKD
• Most patients with CKD will develop hypertension,
regardless of initial cause
• 10 mmHg reduction of mean arterial pressure is
associated with preservation of 3.7 mL/min of
glomerular filtration
• Treatment goal of < 130/80, lower (< 125/75) in
patients with > 1 gram/day of proteinuria
*Some drugs cause spurious elevation of creatinine but do not
decrease GFR: cimetidine, trimethoprim, cefoxitin, flucytosine
Anti-Hypertensive Treatment in CKD
• Recommended therapy:
– 1st agent: ACE-I or ARB, particularly in diabetic patients
or patients with significant proteinuria
– 2nd agent: Diuretic
– 3rd agent: Calcium channel blocker or beta-blocker
• Most patients require ≥ 2 agents for adequate BP
control
• In patients with proteinuria, ACE-I appear to offer
reno-protective benefits over other anti-hypertensive
therapies
5
Average Number of Anti-Hypertensive
Agents Used to Achieve Target BP
Goal BP
Achieved
BP
Avg # of
drugs per
patient
MDRD
ABCD
HOT
UKPDS
<92
mmHg
MAP*
<75
mmHg
DBP
<80
mmHg
DBP
<85
mmHg
DBP
93
~75
81
82
3.6
2.7
3.3
2.8
Proteinuria in CKD
• Proteinuria is independent risk factor for renal failure
• Protein excretion > 500 – 1000 mg per day increases
risk of progression of CKD
• Reduction in proteinuria is correlated with decreased
progression of CKD
– For each 1 gram/day reduction in proteinuria, rate of GFR
decline decreased by 0.9-1.3 mg/min per year (MDRD study)
*The goal mean arterial pressure (MAP) of <92 mmHg specified in the MDRD trial
corresponds to a systolic/diastolic blood pressure of approximately 125/75 mmHg.
Slide Source
Hypertension Online
www.hypertensiononline.org
Peterson, Ann Intern Med, 2005
Relative Risk of ESRD on ACE-I
By Baseline Proteinuria
ACE Inhibitor in Non Diabetic CKD
0.2 0.4 0.6 0.8 1.0
proteinuria > 500 mg - 1 gm, ACE-I is first line
• Most effective agent for decreasing protein
•
•
•
1.2
Relative Risk
• If serum creatinine >1.5 mg/dl (24hr CrCl <60) and
= no ACEI benefit
1
2
3
4
5
6
7
8
9
10
excretion
Beneficial even in absence of hypertension
Effect independent of BP
Benefits of ACE-I increase with amount of
baseline proteinuria
Baseline Urinary Protein Excretion (grams/day)
Jafar, Ann Int Med, 2001
6
Missed Opportunities
• Only 1/3 of patients with CKD receive ACE-I
• Non diabetics less likely to receive ACE-I than
diabetics
• Likelihood of being on ACE-I not related to
nephrology referral
Case #2
• 65 y.o. man with stage 3 CKD currently on moderate
dose of ACE-I with BP of 130/80
• Positive urine dipstick; follow-up urine
protein/creatinine ratio is 0.7
• You increase the dose of his ACE-I and at a follow-up
appointment, his BP and proteinuria have improved,
but his creatinine increased from 1.4 to 1.7 mg/dL
• What do you do next?
Nissenson, J Am Soc Nephrol, 2001
Case #2
1. Reduce dose of ACE inhibitor
Starting/Increasing ACE Inhibitor
• Check electrolytes and creatinine at baseline and
within 1 week
2. Maintain dose of ACE inhibitor
• Expected short-term decrease in GFR (≤ 30%)
3. Increase dose of ACE inhibitor
4. Stop ACE inhibitor
• If rise in creatinine > 30%, reduce dose by 50% and
recheck labs in 1 week
• If rise in creatinine > 50%, exclude hypoperfusion and
RAS
7
Does ARB = ACE-I?
• > 40 randomized head to head comparisons
• Similar level of BP control and reduction of
proteinuria
• Similar benefits on mortality, CV disease, progression
of CKD, and quality of life
• Relatively little data on long term outcomes or safety
with either drug
• Less cough and angioedema with ARB
• ARBs more costly
Case #3
• 53 y.o. woman with CKD (serum creatinine = 2.2
mg/dL), controlled HTN, and proteinuria (1 gram/24
hrs), on maximum dose ACE-I.
• What changes, if any, would you make in her
treatment?
Case #2
1. Reduce dose of ACE inhibitor
2. Maintain dose of ACE inhibitor
3. Increase dose of ACE inhibitor
4. Stop ACE inhibitor
Case # 3
1. Change the ACE inhibitor to an ARB
2. Combine the ACE inhibitor with an ARB
3. Don’t change treatment
8
ARB + ACE-I for Proteinuria?
• Blocking angiotensin II reduces proteinuria
• Some angiotensin II can form without ACE (ACE-I
flaw)
• ARB’s only block one subtype of angiotensin II (ARB
flaw)
Proteinuria in Monotherapy vs
Combined ACE-I and ARB
• 16 trials
• Similar blood pressure lowering
• Combined therapy lowers proteinuria by about 25%
more than monotherapy
• Do not achieve proteinuria lowering effects from
either agent alone by simple increasing dose
• However....
Kunz, Ann Intern Med, 2008
ONTARGET
• RCT of ramipril (ACE-I) vs telmisartan (ARB) vs
combination therapy
• > 8000 patients with high cardiovascular risk or
diabetes per arm
• Single drug arms equivalent outcomes
• Combination had more adverse effects including
more advanced renal disease without clear benefits
Case # 3
1. Change the ACE inhibitor to an ARB
2. Combine the ACE inhibitor with an ARB
3. Don’t change treatment
ONTARGET investigators, New Engl J Med, 2008
9
to preserve renal function and may arrest
development of ESRD
• Treatment of microalbuminuria slows/prevents
development of proteinuria in diabetics, more
effective if started before proteinuria develops
Risk of Hyperkalemia in CKD
• ACE-I underprescribed due to concerns about
hyperkalemia
• Risk increases with decreasing GFR
Baseline GFR
Event rate per 100 pt-years (95% CI)
≤ 30
6.87 (4.44 – 10.14)
> 30 to ≤ 40
2.75 (1.54 – 4.53)
> 40 to ≤ 50
0.45 (0.09 – 1.32)
> 50
0.52 (0.22 – 1.02)
• Non-diabetic CKD with
proteinuria
• Placebo group switched to
ACE-I
• Late change to ACE-I offered
some benefit
• Early treatment with ACE-I
associated with greater
benefit
• In some patients, ESRD
avoided
GFR
30 35 40 45
• Early intervention in non diabetic CKD more likely
REIN Follow Up Study
•
ACEI/ARB Treatment Timing
45
ACE I
40
35
Placebo
ACE I
30
25
0
1
5
3
Years
10
5
CKD as Risk Factor
• CKD is associated with increased mortality
• Cardiovascular disease is the main cause
• ACE-I greater risk than beta-blockers or CCB
• Can frequently be managed with low potassium diet
and/or diuretics
Weinberg, Arch Intern Med, 2009
10
CV Mortality in General Population &
Dialysis Patients
Age-Standardized Rate of Cardiovascular
Events (per 100 person-yr)
40
Annual % Mortality (Log Scale)
100.000
36.6
35
30
10.000
25
1.000
21.8
20
15
0.100
GP Black
GP White
Dialysis Black
Dialysis White
0.010
11.29
10
5
2.11
3.65
0
0.001
25-34
35-44
45-54
55-64
65-74
75-84
85+
Age (years)
≥60
45-59
30-44
15-29
<15
Estimated GFR (ml/min/1.73 m2)
Foley RN, Am J Kidney Dis, 1998;32(S112-119)
Slide Source
Hypertension Online
www.hypertensiononline.org
Case #4
• 57 y.o. woman with CKD, HTN, hyperlipidemia,
and anemia of chronic disease
• What are the renal and cardiovascular benefits
of treating her hyperlipidemia?
Go et al. N Eng J Med. 351;13:1296-1305
CKD and Cardiac Risk
• 40% of patients have MI or revascularization prior to
dialysis
• Treatment of hyperlipidemia with statins associated
with slowing rate of GFR decline
• Statins associated with decreased risk of CV
events/death in patients with mild-moderate CKD
• Statins not effective in reducing CV events/death in
patients on dialysis
• No large RCTs demonstrating that treating
dyslipidemia in CKD patients prevents CV disease
11
Case #4
• 57 y.o. woman with CKD, HTN, hyperlipidemia,
and anemia of chronic disease
Case # 4
1. Lower risk of cardiovascular events and death
2. Reduce risk of left ventricular hypertrophy
• Her Hgb = 8 gm/dL
3. Both of the above
• How would treating her anemia affect her risk
for cardiovascular disease?
CKD related anemia and
cardiovascular complications
• Anemia is common
– About 50% of patients when GFR < 35
– Almost 90% of patients when GFR < 25
• Associated with CV deaths and LVH in observational
studies
• NKF guidelines recommend use of erythopoietin
when Hgb < 9 gm/dL
• What is the optimal target?
4. Neither of the above
Correction of Hemoglobin and
Outcomes in Renal Insufficiency (CHOIR)
• >1400 adult patients with GFR 15-50 ml/min and
anemia (Hgb<11.0 mg/dl) randomized to Epo SQ with
different treatment targets
• Compared death, MI, CHF hospitalization and stroke
for Hgb 13.5 gm/dl versus 11.3 gm/dl
• Study terminated early due to increased events in high
hemoglobin group (125 vs 97; hazard 1.34) and no
quality of life benefit
Singh, NEJM, 2006
12
Cardiovascular Risk Reduction by Early
Anemia Treatment with Epoetin (CREATE)
• > 600 adult patients with GFR 15-35 ml/min and
anemia (Hgb11.0-12.5 mg/dl) randomized to EPO with
different treatment targets
• Compared death, MI, acute heart failure, stroke, TIA,
or hospitalization for angina, amputation or
arrhythmia for Hgb 13.0-15.0 gm/dl versus 10.5-11.5
gm/dl
• More cardiovascular events and deaths in higher
hemoglobin group but not statistically significant
Correcting Anemia in CKD
• Complete correction not obviously beneficial and
may be harmful
• Several additional studies in field that should help to
determine whether there are benefits to lower
treatment targets
• Current guidelines: goal Hgb = 11-12 g/dl
• Maintain adequate iron stores
• No reduction in LVH in higher Hgb group
Drueke NEJM, 2006
Secondary hyperparathyroidism
• Phosphorus: restrict dietary PO4, add binders
– Add phosphate binders to improve control
– Ca-P product target < 55 mg2/dL2
– Caution with phosphate-containing bowel preparations: risk of
acute phosphate nephropathy
• Calcium: limit supplementation to < 2 g/day
• Treat vitamin D insufficiency (< 30 ng/mL)
• Add vitamin D analogs (calcitriol)
CKD Stage
Target iPTH (pg/mL)
3 (GFR 30-59)
35-70 (3.85-7.7)
4 (GFR 15-29)
70-110 (7.7-12.1)
5 (< 15 or dialysis)
150-300 (16.5-33)
Other Complications of CKD
• Metabolic acidosis
– Develops when GFR < 60 ml/min/1.73 m2
– Increases loss of calcium from bone
– Target CO2 ≥ 22 mEq/L
– Add oral sodium bicarbonate or Bicitra
• Risk of acute aluminum or magnesium toxicity
– Common ingredients in OTC antacids (Maalox, Mylanta)
– Citrate containing preparations (Mg citrate, calcium citrate,
potassium citrate) increase aluminum absorption
13
Bottom Line on Preventing Progression of CKD
and Mortality Risk
• Aggressive BP control to reach target < 130/80
• Screening for CKD and proteinuria in patients with
HTN and DM is cost-effective
• Intervene with ACE-I or ARB to reduce proteinuria
and microalbuminuria (in diabetics)
• Aggressive treatment of cardiovascular risk factors,
especially lipids
• Treat anemia to moderate level
• Monitor and treat secondary hyperparathyroidism
14