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 LDL17% 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?