Identifying and Managing CKD- Chronic Kidney Disease

Identifying and Managing
CKD- Chronic Kidney
Disease
GERALD APPEL, MD
Professor of Clinical Medicine
Columbia University – College of
Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York
Disclosure Statement of Financial Interest
Within the past 12 months, I (Gerald Appel) or my spouse/partner have had a
financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
•
•
•
Research Grants – Teva, Alexion, Questcor , NIH.
Speaker for : Takeda (gout), Genentech (vasculitis).
Consultant: Up-To Date, Takeda, Genentech, Teva, Alexion, Questcor, Amgen, Bristol
Myers Squibb, Ardea, Pfizer, E. Lilly, Boehinger Ingelheim, Chugai.
•
Unfortunately, Dr. Appel has no major stock holdings or ownership of any of the above.
Objectives CKD Lecture
• To understand the definition of CKD.
• To understand the major causes of CKD.
• To know why early detection and management is
important.
• To understand how to slow the progression of CKD.
• To understand the major complications of CKD .
5
NKF Stages of Chronic Kidney Disease
Stage
Description
GFR
1
Kidney damage with normal or elevated
GFR
≥90 mL/min/1.73m2
2
Kidney damage with mildly decreased GFR
60–89 mL/min/1.73m2
3
Moderately decreased GFR
30–59 mL/min/1.73m2
4
Severely decreased GFR
15–29 mL/min/1.73m2
5
Kidney failure
< 15 mL/min/1.73m2 or
dialysis
Stages of CKD
US Prevalence of CKD Stages
Adapted from Coresh J, et al. Prevalence of CKD in the US JAMA. Nov. 7, 2007;298:17.
Number of Patients With Kidney
Failure Is Increasing
Per million population, 1990,
Per million population, 2000,
by HSA, unadjusted
by HSA, unadjusted
United States Renal Data System 2000 Annual Report. Available at:
http://www.usrds.org/atlas_2000.htm. Accessed May 1, 2007.
Etiology of CKD
• United States Kidney Foundation. www.kidney.org.
Distribution of NHANES 2005–2010 participants
with diabetes, cardiovascular disease, & single-sample markers of CKD
Figure 1.1 (Volume 1)
Low GFR or Albuminuria
Low GFR
Albuminuria
NHANES participants 2005–2010, age 20 & older; single-sample estimates
of eGFR & ACR.
CKD Prevalence Increases With Age
Participants With CKD (%)
80
NHANES III (15,853)
KEEP (22,166)
60
40
20
0
18-30
31-45
46-60
61-75
Age in Years
NHANES III=Third National Health and Nutrition Examination Survey.
KEEP=Kidney Early Evaluation Program
CKD defined by serum creatinine >1.5 mg/dL in men; >1.3 mg/dL in women.
National Kidney Foundation. Am J Kidney Dis. 2005;45(suppl 2):S1-S80.
75+
All-cause rehospitalization or death within 30 days after live hospital
discharge, in the general Medicare (no CKD), CKD, & hemodialysis
populations, age 66+, 2011
January 1, 2011 point prevalent Medicare patients, age 66 & older on December 31, 2010, unadjusted. Includes live
hospital discharges from January 1 to December 1, 2011.
Why is Early Detection and Treatment
of CKD Important
• Early management may slow CKD progression and prevent
or delay development of complications
• Slowing the rate of GFR decline by 10% to 30% in patients
with a GFR of ≤60 mL/min could potentially save $19 to $61
billion in direct US healthcare costs in several years.
• CKD is a progressive condition that can affect almost every
body system
The Perils of Using Serum Creatinine Only
to “Guess” Level of Renal Function
SCr
GFR as
estimated
by MDRD
equation
24yo, 75-kg
Black Man
50-yo, 65-kg
White Man
82-yo 42-kg
White Woman
1.2 mg/dL
1.2 mg/dL
1.2 mg/dL
96 mL/min/1.73 m2
68 mL/min/1.73
m2
46 mL/min/1.73
m2
Levey et al. Ann Intern Med. 1999;130:461-470; National Kidney Foundation. Am J Kidney
Dis. 2002;39(suppl 1):S1-S266.
Methods to Slow the Progression
of CKD
• Control the Blood Pressure (< 140/90 , If
proteinuria < 130/80 )
• Block the renin angiotensin system
(ACE inhibitors or AII receptor Blockers)
• For Diabetics control blood sugar
• Use of NaHCO3 to correct acidosis
• Low protein diets?
Blood Vessels of
Glomerular Capillary Network
Afferent
arteriole
Efferent arteriole
17
ANGIOTENSINOGEN
RENIN INHIBITORS
Renin
ANGIOTENSIN I
Angiotensin
Converting
Enzyme
•CAGE
ACE INHIBITORS
•Cathepsin G
•Chymase
ANGIOTENSIN II
AII ANTAGONISTS
AT1 Receptor
Aldosterone
ALDOSTERONE
ANTAGONISTS
ACE-I Is More Renoprotective than Conventional
HBP Therapy in Type 1 Diabetes
20
2
P<.001
0
-20
-40
-60
Other BP
Meds
Decrease in mean arterial
pressure (mmHg)
% change in proteinuria
40
0
2
-4
-6
-8
Captopril
Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.
NS
Other BP
Meds
Captopril
Cumulative % Patients with Primary End Point:
Doubling of Baseline Serum Creatinine
50
45
40
48% risk reduction
35
Other HBP Meds
(N=43)
P=0.007
30
25
20
15
Captopril
(N=25)
10
5
0
Placebo
Captopril
202
207
0.0
0.5
184
199
1.0
173
190
1.5
2.0
2.5
Years of follow up
161
142
99
180
167
120
3.0
3.5
75
82
Adapted from Lewis EJ, at al. NEJM 329;
11,1993 .1456-1462
4.0
45
50
22
24
RENAAL – BP Control in
Risk Reduction: 25%
p=0.006
L
10
0
12
762
751
715
714
0
12
P (+ CT) 762
L (+ CT) 751
24
Months
689
692
36
554
583
48
295
329
36
52
P (+ CT)
L (+ CT)
36
48
347
375
42
69
Risk Reduction: 20%
p=0.010
40
30
P
20
L
10
0
Brenner BM, Cooper ME, de Zeeuw D,
et al. N Eng J Med. 345:861-869, 2001
24
Months
610
625
ESRD or Death
50
% with event
% with event
P
L
10
0
P (+ CT)
L (+ CT)
P
20
20
0
Doubling of Serum Creatinine
30
Risk Reduction: 28%
p=0.002
30
% with event
1500 TIIDM – Placebo
( other BP meds ) vs
Losartan
ESRD
0
12
762
751
715
714
24
Months
610
625
36
48
347
375
42
69
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
% pts with doubling
of baseline Cr or ESRD
Mean rate of GFR decline
(mL/min/month)
REIN Study: ACE Inhibition in
Proteinuric Non-Diabetic Nephropathy
n = 61 n = 36
3–4.5 4.5–7.0
n = 20
 7.0
Placebo
70
60
50
Ramipril
40
30
20
10
0
n = 87 n = 48 n = 31
3–4.5 4.5–7.0  7.0
Baseline urinary protein
Baseline urinary protein
excretion (g/24 h)
excretion (g/24 h)
The GISEN Group. Lancet. 1997;349:1857–1863
JNC 8 Guidelines for HBP
• In patients > 60 yo without DM or CKD goal BP is < 150/90.
• In patients 18-59 yo without major comorbidity goal is
< 140/90.
• In patients > 60 yo with DM or CKD goal is < 140/90.
• Most treatment limited to thiazides, CCBs, ACE inhibitors,
and ARBs.
• In all patients > 18 yo with CKD initial or add on therapy
should be an ACEi or ARB.
• Use of ACEi-ARB combinations should be avoided.
JAMA Dec 2013
Bicarbonate Therapy Slows progression of CKD
deBrito-Ashurst I…Yaqoob MH. JASN 2075-84, 2009
• Randomized controlled trial of 134 pts w Ccr 15-30
cc/min/1.73m2 & HCO3 16-20 mmol/L.
• Oral NaHCO3 given at 1.82 g/d
• End-point rate Ccr decline, % pts with rapid decline,
ESRD.
• Ccr decline slower in HCO3 group ( 5.9 vs 1.88 ml/min )
• Rapid progression 9% HCO3 vs 45% control.
• ESRD 6% vs 33% Control.
Kaplan-Meier analysis to assess the probability of reaching
ESRD for the two groups
de Brito-Ashurst, I. et al. J Am Soc Nephrol 2009;20:2075-2084
Complications of CKD
•
•
•
•
Cardiovascular Disease
Anemia
Malnutrition
Renal Osteodystrophy
Expected Remaining Lifetimes in Patients
With Increasing Morbidity (by Age)
100%
90%
CKD Patients Are More Likely
to Die Than Progress to ESRD
14.9%
6.6%
10.3%
16.2%
80%
27.8%
Patients
70%
60%
50%
64.2%
19.9%
63.3%
74.8%
RRT
Died
40%
30%
1.2%
20%
1.0%
10%
Discontinued
Event free
19.5%
45.7%
24.3%
10.2%
0%
Stage 2 (no
proteinuria)
Stage 2 (with
proteinuria)
Stage 3
Stage 4
RRT = renal replacement therapy Keith D et al. Arch Int Med 2004;164:659-663.
CKD and Risk of Death, CVasc Event,
and Hospitalization
•
•
•
•
•
•
1,120,300 pts followed 2.84 yrs.
3171 (0.28%) begin maintenance Dialysis
329 ( 0.03% ) Transplanted
51,424 deaths
138,291 cardiovascular events
554,651 hospitalizations
• Go A, Chertow GM, Fan D,et al. NEJM 351:1296-1305,2004.
Renal Function vs Death, Cardiovascular
Events, or Hospitalization Endpoints
16
14
12
10
8
6
4
2
0
Rate of Death From Any
Cause (per 100 person-years)*
≥60 45-59 30-44 15-29 <15
Estimated GFR†
*Age-standardized rates
Go et al. N Engl J Med. 2004;351:1296-1305.
40
35
30
25
20
15
10
5
0
Cardiovascular Events Rate
(per 100 person-years)*
≥60 45-59 30-44 15-29 <15
Estimated GFR†
N= 1,120,295
CVD Risk Factors in CKD
Traditional Risk Factors CKD-related Risk Factors
• Hypertension
• Diabetes mellitus
• Elevated LDL cholesterol
• Decreased HDL cholesterol
• Family history of CVD
• Physical inactivity
• Tobacco use
• Anemia
• Malnutrition
• Inflammation
• Thrombogenic factors
• Abnormal calcium and
phosphorus metabolism
• Proteinuria
National Kidney Foundation. Am J Kidney Dis. 2002;39:S1-S266.
Study or Heart and Renal Protection
(SHARP) Trial
• 9,400 Pts ( age 61yo, 63%M, 13% smokers, 23% DM )
• 1/3 on Dialysis + 2/3 CKD ( creatinine > 1.7 males, >
1.5 females )
• No prior MI or revascularization
• No lipid lowering therapy in run in phase.
• Placebo vs 10/20 Vytorin ( ezetimibe/ simvastatin)
Baigent C et al Lancet 377:2181-2192
2011
Lipid Lowering Therapy in CKD Pts
• New ACC/AHA and KDIGO Guidelines – no specific lipid lowering goals treatment based on risk of coronary events and evidence that therapy will
lower the risk.
• Lipid lowering works in CKD ( but not dialysis ) patients – ( SHARP, 4D ) –
CKD patients with lower lipids have less events and live longer
• Specific Guidelines:
• Measure lipids and LDL, HDL cholesterol in all CKD.
• Adults over 50 yo with CKD likely to benefit from Treatment (statin or
stain + ezetimibe)
• 18-49 Treat with statin if CAD, DM, CVA, 10 yr CAD risk > 10%.
Ann Int Med 160: 339-343, 2014; KDIGO Guidelines Kidney Int 3: Nov 2013
Prevalence of Anemia in CKD Patients
Adapted from McClellan et al Curr Med Res Opin. 2004;20:1501-1510.
CHOIR Outcomes: Mortality and CV Morbidity
# Events
Endpoint
HR (95% CI)
Hb 135
p-value
Hb 113
125
97
1.337 (1.025, 1.743)*
Conclusion: The use
of a target
hemoglobin
level0.0312
of
Secondary
13.5 g/dl (as compared with 11.3 g/dl) was
All-cause death
52
36
1.483 (0.969, 2.268)
0.0674
associated with increased risk and no incremental
MI
18
20
0.915 (0.484, 1.720)
0.78
improvement
in the
quality
of life.
Stroke
12
12
1.010 (0.454, 2.249)
0.9803
Composite Primary
Heart Failure
64
47
1.409 (0.967, 2.054)
0.0727
ESRD
155
134
1.186 (0.941, 1.495)
0.15
Cardiovascular hospitalization
233
197
1.225 (1.0131, 1.448)
0.03
* Time for KM curves to separate: ~ 6-8 months
Singh AK et al N. Engl. J. Med. 2006;355:2085-98
Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin beta (CREATE)
Drueke TB, Locatelli F, Clyne N, et al. NEJM 355: 20:2071-2084,2006
CREATE
Reason for Stopping
Last subject followed 2 years
Duration Enrollment (months)
Unknown
Total Study Duration (months)
48
Mean Duration of In
Observation
(years) with chronic kidney
3
Conclusion:
patients
disease,
Arm 1
13.5
early
complete
correction
of
anemia
does not
Hb Achieved
(g/dL)
Arm 2
11.5
reduce
theEvent
risk
cardiovascular
events6 but does
Composite Primary
Rateof
(% per
year)
1
improve Arm
quality
of life. 58
# Composite Primary Events Observed
Arm 2
HR (95% CI) Composite Primary Endpoint
# ESRD Events Observed
47
0.78 (0.53, 1.14)
Arm 1
127
Arm 2
111
Time to ESRD
p = 0.03
Secondary Endpoints
Improved QOL (p = 0.003) in higher Hb arm, but
clinical significance uncertain;
no difference in other secondarys
Trial Of Darbepoetin in DM and CKD
•
•
•
•
•
•
•
4038 Pts with DM, CKD not on dialysis, Anemia randomized.
Death or CVasc Dis in 632 Darbe vs 602 PBO NS
Death or ESRD in 652 Darbepoetin vs 618 PBO NS
Strokes 101 Darbepoetin vs 53 PBO P<.001
Transfusions 297 Darbepoietin vs 496 PBO p<.001
Less fatigue with Darbepoetin
“For many persons involved in clinical decision making , the risk will
outweigh the potential benefits.”
Pfeffer et al. NEJM 361: 2019-2037, 2009
Role of Inflammation and Hepcidin in Anemia of CKD
Spleen
Inflammation
Liver
Plasma
Fe-Tf
Modified from Zaritsky
et al. ASN 2008
Duodenum
RBC
Bone marrow
Serum Hepcidin (ng/mL)
Serum Hepcidin Levels in CKD
Modified from Zaritsky
et al. ASN 2008
1000
100
10
Controls
CKD 2-4
CKD 5
Management of Anemia in CKD
1.
Rule out other causes of Anemia – bleeding, nutritional
deficiences
2.
Once CKD cause of Anemia is established – Evaluate for iron
deficiency – check Iron SAT and Ferritin , consier supplemental
Fe ( oral or IV ) as needed, and Evaluate Hgb response
3.
If anemia persists consider ESA’s – Do Not Over-treat!!!
Hgb >10 is current goal
CKD and Malnutrition
• Evidence shows malnutrition is prevalent in CKD patients
• Higher prevalence of impaired nutritional status occurs
when GFR is <60 mL/min/1.73 m2
• Malnutrition may occur despite appropriate caloric intake
1. Pupim et al. Semin Nephrol. 2006;26:134-157. 2. National Kidney Foundation.
Am J Kidney Dis. 2002;39(suppl 1):S1-S266.
Metabolic Bone Disease Associated
With CKD
• Osteitis fibrosa cystica secondary
Hyperparathyroidism
• Osteomalacia - Defect in bone mineralization
• Adynamic bone disease - Low or no remodeling
• Mixed bone disease - Features of high and low
bone turnover
Pathway of Chronic Kidney Disease - Mineral and
Bone Disorder (CKD-MBD)
Renal function
FGF23
Phosphate retention
VDR expression
PTH
Altered parathyroid gland function
Hyperplasia Secondary hyperparathyroidism
Renal osteodystrophy
VDR=vitamin D receptor
PTH=parathyroid hormone
Ca2+=calcium ions
PO4 =phosphate
CONSEQUENCES
Fractures Calcification
Morbidity and mortality
1,25 D production
Ca2+
PO4
Hyperphosphatemia
Cardiovascular disease
Hyperphosphatemia Association with
Increased Risk of Death in HD Patients
2.5
2.03
2
1.68
RR of Death*
1.50
1.42
1.5
1.25
1.00
1.00
3-4
4-5
1
1.08
0.5
Block, JASN
2004
0
<3
5-6
6-7
7-8
8-9
Serum phosphorus concentration (mg/dL)
>9
Arterial Media Calcification in CKD
and ESRD
Modified from London GM, Guerin
AP, Marchais SJ, et al . Nephrol Dial
Transplant. 2003;18:1731-1740.
Arterial Medial
Calcification*
Arterial Intimal
Calcification*
• usually observed in…
− older patients with a
clinical history of
atherosclerosis before
starting HD
− those with typical risk
factors associated with
atherosclerotic disease
• usually observed in…
− Younger patients without
conventional atherosclerotic
risk factors
− associated with
− duration of HD
− calcium-phosphate
disorders + oral dose of
calcium prescribed as a
phosphate binder (CaCO3)
Mortality in CKD Pts Treated with PO4
Binders: A Randomized Trial
• 212 Stage 3-4 CKD pts rnadomized , multicenter, nonblinded trial of sevelemer
(107) vs Ca carbonate (105).
• Endpoints : Primary end-point -All cause mortality
: Secondary Endpoint – Dialysis inception ,
and both dialsis and mortality.
• Phosphorus maintained at KDOQI guidelines
• CAC score checked 0,6,12,18,24 months.
Di Iorio B et al. CJASN 7:487-493, 2012.
Survival in patients randomized either to sevelamer
(dotted line) or calcium carbonate (continuous line)
Di Iorio B et al. CJASN 2012;7:487-493
©2012 by American Society of Nephrology
Event-free survival from the composite end point of all-cause mortality
and dialysis inception among patients treated either with sevelamer
(dotted line) or calcium carbonate (continuous line)
Di Iorio B et al. CJASN 2012;7:487-493
©2012 by American Society of Nephrology
FGF23 in CKD Pts
• Levels of PTH and FGF23 increase early in CKD –
before increases in PO4
• FGF23 is a phosphaturic hormone produced by
osteocytes that directly downregulates 1,25 Vit D
production and expression of the 2a and 2c Na+PO4 cotransporters in proximal tubule.
• Higher FGF23 levels correlate with vascular
calcificaion, CKD progression, and mortality
Progressive Vitamin D Deficiency in CKD
Prevalence of 1,25(OH)2D3 and
25(OH)D3 deficiency by GFR
80
Adapted from Levin et al.
Kidney Int. 2007;71:31-38
25(OH)D3 <15 ng/ mL
60
Patients (%)
1,25(OH)2D3 <22 pg/ mL
40
20
0
(n=61)
79–70
(n=117)
GFR = glomerular filtration rate
69–60
(n=230)
59–50
(n=396)
49–40
(n=355)
GFR level (mL/ min)
39–30
(n=358)
29–20
(n=204)
< 20
(n=93)
Complications of CKD
•
•
•
•
Cardiovascular Disease
Anemia
Malnutrition
Calcium – Phosphorus – Vit D and metabolic
and CVasc consequesnces
53

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