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Chronic Kidney Disease and CKD-MBD
Akram Al-Makki, MD, FACP, FASN
Nephrology Department
Chronic Kidney Disease (CKD)
A CKD diagnosis is made when
– Kidney damage is present for ≥3 months, with or
without decreased glomerular filtration rate (GFR),
manifested by either
Pathologic abnormalities, or
Markers of kidney damage, including abnormalities in
blood, urine, or imaging tests
– A GFR level <60 mL/min/1.73m2 persists for
≥3 months, with or without kidney damage
National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease
in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
Staging of CKD
Stage
Description
GFR
mL/min/1.73 m2
1
Kidney damage with normal or
elevated GFR
2
Kidney damage with mildly decreased
GFR
60–89
3
Moderately decreased GFR
30–59
4
Severely decreased GFR
15–29
5
Kidney failure
≥90
<15
or dialysis
National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease
in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
Prevalence of CKD
In 2000, approximately 26 million adults in the US had
chronic kidney disease and most were unaware of
their condition1
Contributors to the growing prevalence2,3:
– Aging population
– Increasing prevalence of diabetes mellitus
– Increasing prevalence of hypertension
1. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. Nov. 7, 2007;298:17.
2. U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease
in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, MD, 2007.
3. National Kidney Foundation. Part 4. Definition and classification of stages of chronic kidney disease.
American Journal of Kidney Diseases. 2002;39(Suppl 1):S46-S75.
US Prevalence:
Breakdown Based on CKD Stage
20
US adults* with CKD
15.5 1
million
15
10
6.5
million
*
5
3.6
million
1
1
0.7
million
1
0.3
million
2
0
CKD Stage 1
* >20 years old
1.
2.
CKD Stage 2
CKD Stage 3
Year 2000 estimates
Coresh J, Selvin E, Stevens LA, et al. JAMA. 2007;298:2038-2047.
Coresh J, et al. Am J Kidney Dis. 2003 Jan;41(1):1-12.
CKD Stage 4
CKD Stage 5
1995-1999 estimates
Risk Factors for CKD
Diabetes (type 1 and type 2)
Hypertension
Advancing age
Proteinuria
Family history of kidney disease
Environmental nephrotoxins
Race
Healthy People 2010; Nelson NA et al, Am J Nephrol, 1999; US Renal Data System. 2001 Atlas
of ESRD in the United States.
Prevalence of CKD Contributors*
Urologic disease
2.8%
Cystic kidney disease
4.6%
Other known cause
10.2%
Unknown cause
3.9%
Missing cause
1.2%
Glomerulonephritis
16.2%
Diabetes
36.9%
Hypertension
24.2%
*Based on 2005 data
United States Renal Data System 2007 Atlas. Bethesda, MD: National Institutes of Health National,
National Institute of Diabetes & Digestive & Kidney Diseases, 2007.
Consequences of CKD
Hospitalization
CV Events
144.61
16
36.6
14
35
120
86.75
100
80
45.26
60
40
17.22
13.54
20
0
Rate of cardiovascular event*
Rate of Hospitalization*
140
40
30
25
21.8
20
15
11.29
10
5
2.11
3.65
≥60 45-59 30-44 15-29 <15
eGFR (mL/min/1.73 m2)
11.36
12
10
8
4.76
6
4
2
0.76
1.08
0
0
0
Rate of death from any cause*
160
Death
From Any Cause14.14
≥60 45-59 30-44 15-29 <15
eGFR (mL/min/1.73 m2)
eGFR = estimated glomerular filtration rate
*Age-standardized rates per 100 person-years
N=1,120,295 ambulatory adults
Adapted from Go AS et al. N Engl J Med. 2004;351:1296-1305.
≥60 45-59 30-44 15-29 <15
eGFR (mL/min/1.73 m2)
ABC of CKD management
Appropriate screen and diagnose early CKD.
Be aware of complications and comorbidities:
Anemia
Bone and mineral abnormalities
Cardiovascular and renal.
Consult nephrologist in a timely manner
Definition of CKD-MBD And Renal
Osteodystrophy
Definition of CKD-MBD
– A systemic disorder of mineral and bone metabolism due to CKD
manifested by either one or the combination of the following:
Abnormalities of calcium, Phosphorus, PTH, or Vitamin D
metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth,
or strength.
Vascular or other soft-tissue calcification
Definition of Renal Osteodystrophy
– Renal osteodystrophy is an alteration of bone morphology in
patiens with CKD.
– It is one measure of the skeletal Component of the systemic
disorder of CKD-MBD that is quantifiable by histomorphometry of
bone biopsy.
–
Uhlig et al, AJKD Vol 55, No 5, May 2010.
Consequences of Phosphorus
Dysregulation
CKD-MBD: Dysregulation and Clinical Manifestations
of an Increasingly Compromised System
Alterations in Mineral Metabolism Occur in
Early Stages of CKD
An increasingly compromised system leads
to disturbances in mineral metabolism
1200
*
1000
†
800
600
400
200
n=
CKD1 CKD2 CKD3 CKD4 CKD5
14
75
180
43
7
CKD Stage
*P<0.05 CKD2 vs CKD3
†P<0.05 CKD3 vs CKD4
250
50
40
Urine calcium
(mg/24 hours)
1,25-dihydroxyvitamin D
(pg/mL)
Urine phosphate (mg/24 hours)
1400
Decline in urine calcium excretion1
Progressive depletion of 1,25(OH)2D31
Steady decline in urine phosphate excretion1
*
†
30
‡
20
10
200
*
150
†
100
50
0
0
n=
CKD Stage
(n=319)
n=
CKD1 CKD2 CKD3 CKD4 CKD5
15
87
221
156
43
CKD Stage
(n=522)
*P<0.05 CKD2 vs CKD3
†P<0.05 CKD3 vs CKD4
‡P<0.05 CKD4 vs CKD5
CKD1 CKD2 CKD3 CKD4 CKD5
14
74
179
43
7
*P<0.05 CKD2 vs CKD3
†P<0.05 CKD3 vs CKD4
Shading=statistical significance between levels.
Urine phosphate excretion decreases and leads to phosphate retention
1,25D production decreases, leading to 1,25D depletion and contributing to elevated PTH
Urine calcium excretion decreases, impacting calcium balance
Adapted from Craver L, et al. Nephrol Dial Transplantation. 2007;22:1171-1176.
(n=317)
Serum Phosphorus Levels and Mortality in
CKD Non-Dialysis Patients
Mortality rates by phosphate category
Adjusted hazard ratio (HR)
2.00
1.90
1.83
1.80
72% of patients
1.60
1.40
1.32
1.34
3.5-3.99
4.0-4.49
1.15
1.20
1.00
1.00
2.5-2.99
3.0-3.49
4.5-4.99
Phosphorus (mg/dL)
>5.0
(n=3,289)
Mortality risk increases as phosphorus levels rise, even within normal range
Each 0.5 mg/dL increase in serum phosphorus was associated with increased mortality
Statistically significant increases in mortality were noted when phosphorus levels reached 3.5 mg/dL
or above
Adapted from Kestenbaum B, Sampson JN, Rudser KD, et al. J Am Soc Nephrol. 2005;16:520-528.
Elevated Serum Phosphorus
and Mortality Risk in Dialysis Patients
Relative risk of death*
2.2
N = 40,538
2.0
1.8
1.6
Referent
Range
1.4
1.2
1.0
0.08
0.00
<3
3-4
4-5
5-6
8-9
6-7
7-8
Serum phosphorous concentration (mg/dL)
*Multivariable adjusted
With permission from Block GA, Klassen PS, Lazarus JM, et al. J Am Soc Nephrol. 2004;15:2208-2218.
>9
KDIGO Focus: Normal Treatment Target
Ranges for Phosphorous and Calcium
Stage
3
4-5
5D
Target PO41,2
Target Ca1,2
KDIGO: Maintain Normal
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDOQI: Normal for Lab
KDIGO: Maintain Normal
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDOQI: Normal for Lab
KDIGO: Towards Normal
KDIGO: Maintain Normal
KDOQI: 3.5-5.5 mg/dL
KDOQI: 8.4-9.5 mg/dL
Emphasis on individual levels of serum calcium and phosphorus
rather than Ca x P product
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline
for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)
Kidney Int. 2009;76(suppl 113):S1-S130.
2. National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney
disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
Survival according to phosphate levels relative to KDOQI
guidelines.
Eddington H et al. CJASN 2010;5:2251-2257
©2010 by American Society of Nephrology
Common phosphate binders
Aluminum hydroxide
Calcium carbonate
Calcium acetate
Lanthanum carbonate
Sevelamer
Summary Slide
Despite early phosphate retention, many patients have
serum phosphorus levels within normal range
Mortality risk increases as phosphorus levels rise,
even when levels remain within normal range
Increased serum phosphorus levels are associated
with CV events and mortality
Importance of Vitamin D
in CKD-MBD
Hepatic and Renal Metabolism
of Vitamin D2 and D3
Normal metabolism of vitamin D: production of active hormone1,2
Sunlight
Dietary
sources
Vitamin D
(parent compound)
Liver
Hydroxylation of the 25 carbon
25(OH)D or 25D
–Inactive metabolite–
Kidney
1 α hydroxylation
In a CKD patient, the ability to
convert 25D to 1,25D is lost as
kidney function declines. This
would require treatment with
vitamin D hormone (1,25D).
1,25(OH)2D or 1,25D
–Active hormone–
Released into plasma and carried to target organs
where it binds to vitamin D receptors
1. Drueke TB, Moe SM, Langman CB. Treatment approaches in CKD. In: Olgaard K, ed. Clinical guide to bone and mineral metabolism in CKD. New York,
NY: National Kidney Foundation;2006:119-127.
2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guidelines for the diagnose, evaluation, prevention,
and treatment of chronic kidney disease-mineral and bone disorder (CKD-MED). Kidney Int. 2009; 76(suppl 113):S1-S130.
Impact of CKD on Vitamin D
Normal
1,25(OH)2D
25(OH)D
1-hydroxylase
Decreasing Renal Mass
CKD
25(OH)D
1,25(OH)2D
1-hydroxylase
In a CKD patient, the ability to convert 25D to 1,25D
is lost as kidney function declines.
1. Levin A, et al. Kidney Int. 2007;71:31-38.
2. Holick MF. N Engl J Med. 2007;357:266-281.
Physiologic Effects of Vitamin D
Throughout the Body
25(OH)D
Major Circulating Metabolite
Colon
Prostate
Kidney
Breast, etc.
1,25(OH)2D
Biologically Active
Calcium and
Phosphorus
Homeostasis
Bone Health
Growth & Regulation
Antiproliferation
Prodifferentiation
Apoptotic
Anti-angiogenic
Prostate,
Colon,
Breast Cancers etc.
Immunomodulatory
Effects
Multiple Sclerosis
Type 1 Diabetes
(via ß-islet cell
destruction)
Psoriasis
Rheumatoid Arthritis
Inflammatory Bowel
Disease
Periodontal Disease
Adapted from: Holick MF. Mayo Clin Proc. 2006;81:353-373.
Cardiovascular
Effects
Renin-Angiotensin
Regulation
Decreased Risk for:
Hypertension
Type II Diabetes
(via stimulation of pancreatic
insulin production)
Heart Failure
Neuromuscular
Effects
Muscle Mass
Muscle Strength
Better Balance
25(OH)D vs 1,25(OH)2D Deficiency
Patients with CKD have a high prevalence of both
25(OH)D and 1,25(OH)2D deficiency1
Nutritional vitamin D supplements can replete
diminished 25(OH)D substrate in stages 1-5 CKD2
– A single monthly 50,000 IU ergocalciferol capsule safely
repletes almost all vitamin D-deficient dialysis patients
within 6 months3
The ability to convert 25(OH)D to its active form
(1,25(OH)2D) in the kidney is lost as renal function
declines4
Active vitamin D therapy is given to correct 1,25(OH)2D
deficiency in stages 3 to 5 CKD2
1.
2.
3.
4.
Wolf M, et al. Kidney Int. 2007;72:1004-1013.
Jones G. Semin Dial. 2007;20:316-324.
Saab G, et al. Nephron Clin Pract. 2007;105:c132-138.
Levin A, et al. Kidney Int. 2007;71:31-38.
Progressive Vitamin D Deficiency in CKD
Prevalence of 1,25(OH)2D3 and
25(OH)D3 deficiency by GFR
100
80
25 (OH)D3 <15 ng/mL
Patients (%)
1,25 (OH)2D3 <22 pg/mL
60
40
20
0
≥80
(n=61)
79-70
(n=117)
69-60
(n=230)
59-50
(n=396)
49-40
(n=355)
GFR level (mL/min)
Adapted from Levin A, et al. Kidney Int . 2007;71:31-38.
39-30
(n=358)
29-20
(n=204)
<20
(n=93)
1,25(OH)2D3 Levels and
Mortality in Dialysis Patients
A
B
10
10
8
Active vitamin D therapy
No active vitamin D therapy
6
*
Odds ratio of CV mortality
Odds ratio of all-cause mortality
Active vitamin D therapy
*
4
2
R
0
8
No active vitamin D therapy
*
6
4
2
R
0
<5
6–13
>13
1,25-dihydroxyvitamin D (pg/mL)
<5
6–13
>13
1,25-dihydroxyvitamin D (pg/mL)
1,25-dihydroxyvitamin D levels and 90-day all-cause (A) and CV mortality (B) in hemodialysis
patients according to whether patients received active vitamin D therapy
*P<0.05 for the comparison of the individual vitamin D level―vitamin D treatment groups with the corresponding referent groups.
R=subjects treated with active vitamin D and 1,25-dihydroxyvitamin D levels ≥13 pg/mL.
With permission from Wolf M, et al. Kidney Int. 2007;72:1004-1013.
Summary
Patients with CKD have a high prevalence of both
25(OH)D and 1,25(OH)2D deficiency
As kidney function declines, patients lose the ability
to convert 25(OH)D to 1,25(OH)D
Patients with lower levels of 1,25(OH)2D had a higher
risk of mortality
Chronic Kidney Disease
and
Secondary Hyperparathyroidism (SHPT)
CKD-MBD: Dysregulation and Clinical
Manifestations of an Increasingly Compromised
System
Compensatory Mechanism of PTH During
Disturbances in Mineral Metabolism
Median values of 1,25-dihydroxyvitamin D, 25 Hydroxyvitamin D,
and intact PTH by GFR levels
50
150
1,25-dihydroxyvitamin D (pg/mL)
25 Hydroxyvitamin D (ng/mL)
Intact PTH (pg/mL)
40
35
100
30
25
20
50
15
10
5
0
0
>80
79-70 69-60 59-50 49-40 39-30 29-20
GFR level (mL/min)
With permission from Levin A, et al. Kidney Int. 2007;71:31-38.
<20
Intact PTH (pg/mL)
1.25-dihydroxyvitamin D (pg/mL)
25 Hydroxyvitamin D (ng/mL)
45
Rate of cardiovascular disease, %
Elevated PTH Levels and Cardiovascular Disease
in Patients with CKD Stages 3 and 4
50
49
P<0.001
45
41
40
37
35
30
<35
35-70
Parathyroid hormone level, pg/mL
With permission from Bhuriya R, et al. Am J Kidney Dis. 2009;53 (4 suppl 4):S3-S10.
>70
Elevated PTH and All-Cause Mortality
CKD Stages 3 to 5 (non-dialysis patients)
N = 515
2
CKD STAGE 3
Log relative hazard
Log relative hazard
2
1
0
-1
CKD STAGE 4–5
1
0
-1
30
55
80
105
130
155
180
PTH (pg/mL-1)
50
100
150
200
250
PTH (pg/mL-1)
Estimated log relative hazard
Estimated log relative hazard
95% pointwise CI
95% pointwise CI
With permission from Kovesdy CP, et al. Kidney Int. 2008;73:1296-1302.
380
KDIGO Focus: Consider Normal
Limit for PTH
Stage
3
4
5
5D
Treatment Target Range
KDIGO: Upper Limit of Normal* (2C)
KDOQI: 35-70 pg/mL
KDIGO: Upper Limit of Normal* (2C)
KDOQI: 70-110 pg/mL
KDIGO: Upper Limit of Normal* (2C)
KDOQI: 150-300 pg/mL
KDIGO: 2 to 9 times Upper Limit of Normal (2C)
KDOQI: 150-300 pg/mL
*In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains
persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with
calcitriol or vitamin D analogs is suggested. (2C)
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline
for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)
Kidney Int. 2009;76(suppl 113):S1-S130.
2. Adapted from National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in
chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
Treatment of Secondary Hyperparathyroidism
Intact PTH most the earliest and most sensitive marker
for abnormal bone metabolism
– If PTH above recommended range, initiate replacement
therapy with active 1,25-OH vitamin D substitute or CaR
agonist
Calcitriol (Rocaltrol)
Doxercalciferol (Hectorol)
Paricalcitol (Zemplar)
Cinacalcet (Sensipar) Is not a vitamin D but CaR agonist
– Monitor PTH, Calcium, and Phosphorous monthly while
adjusting therapy
Summary
Elevated PTH levels are a compensatory mechanism
for 1,25D depletion — both are prominent and
progressive across the CKD continuum
Elevated PTH levels and 1,25D depletion have each
been independently associated with higher mortality
Future Research:
the bone-kidney endocrine axis
FGF 23 (Fibroblast
Growth Factor 23)
Klotho
Hu MC, et al. J Am Soc Nephrol. 2011 Jan;22(1):124-36.
Thank You
Questions?
Akram Al-Makki, MD, FACP, FASN
IU Health
Nephrology Department
Lafayette, Indiana, USA
(765)838-6365