4. Evolutionof CKD-MBD
Bone changes in renal failure patients, mainly
hyperparathyroidism, begin early in the natural history of
the disease.
About 50% of the patients have histological evidences of
bone disease when GFR is halved.
Almost all patients with CRF on regular heamodialysis
has evidance of ROD
5. Renal Bone Disease
This disorder is often subclinical, and its
presence is suggested from abnormal laboratory
tests such as;
hyperphosphatemia, high circulatory levels of
PTH, and low levels of 1,25(OH)2D3.
In other patients, however, renal osteodystrophy is
a cause of great morbidity.
6. Population Attributable Risk of All
Cause Mortality in CKD 5D
• 17.5% Mineral metabolism abnormalities
(Phosphorus > 5.0 mg/dl, Calcium > 10 %
mg/dl, intact PTH > 600 pg/ml)
• 11.3% Anemia (hgb < 11 g/dl)
• 5.1% Inefficient Dialysis (URR < 65%)
Corollary: We should be able to significantly improve
mortality of CKD patients by improving control of
mineral metabolism
•Block et al JASN 2004Block et al JASN 2004
7. Akmal M et al. Kidney Int. 1995;47:158-163.
Drüeke TB. Nephrol Dial Transplant. 1996;11(suppl 3):37-42.
Hsu CH. Am J Kidney Dis. 1997;29:641-649. .
Soft-Tissue Calcification
Type of Calcification Morbid Effects
Myocardiam and valves Atrioventricular block, cardiac failure,
pulmonary hypertension, arrhythmia, left and
right ventricular hypertrophy, sudden death
Peripheral arteries Bone and soft tissue necrosis, amputation
Skin arterioles Calcific uremic arteriolopathy (calciphylaxis)
Pulmonary Cough, dyspnea, restrictive defects,
decreased diffusion, hypoxia
8. *P=0.01 vs Ca × P product 43-52 mg2
/dL2
.
Block GA et al. Am J Kidney Dis. 1998;31:607-617.
The Importance of Ca × P Product:
A Key Determinant of Mortality Risk
1.06
1.00
1.08
1.13
1.34*
1.00
1.25
1.50
1.1-3.4 40-45 50-55 56-65 66-780
RelativeMortalityRisk(RR)
n=2669
Ca × P Product Quintile (mg2
/L2
)
9. *P=0.03 vs phosphorus 4.6-5.5 mg/dL.
†
P<0.0001 vs phosphorus 4.6-5.5 mg/dL.
Block GA et al. Am J Kidney Dis. 1998;31:607-617.
Elevated Serum Phosphorus Increases
Mortality Risk
1.00
1.25
1.50
0.40-1.45 1.46-1.80 1.81-2.10 2.11-2.55 2.56-5.50
RelativeMortalityRisk(RR)
Serum Phosphorus Quintile (mmol/L)
1.00 1.00
1.02
1.18*
1.39†N=6407
10. Coronary-artery calcificationsCoronary-artery calcifications
increase with years of dialysisincrease with years of dialysis
1.0
0
Years of dialysis
Proportionwith
calcification
0.8
0.6
0.4
0.2
0.0
4 8 12 16 20 24
Patients with coronary-
artery calcification (n = 39)
Estimates by logistic
regression analysis
Goodman WG et al. N Engl J Med 2000;342:1478–83.
11. Definition, Evaluation and Classification
of Renal Osteodystrophy:
ApositionstatementfromKidneyDisease
ImprovingGlobalOutcomes (KDIGO)
April, 2006
13. Definition of CKD-MBD
A systemic disorder of mineral and bone
metabolism due to CKD manifested by
either one or a 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
• Moe et al Kidney International June 2006
14. Standardization of Terms
• The term renal osteodystrophy (ROD) should
be used exclusively to define the bone
pathology associated with CKD.
• The clinical, biochemical, and imaging
abnormalities should be defined more broadly
as a clinical entity or syndrome called Chronic
Kidney Disease-Mineral and Bone Disorder
(CKD-MBD).
15. A Framework for Classification of CKD-MBD
Type*
Laboratory
Abnormalities
Bone Disease
Calcification of
Vascular or Other
Soft Tissue
L + - -
LB + + -
LC + - +
LBC + + +
* L = laboratory abnormalities (of calcium, phosphorus, PTH,
alkaline phosphatase or vitamin D metabolism); B = bone disease
(abnormalities in bone turnover, mineralization, volume, linear
growth, or strength); C = calcification of vascular or other soft
tissue.
•KidneyInternationalJune2006
16. KI (2007) 71, 31-38. Levin et. al.
Prevalence of Abnormal Mineral Metabolism in CKD
•>4.6
17.
18.
19.
20. The factors involved in the pathogenesis of secondary hyperparathyroidism.
Kevin J. Martin, and Esther A. González JASN 2007;18:875-885
25. Consequences of HyperphosphatemiaConsequences of Hyperphosphatemia
P
Mortality
Risk of
Calcification
Parathyroid
Cell Growth
PTH Secretion
PTH Resistance
Ca++
Calcitriol Resistance
Calcitriol
26. VDR = vitamin D receptor; CaR = Ca-Sensing receptor.
Adapted from Murayama A et al. Endocrinology. 1999;140:2224-2231. Satomura K et al. Kidney Int. 1988;34:712–716
CKD ProgressionCKD Progression
Normal Diffuse Early
nodular
Nodular
hyperplasia
Single nodule
Monoclonal nodules
Decline in
receptor density
of VDR, CaR
Cells with lower density of VDR
proliferate vigorously to form
several monoclonal nodules
Progression of PTH Gland Hyperplasia
in CKD
27.
28. Increased FGF23 develops earlier than
increased phosphate or PTH
Isakova T et al., Kidney Int 2011
29.
30. Pathogenesis of Different Types of ROD
There are five components in the pathogenesis of renal
osteodystrophy:
1- Secondary hyperparathyroidism (HTO) due to:
-Phosphate retention. - An abnormal set point for calcium.
- Altered metabolism of vit.D. - Skeletal resistance to PTH.
- Impaired degradation of PTH.
- Altered feed back regulation of PTH by calcium.
2- Adynamic bone disease: (Defective meniralization of bone (LTO)
- Altered vitamin D metabolism. - Acidosis.
- Altered synthesis and maturation of collagen.
- Retention of aluminum. - Retention of iron.
- Skeletal accumulation of magnesium, fluoride,pyrophosphate, and
oxalately stranchium..
3- MUD.
4 - Osteosclerosis.
5- -Osteoporosis .
31.
32. Clinical Manifestations of Renal
Osteodystrophy
The symptoms of renal osteodystrophy usually
appear when renal failure is advanced and
thus appear in dialysis patients, except in some
etiologies of renal failure when there is
prolonged course of disease before the need of
dialysis, as in
– analgesic induced renal disease, or
– when the patient present late in-spite of advanced
renal failure
– Renal transplant patients.
34. Bone Pains
Causes are: osteitis fibrosa cystica,
osteomalacia, osteoarthritis, β2-
microglobulin amyloidosis.
Fibromyalgia induces more diffuse
muscle and soft tissue pain.
Radiography may reveal
pseudofractures of the pelvis, femurs,
metatarsals, or lateral margins of the
scapulae.
Therapy of chronic pain has to be
adapted to the individual patient with
special regard to the presence of a high
or low bone turnover osteopathy.
36. UREMIC MYOPATHY
MUSCLE WEEKNESS
The development of a myopathy in CKD causes
proximal muscle weakness and wasting, predominantly
in the muscles of the lower limbs.
Uremic myopathy typically develops with glomerular
filtration rates of <25 ml/min, and has been associated
with fatigability and reduced exercise capacity.
Electromyography and creatine kinase levels are
generally normal, and the diagnosis is, therefore, made
largely on clinical grounds.
Campistol,. Kidney Int. 62, 1901-1913 (2002).
38. Bone Fractures
Worldwide, one in three women and one in five
men over the age of 50 will have a fracture
This is very different from what is known in men
and women with chronic kidney disease (CKD).
Data from a large cohort of patients of (NHANES
III) in USA demonstrate that compared with those
with (eGFR) of greater than or equal to 60 ml/min,
those with an eGFR less than 60 ml/min had a
twofold increased risk of hip fractures.
39. Bone Fractures
On the other hand, the prevalence
of vertebral fractures in CKD
patients is similar to that in the
general population.
– Fusaro et al., Calcif Tissue Int 2013
There are data indicating that impaired
neuromuscular function, probably
resulting in increased incidence
of falls, is assciated with fractures in
patients with CKD.
– Barreto, Kidney Int 2008
40. Yearly incidence of hip fracture
Reference Country HD General population with simil
USA 1% 0.22%
2012 DOPPS 2 countries 0.89% 0.47–1.57% 0.07–0.22%*
↵*References available in [2].
Michel Jadoul, NDT, 2012
41. Pseudogout
Calcium pyrophosphate dihydrate deposition disease is a crystal
arthritis, crystal deposition in the articular cartilage or synovium.
In chronic kidney disease patients, the major causes of crystal
arthritis are calcium oxalate crystals and basic calcium
phosphate crystals.
Although considered uncommon, pseudogout may cause acute
arthritis in chronic renal failure more often than previously
suspected.
Joint aspiration and identification of CPPD crystals with
compensated polarized light microscopy will establish the diagnosis of
pseudogout.
– Michael et al., Arch Intern Med .1979.
42. Tendon Rupture
• Spontaneous tendon
rupture is a rare complication
which severely disables
patient's activity.
• It generally occurs in
association with different
chronic metabolic disorders,
chronic renal failure, gout and
obesity.
• Especially rare are
simultaneous, spontaneous,
(the quadriceps femoris,
Achilles and patellar tendon).
• Nikolina KIDNEY AND BLOOD PRESSURE RESEARCH ·
2009
43. Pruritus
A terrible symptom that may be related to
PTH
Persistent uremic pruritus of patients with
secondary hyperparathyroidism decreased
after parathyroidectomy
Intradermal application of parathormone did
not cause a significant skin reaction in
humans.
Itching can occur in patients with accepted
PTH serum level.
Kleeman CR et al. Trans Assoc Am Physicians. 1968;81:203–212.
Massry SG et al. N Engl J Med. 1968;279(13):697–700.
Ståhle-Bäckdahl M et al. J Intern Med. 1989;225(6):411–415.
7
46. Extra-skeletal manifestations
It is a systemic disorder affecting soft tissues, particularly
vessels, heart valves and skin.
Coronary artery and vascular calcifications occur
frequently in CKD 5 (and increase each year on dialysis)
CVD accounts for around half
of all deaths of dialysis patients.
47. “If we X-Ray most of our patients, they’ve got “tram tracks” – we hardly
need an angiogram!”
48. Types of calcification
1. Focal calcification associated
with lipid laden atherosclerotic plaques
• Increases fragility and risk of plaque rupture
1. Diffuse calcification
• not in atherosclerotic plaques and occurs in media of vessels
• Called “Monckeberg’s sclerosis”
• Increases blood vessel stiffness and reduces vascular
compliance
Results in widened pulse pressure
Increased afterload
LVH
• Contributing to CVD morbidity
49.
50.
51.
52. Extra-skeletal manifestations
• Important to recognize
disordered bone and mineral
metabolism is a systemic
disorder affecting soft tissues,
particularly vessels, heart
valves and skin.
• CVD accounts for around half
of all deaths of dialysis
patients.
• Coronary artery and vascular
calcifications occur frequently
in CKD 5 (and increase each
year on dialysis)
53. Calciphylaxis or calcemic uremic arteriolopathy (CUA)
–Seen primarily in CKD 5
–Occurs in 1-4% of dialysis
patients
–Presents with extensive
calcification of the skin,
muscles and SC tissues.
Extensive medial calcification of
small arteries, arterioles, capillaries
and venules.
Clinically they may have skin
nodules, skin firmness, eschars,
livedo reticularis and painful
hyperaesthesia of the skin.
May lead to non healing ulcers and
gangrene
Brandenburg et al., Journal of nephrology 2011
54. Calciphylaxis
• A, Confluent calf plaques (borders
shown with arrows).
Parts of the skin are erythematous,
which is easily confused with simple
cellulitis.
• B, Gross ulceration in the same patient
3 months later. The black escharhas
been surgically débrided.
• C, Calciphylactic plaques, a few of
which are beginning to ulcerate.
• (Photographs courtesy of Dr. Adrian Fine. Up To
Date)
55. Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of the eschar.
56. Amyloidosis
Pts on dialysis for 7- 10 years can develop osteoarticular amyloid
deposits.
May present with carpel tunnel syndrome and arthritis
58. Management of ROD
• Detection of the type of ROD
• Define goals of therapy
• Follow the guidelines (KDOQI)
• Prevent ROD in predialysis patient
(CKD III, IV)
59. Management of ROD
• Diagnosis of ROD
• Biochemical Markers
• Radiology
• Histology and Pathology
61. X-Ray studies:
Traditional X-ray cannot help in defining the existent
histologic pattern of osteodystrophy and the rate of bone
turnover.
Bone densitometric studies:
It is probably safe to state that densitometric techniques
in renal disease are mainly useful in the follow up control
of renal bone diseases.
62. Radiographic signs in hand skeletons of haemodialysis
patients with severe secondary hyperparathyroidism
•)b) periostal new bone formation
)periostal neostosis) )arrow);
• )c) subperiostal resorption zones )arrow).
• Both )b) and )c) show cortical thinning, cortical striation, and fluffy trabecular
structure.
63. Resorptive defects of diploë (pepper-pot aspect) in the skull of a
haemodialysis patient with severe hyperparathyroidism.
64. Increased density of ground plates of vertebrae contrasting with
radiolucency of the central vertebral slices (rugger jersey spine) in a
haemodialysis patient with severe hyperparathyroidism. Note the severe
aortic calcification.
65. Bone Biopsy and Histomorphometry
Bone biopsy can be taken either by needle
and is satisfactory for clinical purposes, or by
using electrical drill.
Bone dynamic studies:
The administration of tetracycline, that
localizes at the mineralizing surface and
whose fluorescence can be detected by
ultraviolet microscopy, is able to provide
dynamic information’s about bone turnover.
66.
67. Therapeutic Modalities of Renal
Osteodystrophy:
•I-Control of calcium:
•Calcium supplementation.
•Vitamin D analogues.
•Choice of dialysate calcium
concentration.
•II-Control of phosphorus:
•Dietary phosphate restriction.
•Removal of phosphorus by
dialysis
•Phosphate-binding.
68. •III-Control of Parathyroid glands:
•Control of phosphorus
•Control of calcium
•Vit D Analogues
•Calcimimetics
•Parathyroidectomy.
•V-Removal of aluminum: disferrioxamine.
69. The new vitamin D analogues
Paricalcitol (Zemplar), or 19-nor-1alpha,25-
dihydroxyvitamin D2. .
• It binds specifically with vitamin D receptors on the
parathyroid gland, where it suppress the secretion of
PTH by about 60%,,and at the same time it does not
increase the intestinal absorption of calcium or
phosphorus.
Paricalcitol results in 10 times less elevation of serum
calcium than calcitriol It is 10 times less effective in
mobilising calcium and phosphorus from bone side
effect includes: fever, chills, feeling unwell.
Block GA. Clin Nephrol. 2000;54:318-324.
70. The new vitamin D analogues
Doxercalciferol (Hectorol), is a synthetic vitamin D2
undergoes metabolic activation in vivo to form 1a,25-
dihydroxyvitamin D2 (1a,25-(OH)2D2)
• Doxercalciferol is absorbed from the gastrointestinal
tract and activated by CYP 27 in the liver to form 1 ,25-
(OH)2D2 (major metabolite) and 1 ,24-
dihydroxyvitamin D2 (minor metabolite)..
• Precautions in:
• liver disease
• Pregnancy
• breast-feeding
Block GA. Clin Nephrol. 2000;54:318-324.
71. Summary
Calcium
In hypocalcemic patients
Calcium supplement
Calcium
Calcium containing PO
binders
In hyercalcemic patients
Calcium restrictions
Avoid Calcium Containing
PO binders
Dialysate calcium
Phosphorus
• Dietary Phosphate
Restriction
• Dialysis
• Phosphate Binding
Agents
• Ca containing
• Non Ca
Containing
• Metal based
• Ferric citrate
Parathyroid Gland
• Phosphorus
• Calcium
• Vitamin D analogues
• Parathyroidectomy
• Local Parathyroid gland
injection
• Alcohol
• Vitamin D
• Calcimimetics
72. Recommendations
• Aim for long-term serum phosphorus 3.0-
5.5 mg/dL
• Aim for long-term Ca × P product of <55
mg2
/dL2
• Monitor PTH level.
• Monitor calcium intake.
• Avoid agents that accumulate and cause
metal toxicity (aluminum)
• Avoid unneeded use of Vit. D analogues
Block GA. Clin Nephrol. 2000;54:318-324.
Llach F. Am J Kidney Dis. 1998;32:514-518.
Editor's Notes
Key Point: Soft-tissue calcification can affect many tissues, including the heart, peripheral blood vessels, and lungs. Deposition of calcium in these tissues can result in a wide range of adverse events.
Depending on the location and severity of calcification, patients may experience a range of morbid effects, some of which can be severe and potentially life threatening. Myocardial and valvular calcification have the potential to result in atrioventricular block, cardiac failure, pulmonary hypertension, arrhythmia, and left and right ventricular hypertrophy. Calcification of peripheral arteries may result in bone and soft tissue necrosis and requirement for amputation. Calcification of skin arterioles may result in calcific uremic arteriolopathy. Pulmonary deposition of calcium may lead to cough, dyspnea, restrictive defects, decreased diffusion, and hypoxia. [Drüeke, 1996, 37A,B, 38A, 40A; Rostand, 1988, 651A-C; Akmal, 1995, 158A,B, 160A; Hsu, 1997, 645A; Janigan, 2000, 588A]
Akmal M, Barndt RR, Ansari AN, Mohler JG, Massry SG. Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int. 1995;47:158-163.
Drüeke TB. A clinical approach to the uraemic patient with extraskeletal calcifications. Nephrol Dial Transplant. 1996;11(suppl 3):37-42.
Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis. 1997;29:641-649.
Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified subcutaneous arterioles with infarcts of the subcutis and skin (&quot;calciphylaxis&quot;) in chronic renal failure. Am J Kidney Dis. 2000;35:588-597.
Rostand SG, Sanders C, Kirk KA, Rutsky EA, Fraser RG. Myocardial calcification and cardiac dysfunction in chronic renal failure. Am J Med. 1988;85:651-657.
Key Point: Elevated Ca P product is associated with increased mortality risk in stage 5 CKD patients.
Block and colleagues demonstrated that an elevated calcium-phosphorus product (Ca P) was associated with increased risk of death in patients included in Case Mix Adequacy Study (CMAS) and Dialysis Morbidity and Mortality Study (DMMS) Wave 1. Serum phosphorus analysis was based on combined data from CMAS and DMMS (N=6407), while the Ca P analysis was derived from DMMS (n=2669) alone (CMAS did not include Ca P data). Patients with Ca P product &gt;5.8 mmol2/L2 had a 34% higher risk of death relative to patients with a Ca P product in the reference range (3.5-4.2 mmol2/L2, P&lt;0.01). This Ca P reference range was chosen based on published findings that cited it as desirable in the stage 5 chronic kidney disease (CKD) population. [Block, 1998, 610A, 612B, 613A,B]
Block GA, Hulbert-Shearon TE, Levin NE, Port FK. Association of serum phosphorus and calcium phosphorus product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31:607-617.
Key Point: Risk for mortality in dialysis patients rises with increased serum phosphorus levels.
The clinical significance of poor phosphorus management is well illustrated by results reported by Block and colleagues. [Block, 1998, 607A,B] Retrospective analysis of data from 6407 hemodialysis patients revealed that elevated serum phosphorus levels are associated with increased risk for death. Relative mortality risk by quintiles remained flat when serum phosphorus was &lt;2.1 mmol/L and increased markedly when phosphorus was above this level. Using 2.1, 1.9, and 1.6 mmol/L as cut-off levels for poor phosphorus control, it was shown that patients with phosphorus levels &gt;2.1 mmol/L had a relative mortality risk of 1.27 (P&lt;0.001), patients with phosphorus levels &gt;1.9 mmol/L had a relative mortality risk of 1.19 (P=NS), and patients with phosphorus levels &gt;1.6 mmol/L had a relative mortality risk of 1.11 (P=NS). After adjusting for age at stage 5 chronic kidney disease (CKD) onset, race, sex, diabetes, acquired immunodeficiency syndrome (AIDS), neoplasm, and active smoking, patients with phosphorus levels &gt;2.1 mmol/L had a 27% higher risk of death than patients with phosphorus levels in the range of 0.8 mmol/L to 2.1 mmol/L (P&lt;0.001); 39% of patients had a serum phosphorus level greater than 2.1 mmol/L. [Block, 1998, 607A,B, 610A,B, 611B-E]
Block GA, Hulbert-Shearon TE, Levin NE, Port FK. Association of serum phosphorus and calcium phosphorus product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31:607-617.
The factors involved in the pathogenesis of secondary hyperparathyroidism.
Kaplan-Meier survival curves were generated and a log-rank test was used to detect treatment group differences in time to death.
Baseline CAC score was a significant predictor of mortality in hemodialysis patients.
Figure shows multivariable adjusted survival by baseline CAC score; variables included age, race, gender, and diabetes. The P-value represents statistical significance across 3 stratifications based on baseline CAC:
CAC = 0 (Red Line)
CAC 1-400 (Blue Line)
CAC ≥400 (Green Line)
Subjects with no evidence of CAC (CAC=0) had a significantly lower mortality rate (3.3/100 patient years, CI 0.4-6.1) compared to subjects with a CAC score 1-400 (7.0/100 patient years, CI 2.7-11.4) and those with a CAC score &gt;400 (14.7/100 patient years, CI 8.1-21.4) (P=0.002).
After multivariable adjustment, the presence of a baseline CAC score &gt;400 remained significantly associated with increased mortality (HR=4.5, P=0.016, CI 1.33-15.14).
Key Point: Careful management of calcium, phosphorus, and lipids is required to reduce risk in patients with Stage 5 CKD.
The National Kidney Foundation (NKF), as part of its ongoing clinical practice guidelines, has established goals for the management of calcium and phosphorus levels in patients with stage 5 chronic kidney disease (CKD). Previously, Block and associates also set forth goals for these levels. The long-term goal for serum phosphorus is 3.0 to 5.0 mg/dL and that for calcium-phosphorus product (Ca P) is &lt;55 mg2/dL2. They have also noted that treatment with agents that accumulate and cause toxicity should be avoided. [Block, 2000, 318A] Llach has suggested that the calcium level in the dialysate bath be adjusted to meet the needs of the individual patient. [Llach, 1998, 516A, 517A] London and colleagues have stated that “In the dialysis population, with its greatly increased overall cardiac risk, prevention of calcification and its progression must be a primary goal.” [London, 2000, 781A] These investigators have recommended the use of calcium-free phosphate binders.
Patients with CKD should be placed in the highest National Cholesterol Education Program (NCEP) coronary heart disease (CHD) risk category and their low-density-lipoprotein cholesterol (LDL-C) target should be &lt;100 mg/dL. Specific goals for high-density-lipoprotein cholesterol (HDL-C) and triglycerides (TG) are not stated in the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) dyslipidemia guidelines. However, they do indicate that patients with very high TG (500 mg/dL) should be treated to reduce TG levels &lt;500 mg/dL; furthermore, patients with TG 200 mg/dL and non-HDL-C 130 mg/dL should be treated to reduce non-HDL-C &lt;130 mg/dL. [NKF K/DOQI, 2003, S39]
Block GA. Prevalence and clinical consequences of elevated Ca P product in hemodialysis patients. Clin Nephrol. 2000;54:318-324.
Llach F. Calcific uremic arteriolopathy (calciphylaxis): an evolving entity? Am J Kidney Dis. 1998;32:514-518.
London GM, Pannier B, Marchais SJ, Guerin AP. Calcification of the aortic valve in the dialyzed patient. J Am Soc Nephrol. 2000;11:778-783.
National Kidney Foundation. K/DOQI clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J Kidney Dis. 2003;41(suppl 3):S1-S91.