This document summarizes chronic kidney disease-mineral and bone disorder (CKD-MBD), including its definition, pathogenesis, diagnosis, and management recommendations. Specifically: - CKD-MBD is defined as a systemic disorder involving abnormalities in calcium, phosphorus, vitamin D, PTH, and bone. It can cause skeletal and extraskeletal complications. - As kidney function declines, abnormalities in mineral metabolism develop, leading to high or low bone turnover diseases. Phosphate retention, low calcitriol, and parathyroid gland changes drive secondary hyperparathyroidism. - Diagnosis involves monitoring mineral levels and PTH. Bone biopsy determines the type of renal osteodystrophy

1. "Chronic Kidney Disease-Mineral and Bone Disorder"
Dr Sampada Sinha
B.Sc(Physics Honours) ; M.B.B.S (Lady Hardinge Medical College)
Presentation made in Interfaith Medical Center, Brooklyn

2. Chronic kidney disease (CKD) is an important source of long-term morbidity and mortality. It
has been estimated that CKD affects more than 20 million people in the United States.(1)
NKF-K/DOQI(Kidney Disease Outcomes Quality Initiative) Definition of CKD:
CKD is an irreversible, progressive reduction in renal function.
The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI)
guidelines define CKD as sustained kidney damage indicated by the presence of structural
or functional abnormalities (e.g., microalbuminuria/proteinuria, hematuria, histologic or
imaging abnormalities), and/or reduced glomerular filtration rate (GFR) to less than
60 mL/min/1.73 m2 for at least 3 months(1)

3. K/DOQI classification of the stages of chronic kidney disease
(2002)
GFR (mL/min/1.73 m2)
Stage Description Plan
Action
1 Kidney damage with ≥90 Diagnosis, treatment of
normal or elevated underlying condition
GFR and comorbidities,
cardiovascular disease
risk reduction
2 Kidney damage with 60-89 Estimating progression
mildly decreased GFR
3 Moderately decreased 30-59 Evaluating and treating
GFR complications
4 Severely decreased 15-29 Preparation for renal
GFR replacement therapy
5 Kidney failure (ESRD) <15 (or dialysis, Replacement therapy
transplantation) (dialysis or
transplantation)
ESRD, end-stage renal disease; GFR, glomerular filtration rate.
Adapted from the National Kidney Foundation: K/DOQI Clinical practice guidelines for
chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis
2002;39:S1-S26(1)

4.  As kidney function declines, there is a progressive deterioration in mineral
homeostasis, with a disruption of normal serum and tissue concentrations of
phosphorus and calcium, and changes in circulating levels of hormones. These include
parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D
(1,25(OH)2D), and other vitamin D metabolites, fibroblast growth factor-23 (FGF-23),
and growth hormone.(1)
 Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a common
complication of chronic kidney disease and is a part of broad spectrum disorders of
mineral metabolism that occur in clinical setting(3).It involves biochemical
abnormalities (i.e, serum phosphorus, PTH, vitamin D levels, and alkaline phosphatase)
related to bone metabolism(7)
 The disorder of the bone have to be considered not only with regard to the bone itself
but also with regard to the consequences of disturbed mineral metabolism of extra
skeletal sites, including the vasculature.(3)

5. Table 1 | KDIGO Classification 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 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.
Definition of renal osteodystrophy
 Renal osteodystrophy is an alteration of bone morphology in patients 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.
_________________________________________________________________________________
CKD, chronic kidney disease; CKD–MBD, chronic kidney disease–mineral and bone disorder; KDIGO, Kidney Disease: Improving Global Outcomes; PTH, parathyroid hormone.
Adapted with permission from Moe et al.(1)

6. Chronic Kidney Disease-Related Mineral and Bone Disorder: Public
Health Problem. Kerry Willis PhD National Kidney Foundation (5)

7. Pathogenesis of Metabolic Bone Disease in CKD
Renal bone disease is a common complication of chronic kidney disease. It results in both
skeletal complications (eg, abnormality of bone turnover, mineralization, linear growth)
and extraskeletal complications (eg, vascular or soft tissue calcification).(7)
Several types of bone diseases are known to occur in CKD patients:
Excessive secretion of parathyroid hormone (PTH) due to secondary hyperparathyroidism
(SHPT) causes high-turnover bone disease, called osteitis fibrosa.
 Among low-turnover bone disease (LTBD), osteomalacia which is characterized by
calcification defect (defective mineralization) is often complicated with VD deficiency
and/or aluminum accumulation.
Recently, frequency of adynamic bone disease caused by PTH suppression, another type
of LTBD, is increasing probably due to calcium salts as phosphate binder with or without
VD treatment.(2)
Mixed disease.(7)
Beta-2-microglobulin associated bone disease.(7)


8. High-Turnover Metabolic Bone Disease in CKD
High-turnover bone disease is the result of the development of secondary
hyperparathyroidism. Factors involved in the pathogenesis of secondary
hyperparathyroidism are:
 Retention of Phosphorus
 Hypocalcemia
 Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or
calcitriol)
 Intrinsic alterations within the Parathyroid gland that give rise to increased PTH
secretion as well as increased parathyroid growth, skeletal resisitance to the actions of
PTH and hypocalcemia.(3)

9. Role of Phosphate Retention
Phosphate retention begins in early chronic kidney disease; when the GFR falls.
As functional mass declines, the fractional excretion of phosphate drops, leading
to an increase in the serum Phosphate level. This is accompanied by a reciprocal
decrease in serum calcium concentration. These events lead to an increase in
parathyroid hormone (PTH) release(post-transcriptional effect); this has a
phosphaturic effect, resulting in the return of phosphate and calcium to normal
levels. As GFR continues to decline, this cycle maintains serum calcium and
phosphate concentrations within the normal ranges, at the expense of rising
PTH levels. When further renal mass is lost and GFR drops below
30 mL/min/1.73 m2, (chronic kidney disease stage 4-5) despite the
compensatory hyperphosphaturia, hyperphosphatemia becomes sustained.(4)

10. Decreases in the level of Calcitriol
Parallel to this, as nephron mass decreases, the 1α-hydroxylation in the kidney of
25-hydroxyvitamin D [25-(OH)vitamin D] declines, leading to lower serum levels
of 1,25-dihydroxyvitamin D [1,25-(OH2)vitamin]. Hyperphosphatemia suppresses
the renal hydroxylation of inactive 25-hydroxyvitamin D to calcitriol, so serum
calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m2(4). This lack
of 1,25-(OH2)vitaminD contributes to the development of hypocalcemia, given
its role of enhancing calcium absorption in the gut and enhancing PTH-mediated
calcium release from bone. The combination of all these factors contributes to
the development of secondary hyperparathyroidism and renal osteodystrophy.
Calcitriol levels seem to decline slowly and progressively throughout the course
of CKD.(7)

11. Role of Intrinsic Alterations in the Parathyroid Gland
Hypocalcemia is a powerful stimulus for PTH secretion and for parathyroid growth.
Decreased levels of Calcitriol also may contribute to the parathyroid abnormalities.(3)
Calcitriol is a major regulator of PTH secretion, and vitamin D receptor is expressed in the
parathyroid glands. Concomitant decreases in VD receptor and calcium sensing receptor in
the parathyroid glands render them more resistant to the action of VD and calcium, and
accelerate parathyroid cell growth(2)
Skeletal Resistance to the Actions of PTH
Many factors are involved in skeletal resistance, including phosphorus retention,
possibly decreased levels of calcitriol, downregulation of the PTH receptor and the
potential actions of PTH fragments that have shown to blunt the calcemic effect of
PTH (3)

12. The factors involved in the pathogenesis of secondary hyperparathyroidism
Martin K J , González E A JASN 2007;18:875-885 (5)
©2007 by American Society of Nephrology

13. Low-Turnover Metabolic Bone Disease (LTBD) in CKD:
 Low-turnover bone disease(LTBD) is commonly observed in patients with kidney disease, especially in
patients who are on dialysis, and is characterized by an extremely slow rate of bone formation.(3)
 Low turnover bone disease has two subgroups, osteomalacia and adynamic bone disease. Both
lesions are characterized by a decrease in bone turnover or remodeling, with a reduced number of
osteoclasts and osteoblasts, and decreased osteoblastic activity.
 In osteomalacia there is an accumulation of unmineralized bone matrix, or increased osteoid
volume, which may be caused by vitamin D deficiency or excess aluminum.
 Adynamic bone disease is characterized by reduced bone volume and mineralization and may be due
to excess aluminum or oversuppression of PTH production with calcitriol.(8)
 Therefore, both forms facilitate the availability of Ca and P, which ends up being deposited in soft
tissues such as arteries. (6)
 Dialysis-related amyloidosis from beta-2-microglobulin accumulation in patients who have required
chronic dialysis for at least 8-10 years is another form of bone disease. It manifests with cysts at the
ends of long bones(7)

14. Factors Involved In the Pathogenesis of Adynamic Bone Disease in CKD
Martin K J , González E A JASN 2007;18:875-885 (3)
©2007 by American Society of Nephrology

15. Clinical Signs and Symptoms of Metabolic Bone Disease in CKD
Often is asymptomatic, and symptoms appear only in the late course of the
disease.
Many of the symptoms are non-specific and include pain and stiffness in joints,
spontaneous tendon rupture, predisposition to fracture, and proximal muscle
weakness.(3)
A similar set of symptoms may be seen in both the low- and high-turnover type
of skeletal abnormality.
It is important to emphasize that the absence of clinical signs and symptoms of
metabolic bone disease do not underscore the importance of these
abnormalities, because many of the processes that contribute to the underlying
metabolic bone disease also have consequences at extra-skeletal sites, and the
control of these processes is also important to decrease the morbidity and
mortality.(3)

16. Diagnosis of CKD-MBD: biochemical abnormalities
• Bone Biopsy- Although histologic examination of un-decalcified sections of bone
remains the gold standard for the precise diagnosis of renal bone disease, bone
biopsy is not widely used in clinical practice because of the invasive nature of the
technique.
• Measurements of calcium and phosphorus concentrations
• Measurements of PTH.
• A number of biologic markers of bone formation and bone resorption might be
used in conjunction with measurement of the mineral ions and PTH to gauge cell
activity. Of these, alkaline phosphatase and bone-specific alkaline phosphatase
are most useful in this regard.(3)

17. Prevention and Management of Metabolic Bone
Disease in CKD

18. A “stepped-care” approach to the prevention and treatment of secondary
hyperparathyroidism in CKD.
Martin K J , González E A JASN 2007;18:875-885
©2007 by American Society of Nephrology

19. K/DOQI™ Clinical Practice Guidelines on Bone Metabolism Target Levels
*Evidence

20. RECOMMENDATIONS
Monitoring serum levels of calcium, phosphorus, PTH, and alkaline phosphatase
activity beginning in CKD stage 3 . In children, such monitoring beginning in CKD
stage 2.
In CKD stage 3: for serum calcium and phosphorus, every 6-12 months; and for
PTH, based on baseline level and CKD progression.
In CKD stage 4: for serum calcium and phosphorus, every 3-6 months; and for
PTH, every 6-12 months.
In CKD stages 5, including 5D: for serum calcium and phosphorus, every 1-3
months; and for PTH, every 3-6 months.
In CKD stages 4-5D: for alkaline phosphatase activity, every 12 months, or more
frequently in the presence of elevated PTH.

21. Treatment Recommendations
(Stages 3 & 4)
• Decrease total body phosphorus burden by dietary restriction and
phosphorus binder therapy- 2.7- 4.6 mg/dL; begin when EITHER
elevated serum phosphorus OR elevated serum PTH
• Treat elevated PTH with active oral vitamin D sterol to target of 35-70
(CKD 3) or 70-110 (CKD 4) pg/mL by intact assay
• Normalize serum calcium

22. Treatment Recommendations
Stage 5 (dialysis)
• Normalize serum phosphorus by diet and phosphorus binder therapy-
3.5-5.5 mg/dL (1.13 -1.78 mmol/L);
• Limit elemental calcium intake from binders to 1500 mg/day
• Normalize serum calcium- ideally 8.4 -9.5 mg/dL (2.10-2.38 mmol/L),
and always < 10.2 mg/dL (2.55 mmol/L); Ca X P < 55 mg2/dL2
• Treat elevated PTH with active vitamin D sterol to target of 150-300
pg/mL (16-32 pmol/L) by intact assay

23. References:
1. Introduction and definition of CKD–MBD and the development of the guideline statements Kidney International (2009) 76 (Suppl 113), S3–S8;
doi:10.1038/ki.2009.189. KDIGO(Kidney disease improving global outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention,and Treatment
of Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD)
2. PMID: 15577032 [PubMed - indexed for MEDLINE] . PUBMED: Pathogenesis of secondary hyperparathyroidism and renal bone disease. Department of Internal
Medicine, Showa University, Northern Yokohama Hospital.
3.Journal of the American Society of Nephrology (Metabolic bone disease in chronic kidney disease by Kevin J Martin and Esther A Gonzalez)
4.Chronic Kidney Disease : Co-authored by Martin E. Lascano, Martin J. Schreiber and Saul Nurko of the Cleveland Clinic
5. Chronic Kidney Disease-Related Mineral and Bone Disorder: Public Health Problem. Kerry Willis PhD National Kidney Foundation
6. PMID: 19018742 [PubMed - indexed for MEDLINE] [Changes in mineral metabolism in stage 3, 4, and 5 chronic kidney disease (not on dialysis)].[Article in
Spanish]Lorenzo Sellares V, Torregrosa V.Source H. Universitario de Canarias.
7. MEDSCAPE: Chronic Kidney Disease Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN
8. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification