"Chronic Kidney Disease-Mineral and Bone Disorder"Dr Sampada SinhaB.Sc(Physics Honours) ; M.B.B.S (Lady Hardinge Medical College)

Presentation made in Interfaith Medical Center, Brooklyn

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)

K/DOQI classification of the stages of chronic kidney disease (2002)

Stage DescriptionGFR (mL/min/1.73 m2)

ActionPlan

1 Kidney damage with

normal or elevated

GFR

≥90 Diagnosis, treatment of

underlying condition

and comorbidities,

cardiovascular disease

risk reduction

2 Kidney damage with

mildly decreased GFR

60-89 Estimating progression

3 Moderately decreased

GFR

30-59 Evaluating and treating

complications

4 Severely decreased

GFR

15-29 Preparation for renal

replacement therapy

5 Kidney failure (ESRD) <15 (or dialysis,

transplantation)

Replacement therapy

(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)

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)

Table 1 | KDIGO Classification of CKD–MBD and Renal Osteodystrophy_________________________________________________________Definition of CKD–MBDA 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)

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

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)

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)

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)

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)

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)

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

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)

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

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)

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)

Prevention and Management of Metabolic Bone Disease in CKD

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

K/DOQI™ Clinical Practice Guidelines on Bone Metabolism Target Levels

*Evidence

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.

• 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

Treatment Recommendations(Stages 3 & 4)

Treatment RecommendationsStage 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

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