1. Oral phosphate binders in patients with kidney failure
N Engl J Med Apr 8;362(14):
신장내과 R4
강혜란

2. Hyperphosphatemia Universal complication of kidney failure
Accompanied by hypocalcemia, low serum levels of vitamin D
Usually lead to severe secondary hyperparathyroidism
-> painful fractures, brown tumors, generalized osteopenia
Inorganic phosphorus : essential for multiple biologic functions
intracellular signal transduction
the production and function of cell membranes
energy exchange
보편적인

3. Hyperphosphatemia Body phosphorus
80% : stored in bone and teeth
found in the intracellular compartment and in serum (primarily in the form of anions : H2PO4 − and HPO4 2−)
Kidney function is impaired -> excretion of phosphate declines
However, serum phosphate levels do not rise appreciably until the GFR < 30 ml /minute/1.73 m² BSA
compensatory reduction in tubular resorption mediated by increased levels of serum parathyroid hormone, fibroblast growth factor 23, and phosphate itself

4. Phosphate Metabolism in Kidney Failure and in Health
정상인에서 혈청 인수치는 dietary absorption, bone formation and resorption, renal excreation의 regulation및 intracellular stores의 equilibration에 의해 physiologic range를 유지함. Kidney function이 저하됨에 따라 kidney의 인배설이 감소.
1) Dietary phosphorus restriction
2) Elimination of inorganic phosphate by dialysis
3) Phosphate binder
In healthy adults, phosphate intake is matched by phosphate excretion in feces and urine, and the flux of phosphate between the skeleton and the extracellular phosphate pool is approximately the same in both directions. In patients with kidney failure, dietary restriction of phosphate is insufficient to compensate for the decrease in renal phosphate excretion, resulting in a positive phosphate balance. In addition, bone is often resorbed more rapidly than it is formed because of abnormal bone remodeling in kidney failure. Together, these abnormalities may confer a predisposition to vascular calcification, especially when serum phosphate levels are suboptimally controlled.
The phosphate values shown are for illustrative purposes only, since these values vary from patient to patient.

5. Putative Mechanisms Linking Hyperphosphatemia and Cardiovascular Disease
Elevated serum phosphate levels are associated with an increased risk of cardiovascular disease among patients with and those without kidney failure, although it is unclear whether phosphate plays a causal role or is simply a marker of a poor outcome. Although much of the research has focused on the role of elevated phosphate levels in vascular calcification, multiple potential mechanisms linking phosphate to cardiovascular disease have been proposed. Hyperphosphatemia may also directly affect vascular health by increasing reactive oxygen species, thereby causing oxidative damage and endothelial dysfunctio. Indirectly, hyperphosphatemia increases levels of parathyroid hormone and fibroblast growth factor 23, both of which have been suggested to have direct pathogenic cardiovascular effects. Increased phosphate levels have also been associated with inhibition of 1,25-dihydroxyvitamin D synthesis, which is associated with vascular calcification and myocardial disease. Finally, hyperphosphatemia might also identify patients who are less likely to comply with dietary restrictions (and other aspects of their care), which could confer a predisposition to cardiovascular disease.

6. Dietary P restriction IJKD 2010;4:89-100
Dietary phosphorus control is often a main strategy in the management of patients with chronic kidney disease.
Dietary protein is a major source of phosphorus intake. Recent data indicate that imposed dietary phosphorus restriction may compromise the need for adequate protein intake, leading to protein-energy wasting and possibly to increased mortality.
The two main sources of dietary phosphorus are organic, including animal and vegetarian proteins, and inorganic, mostly food preservatives(보존제). Animal-based foods and plant are abundant in organic phosphorus. Usually 40% to 60% of animal-based phosphorus is absorbed; this varies by degree of gastrointestinal vitamin-D-receptor activation, whereas plant phosphorus, mostly associated with phytates, is less absorbable by human gastrointestinal tract. Up to 100% of inorganic phosphorus in processed foods may be absorbed; ie, phosphorus in processed cheese and some soda (cola) drinks. A recent study suggests that a higher dietary phosphorus-protein intake ratio is associated with incremental(증가) death risk in patients on long-term hemodialysis. Hence, for phosphorus management in chronic kidney disease, in addition to absolute dietary phosphorus content, the chemical structure (inorganic versus organic), type (animal versus plant), and phosphorus-protein ratio should be considered. We recommend foods and supplements with no or lowest quantity of inorganic phosphorus additives, more plant-based proteins, and a dietary phosphorus-protein ratio of less than 10 mg/g. Fresh (nonprocessed) egg white (phosphorus-protein ratio less than 2 mg/g) is a good example of desirable food, which contains a high proportion of essential amino acids with low amounts of fat, cholesterol, and phosphorus.
KDOQI guidelines recommend up to 1000mg/d dietary P
Inorganic P are not protein bound; they are salts that more readily disassociate and are absorbed in the intestinal tr.
Turkey; 칠면조
IJKD 2010;4:89-100

7. Selected Sources of Dietary Phosphorus
No or lowest quantity of inorganic phosphorus additives
More plant-based proteins
Dietary phosphorus-protein ratio < less than 10 mg/g
Fresh (nonprocessed) egg white (phosphorus-protein ratio < 2 mg/g)
Contains a high proportion of essential amino acids with low amounts of fat, cholesterol, and phosphorus
IJKD 2010;4:89-100

8. Phosphate binder Aluminum containing (Amphojelⓡ) ~ mid 1980s, mainstay
Systemic aluminum toxicity
Encephalopathy, dementia
Osteomalacia
Anemia
Short period, Ca containing binder의 사용에 제한이 있을때(hypercalcemia, extensive vascular calcification, calciphylaxis)

9. Phosphate binder Ca based phosphate binders : Ca carbonate, Ca acetate
Most commonly used phosphate binders
Taken with meals effectively binds phosphates and limits their absorption
Doses
Patient’s compliance with dietary phosphate restriction
The CKD stage
Element Ca intake : max. 1500mg/d (diet + binder; 2000mg/d 미만)
Hypercalcemia-associated risks
extraskeletal calcification, PTH suppression, adynamic bone disease
-> bone의 buffer capacity 감소 -> soft tissue calcium 침착 증가, 심혈관 예후 악화

10. Phosphate binder Sevelamer
Non-absorbable, Anion-exchange resin (칼슘, 금속 기반 아닌 인결합제)
Sevelamer hydrochloride (Renagelⓡ) : metabolic acidosis
Sevelamer carbonate (Renvela ⓡ)
Vs Ca based phosphate binders
Low hypercalcemia incidence & vascular calcification
Mortality 차이없음
현재는 sevelamer carbonate가 FDA승인받고 생산, 효과는 비슷하고 산증 덜 일으킨다.
현재까지 study는 대부분 sevelamer hydrochloride로 이루어짐.

11. Phosphate binder Lanthanum carbonate (Fosrenolⓡ)
Nonaluminum, noncalcium phosphate-binding agent
Some lanthanum appears to accumulate in bone and liver
No good quality studies have been powered to examine the effect of lanthanum
Vs Ca based phosphate binders
Similarly effective in reducing serum phosphate concentrations
(limitation : lack of blinding, loss to follow-up)
Adverse events were more frequent : peripheral edema, myalgia
금속 기반의 인결합제
Sevelamer에 비해 적은양 복용, chewable
Cleared primarily by the liver
Some lanthanum appears to accumulate in bone and liver

12. Phosphate binder
Calcium-containing phosphate binders : cost-effective first-line treatment option for the control of hyperphosphatemia, although the risk of long-term calcium exposure remains a concern
Persistent hyperphosphatemia -> Sevelamer
Sevelamer 800mg/1T 877원 > 2.4g/d복용 시 78930원/month
CaCO3 500mg 1T 30원 > 1.5g (element Ca 600mg)/d 복용 시 2700원/month
Sevelamer 보험기준 : 투석을 받고 있는 ESRD 환자중 혈액검사상(매월 1회정도) 혈중 인(P) 수치가 5.5㎎/㎗ 이상이면서 Ca× P산물(product)이 55mg2/㎗2 이상인 환자에게 인정

13. NEJM 2010;362:1312-24 CaCO3; GI effect가 m/c A/E이지만, Sevelamer에서보다는 적다.
* Trade names may vary among countries; the examples given here are for illustrative purposes only.
† Where multiple studies are cited, the percentages are median values, with ranges given in parentheses.
‡ The mean serum bicarbonate level is 1.43 mmol per liter higher with sevelamer carbonate than with sevelamer hydrochloride.
§ Some preparations of Gaviscon contain aluminum rather than magnesium carbonate.
NEJM 2010;362:

14. Phosphate binder NEJM 2010;362:1312-24
* Costs are based on average dose requirements for patients with end-stage renal disease, as recommended in the product monographs.
Doses are consistent with those reported in the largest clinical trials.33,75,81,85 The costs shown are average wholesale prices and were obtained from the Thomson Healthcare 2009 Red Book95 (except for the costs of magnesium hydroxide and magnesium carbonate, which were obtained from McKesson Canada pharmaceutical data). Purchasers such as Medicare may receive substantial discounts on average wholesale prices. To convert the values for phosphate to millimoles per liter, multiply by To convert the values for calcium to millimoles per liter, multiply by
† Trade names may vary among countries; the examples given here are for illustrative purposes only.
‡ Some preparation of Gaviscon contain aluminum rather than magnesium carbonate.
§ Sevelamer carbonate has replaced sevelamer hydrochloride because of concerns about metabolic acidosis due to the hydrochloride moiety.
NEJM 2010;362:

15. NEJM 2010;362:

16. Management of hyperphosphatemia
Dietary phosphate restriction effectively
Oral phosphate binders
Improve phosphate control
Patient’s pill burden
Risk of adverse events
Cost

17. <순천향 서울병원 가이드라인>
>10.2시 Hypercalcemia
PTH 정상수치 8-76
Ca x P extraskeletal calcification의 risk factor로 알려져 있어 <55로 유지하도록 함
P을 정상수치로 유지해야 <55라는 목표에 도달할수 있음.
<순천향 서울병원 가이드라인>

18. References Kidney International (2009)
KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
Iran J Kidney Dis Apr;4(2):89-100
Organic and inorganic dietary phosphorus and its management in chronic kidney disease
N Engl J Med Apr 8;362(14):
Oral phosphate binders in patients with kidney failure

19. Treatment of abnormal PTH level

20. Secondary hyperparathyroidism
VDRA( Vit D receptor activator )
Calcimimetics
Parathyroidectomy

21. Vitamin D therapy Calcitriol (1,25-dihydroxyvitamin D) (Rocaltrolⓡ)
Parathyroid gland의 the vitamin D receptor (VDR) 에 작용하여 PTH transcription을 억제, Parathyroid cell 증식 감소
뼈와 장에서 칼슘 흡수 증가시켜 혈청 칼슘을 증가 -> PTH분비 억제
S/E : Hypercalcemia, hyperphosphatemia, vascular calcification, adynamic bone disease
Paricalcitol (19-nor-1-alpha,25-dihydroxyvitamin D2 ( Zemplarⓡ)
"second generation" vitamin D analogue. Selective VDRA
less severe increments in serum calcium and phosphate (prospective randomized trial is needed)
Vitamin D derivatives should not be given until the serum phosphate concentration has been controlled ( < 5.5 mg/dL) and the serum calcium is less than 9.5 mg/dL
: metastatic calcification risk
(P <5.5 & Ca<9.5 가 아니라면 vitamin D 투여 금기)
Calcitriol; activated form의 vitamin D
Vitamin D analogue (paricalcitol, doxercalciferol, alfacalcidol)
인이 조절되지 않은 상태에서 hypercalcemia발생시 metastatic calcification risk가 증가함.

22. Calcimimetics
Acts as a positive allosteric modulator of the Ca sensing Rc (CaR), increase the sensitivity of the CaR in the parathyroid gland to calcium
Hypocalcemia and the calcium-sensing receptor — The CaSR, which is highly expressed in the parathyroid glands, permits variations in the serum calcium concentration to be sensed by the parathyroid gland, leading to the desired changes in PTH secretion. The fall in serum calcium concentration with renal failure, as sensed by the CaSR, is a potent stimulus to the release of PTH

23. Calcimimetics
Efficacy: Cinacalcet added to standard therapy facilitates the achievement of the Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines
46% vs 33%
56% vs 10%
42% vs 24%
41% vs 6%
Kidney Int. 2005;67(2):760

24. Calcimimetics Cinacalcet(Regparaⓡ)
Indication : PTH > 300pg/mL, sCa > 8.4mg/dL
Dose
Starting dose 30mg/d,
Stepwise increments to 60,90,180mg/d q 4wks
Should not be started if serum calcium is below 8.4 mg/dL

25. CKD-MBD Systemic disorder of mineral & bone metabolism due to CKD
Abnormalities of Ca, P, PTH or Vit.D metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
Vascular or other soft tissue calcification
KDIGO guideline_2009

26. Pathogenesis 신기능이 감소함에 따라 신장에서 인배설이 감소하면서 혈청의 인 수치가 상승하게 됨.
신기능이 감소함에 따라 신장에서 인배설이 감소하면서 혈청의 인 수치가 상승하게 됨.
Serum P level은 GFR이 30이하로 감소할때까지 상승하지 않고 유지 – increased PTH 및 FGF(fibroblast growth factor)-23, P inself에 의해 tubular resorption이 감소

27. => CKD 3부터 MBD에 대한 평가 및 조절필요
In mild to moderate CKD, a normal serum phosphate concentration does not necessarily indicate normal parathyroid status
Efforts to control phosphate, including dietary phosphate restriction and the use of phosphate binders should not be delayed until frank hyperphosphatemia develops
=> CKD 3부터 MBD에 대한 평가 및 조절필요
Ionized calcium and parathyroid hormone (PTH) levels in chronic renal failure. 
Levels of ionized calcium are maintained in advancing renal failure by progressive increases in PTH

28. 치즈, 우유, 유제품, 두유, 아몬드,호두,달걀 노른자,돼지&소 간,초콜릿,콜라,사골국
달걀흰자,
닭다리, 닭가슴살, 대구
소고기&돼지고기(내장부위 제외) 두부
P to protein ratio < 5mg : egg white, pork rinds(돼지껍질 튀겨서 시원하게 먹는 스낵), orange roughy fish
P to protein ratio 5~10; lamb, tuna/canned in water, chicken drumstick, beef(excludes organ meats), ground beef, chicken breast, pork(excludes organ meats). Cod fish 콩류
치즈, 우유, 유제품, 두유, 아몬드,호두,달걀 노른자,돼지&소 간,초콜릿,콜라,사골국
KDOQI guideline_2010

29. Phosphate binders
Comprehensive clinical nephrology