Hyperphosphatemia in CKD

5/23/2014Rehab Rayan & Doaa Hegy 2
INTRODUCTION
THE CAUSES OF HYPERPHOSPHATEMIA, Acute or chronic kidney disease,
Phosphate Retention
GUIDELINE TARGET LEVELS, Treatment of Hyperphosphatemia
1-Phosphate restriction
2-Phosphate binders
1.Aluminum hydroxide
2.Magnesium-containing antacids
3.Calcium salts
4.Non-calcium binders
3-NOVEL THERAPIES
·Nicotinamide
·Polynuclear iron (III)-oxyhydroxide phosphate (PA21)
·Increased and/or extended hemodialysis
Managing hyperphosphatemis in CKD Patients’, Among dialysis patients, Stage 3
to 5 CKD not yet on dialysis

• PHOSPHATE IS AN INORGANIC MOLECULE CONSISTING OF A
CENTRAL PHOSPHORUS ATOM AND FOUR OXYGEN ATOMS.
• IN THE STEADY STATE, THE SERUM PHOSPHATE CONCENTRATION IS
DETERMINED BY THE ABILITY OF THE KIDNEYS TO EXCRETE DIETARY
PHOSPHATE.

• PHOSPHATE INTAKE ABOVE 4000 MG/DAY (130 MMOL/DAY) CAUSES
SMALL ELEVATIONS IN SERUM PHOSPHATE CONCENTRATIONS (THE
INTAKE IS DISTRIBUTED OVER THE COURSE OF THE DAY).
• IF, AN ACUTE PHOSPHATE LOAD IS GIVEN OVER SEVERAL HOURS,
TRANSIENT HYPERPHOSPHATEMIA WILL OCCUR.
• THE DIAGNOSTIC APPROACH TO HYPERPHOSPHATEMIA INVOLVES
EXPLAINING:
• WHY PHOSPHATE ENTRY INTO THE EXTRACELLULAR FLUID EXCEEDS
WHICH CAN BE EXCRETED.
• WHY THE RENAL THRESHOLD FOR PHOSPHATE EXCRETION IS
INCREASED ABOVE NORMAL.

• THE FILTERED LOAD OF PHOSPHATE IS APPROXIMATELY 4 TO 8
G/DAY (130 TO 194 MMOL/DAY).
• ONLY 5 TO 20 % OF THE FILTERED PHOSPHATE IS NORMALLY
EXCRETED, WITH MOST BEING REABSORBED IN THE PROXIMAL TUBULE.

• THE NORMAL PHYSIOLOGIC REGULATION OF RENAL PHOSPHATE
EXCRETION, THE FOLLOWING FACTORS ARE INVOLVED:
• SERUM PHOSPHATE CONCENTRATION – HYPERPHOSPHATEMIA DIMINISH
PROXIMAL TUBULAR REABSORPTION VIA SUPPRESSION OF SODIUM-
PHOSPHATE COTRANSPORTERS.
• PARATHYROID HORMONE – (PTH) INCREASES EXCRETION BY DIMINISHING
ACTIVITY OF SODIUM-PHOSPHATE COTRANSPORTERS.
• PHOSPHATONINS –AS FIBROBLAST GROWTH FACTOR 23 (FGF23) DECREASE
REABSORPTION BY SUPPRESSING THE LUMINAL EXPRESSION OF SODIUM
PHOSPHATE COTRANSPORTERS.

↓GFR
< 20:25
mL/minPO4
Retention
↑
↓
↓
Hypo-
Ca-emia

Tumoral collections of
calcium phosphate
↑mortality in
dialysis
coronary
atherosclerosis
↓
parathyroidectomy

• K/DOQI GUIDELINES — THE 2003 KIDNEY DISEASE OUTCOMES
QUALITY INITIATIVE (K/DOQI) PRACTICE GUIDELINES MADE THE
FOLLOWING RECOMMENDATIONS FOR GOAL SERUM PHOSPHATE AT
DIFFERENT LEVELS OF SEVERITY OF CHRONIC KIDNEY DISEASE (CKD):
• AT AN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) BETWEEN 15
AND 59 ML/MIN PER 1.73 M (STAGE 3 AND 4 CKD), THE SERUM
PHOSPHATE SHOULD BE BETWEEN 2.7 AND 4.6 MG/DL (0.87 AND 1.49
MMOL/L).
• AT AN EGFR <15 ML/MIN PER 1.73 M (STAGE 5 CKD), THE SERUM
PHOSPHATE SHOULD BE BETWEEN 3.5 AND 5.5 MG/DL (1.13 AND 1.78
MMOL/L).

• TWO PRINCIPAL MODALITIES ARE USED IN AN ATTEMPT TO
PREVENT AND/OR REVERSE THE HYPERPHOSPHATEMIA OF
RENAL FAILURE:
• PHOSPHATE RESTRICTION
• PHOSPHATE BINDERS

• PHOSPHATE RESTRICTION :
• APPROXIMATELY 900 MG/DAY IS ACCEPTABLE.
• A LARGE FRACTION OF DIALYZED PATIENTS HAS BORDERLINE
MALNUTRITION. SO, PROTEIN SUPPLEMENTATION RATHER
THAN PROTEIN RESTRICTION IS THE GOAL.
• THE PATIENT SHOULD BE ENCOURAGED TO AVOID UNNECESSARY
DIETARY PHOSPHATE (AS IN PHOSPHORUS-CONTAINING FOOD
ADDITIVES, DAIRY PRODUCTS, CERTAIN VEGETABLES, MANY
PROCESSED FOODS, AND COLAS), WHILE INCREASING THE
INTAKE OF HIGH BIOLOGIC VALUE SOURCES OF PROTEIN (SUCH
AS, MEAT AND EGGS). 5/23/2014Rehab Rayan & Doaa Hegy 20

• ALUMINUM HYDROXIDE :
• THE PHOSPHATE BINDER OF CHOICE, FORMING INSOLUBLE AND
NONABSORBABLE ALUMINUM PHOSPHATE PRECIPITATES IN THE
INTESTINAL LUMEN.
• AVOIDED DUE TO ALUMINUM INTOXICATION DUE TO THE GRADUAL
TISSUE ACCUMULATION OF ABSORBED ALUMINUM , IN THE BONE,
SKELETAL MUSCLE, AND THE CENTRAL NERVOUS SYSTEM (CNS), LEADING
TO VITAMIN D-RESISTANT OSTEOMALACIA; A REFRACTORY,
MICROCYTIC ANEMIA; BONE AND MUSCLE PAIN; AND DEMENTIA.
• MAGNESIUM-CONTAINING ANTACIDS:
• AVOIDED IN PATIENTS WITH KIDNEY DYSFUNCTION BECAUSE OF THE
RISK OF HYPERMAGNESEMIA AND THE DEVELOPMENT OF DIARRHEA.

• CALCIUM-CONTAINING PHOSPHATE BINDERS:
• CALCIUM CONTAINING (MOSTLY CALCIUM CARBONATE AND
CALCIUM ACETATE)
• USE OF CALCIUM-CONTAINING PHOSPHATE BINDERS BECOME
LESS FREQUENT BECAUSE OF CONCERNS ABOUT TOXICITY OF
CALCIUM ACCUMULATION. WE GENERALLY USE NON-CALCIUM-
CONTAINING PHOSPHATE BINDERS FOR:
• NORMOCALCEMIC CKD PATIENTS
• CKD PATIENTS WHO ARE RECEIVING ACTIVE VITAMIN D
ANALOGS FOR PARATHYROID HORMONE (PTH)
SUPPRESSION . 5/23/2014
Rehab Rayan & Doaa Hegy
23

• CALCIUM ACETATE A MORE EFFICIENT PHOSPHATE BINDER THAN
CALCIUM CARBONATE AS CALCIUM CARBONATE DISSOLVES ONLY AT
AN ACID PH, AND MANY PATIENTS WITH ADVANCED RENAL FAILURE
HAVE ACHLORHYDRIA OR ARE TAKING H2-BLOCKERS. CALCIUM
ACETATE, IS SOLUBLE IN BOTH ACID AND ALKALINE ENVIRONMENTS.
• CALCIUM CITRATE AVOIDED IN PATIENTS WITH RENAL FAILURE SINCE
CITRATE CAN MARKEDLY INCREASE INTESTINAL ALUMINUM
ABSORPTION AND ALUMINUM NEUROTOXICITY OR THE RAPID ONSET
OF SYMPTOMATIC OSTEOMALACIA.

• THE DOSE OF CALCIUM-CONTAINING PHOSPHATE BINDERS IS INCREASED UNTIL THE
SERUM PHOSPHATE FALLS TO NORMAL VALUES FOR PATIENTS WITH STAGE 3 TO 5
CKD NOT YET ON DIALYSIS, OR BETWEEN 4.5 AND 5.5 MG/DL FOR DIALYSIS
PATIENTS, OR UNTIL HYPERCALCEMIA OCCUR.
• ONE POTENTIAL COMPLICATION OF CALCIUM THERAPY IS THAT ABSORPTION OF SOME
OF THE ADMINISTERED CALCIUM MAY PROMOTE THE DEVELOPMENT OF CORONARY
ARTERIAL CALCIFICATION (ASSOCIATED WITH CORONARY ATHEROSCLEROSIS).
• TO HELP DECREASE THIS POSSIBILITY, THE TOTAL DOSE OF ELEMENTAL CALCIUM
(INCLUDING DIETARY SOURCES SHOULD NOT EXCEED 2000 MG/DAYAY. IN ADDITION,
THE DOSE OF ACTIVE VITAMIN D SHOULD BE LOWERED OR THERAPY SHOULD BE
DISCONTINUED UNTIL CALCIUM LEVELS RETURN TO 8.4 TO 9.5 MG/DL.

• PHOSPHATE BINDERS ARE MOST EFFECTIVE IF TAKEN WITH MEALS SO
BINDING DIETARY PHOSPHATE OF LEAVING LESS FREE CALCIUM
AVAILABLE FOR ABSORPTION. IN COMPARISON, ADMINISTRATION
BETWEEN MEALS ONLY BINDS THE PHOSPHATE PRESENT IN
INTESTINAL SECRETIONS AND RESULTS IN A GREATER DEGREE OF
CALCIUM ABSORPTION.
• THIS PROBLEM IS MOST LIKELY TO OCCUR IF A VITAMIN D
PREPARATION IS ALSO GIVEN OR IF THE PATIENT HAS DECREASED
BONE.

• NON-CALCIUM BINDERS:
• SEVELAMER
• LANTHANUM

• SEVELAMER :
• SEVELAMER HYDROCHLORIDE (RENAGEL®) AND SEVELAMER
CARBONATE (RENVELA®) ARE NONABSORBABLE AGENTS
THAT CONTAIN NEITHER
CALCIUM NOR ALUMINUM.
• CATIONIC POLYMERS THAT BIND PHOSPHATE THROUGH
ION EXCHANGE.
• RELATIVELY LESS PROGRESSION OF VASCULAR
CALCIFICATION WITH SEVELAMER VERSUS CALCIUM-
CONTAINING PHOSPHATE BINDERS AMONG PATIENTS WITH
CKD. 5/23/2014
28

• ONE PROBLEM ASSOCIATED WITH SEVELAMER HYDROCHLORIDE
IS THE POSSIBLE INDUCTION OF METABOLIC ACIDOSIS. SO,
SEVELAMER CARBONATE HAS BEEN DEVELOPED. IT IS LIKELY THAT
IT WILL BECOME THE PREFERRED BINDER IN THIS CLASS, BUT THESE
AGENTS APPEAR TO BE EQUIVALENT IN THEIR ABILITY TO
CONTROL PHOSPHATE LEVELS.
• SEVELAMER IS MUCH MORE EXPENSIVE THAN CALCIUM-BASED
PHOSPHATE BINDERS

• LANTHANUM :
• IT IS A RARE EARTH ELEMENT, HAS SIGNIFICANT
PHOSPHATE-BINDING PROPERTIES.
• THE RISK OF LANTHANUM ACCUMULATION AND TOXICITY,
HOWEVER, APPEARS TO BE QUITE LOW WITH SHORT-TERM USE.
• THE LOWER PILL BURDEN IS ONE CONSIDERATION THAT MAY
FAVOR THE USE OF LANTHANUM.
• SEVELAMER IS COMMONLY INITIALLY USED OVER LANTHANUM
SINCE, ALTHOUGH EQUALLY EFFECTIVE IN LOWERING
PHOSPHATE, AS THE LONG-TERM DATA ON SAFETY OF
LANTHANUM ARE MORE LIMITED. 5/23/2014
30

NOVEL THERAPIES
• THE CURRENT APPROACH TO MANAGEMENT OF
HYPERPHOSPHATEMIA IS NOT OPTIMAL; A NUMBER OF
ALTERNATIVE THERAPIES ARE UNDERGOING EVALUATION.
• NICOTINAMIDE
• POLYNUCLEAR IRON (III)-OXYHYDROXIDE
PHOSPHATE (PA21)

• NICOTINAMIDE :
• NICOTINAMIDE, A METABOLITE OF NICOTINIC ACID (NIACIN,
VITAMIN B3).
• INHIBITS THE NA/PI CO-TRANSPORT SYSTEM IN THE
GASTROINTESTINAL TRACT AND KIDNEYS AND MAY BE
EFFECTIVE IN LOWERING PHOSPHATE LEVELS IN DIALYSIS
PATIENTS BY REDUCING GASTROINTESTINAL TRACT PHOSPHATE
ABSORPTION.

• POLYNUCLEAR IRON (III)-OXYHYDROXIDE PHOSPHATE
(PA21) :
• VARIOUS DOSES OF POLYNUCLEAR IRON (III)-OXYHYDROXIDE
PHOSPHATE (PA21) WERE COMPARED WITH SEVELAMER IN A
RANDOMIZED, MULTICENTER OPEN-LABEL STUDY, PA21 AT
DOSES OF 5 AND 7.5 G/DAY PRODUCED SIMILAR DECREASES IN
SERUM PHOSPHORUS TO SEVELAMER DOSED AT 4.8 G/DAY.
• FURTHER STUDY IS REQUIRED TO BETTER UNDERSTAND THE
EFFICACY AND SAFETY OF THESE AND RELATED AGENTS IN THIS
SETTING.

INCREASED AND/OR EXTENDED HEMODIALYSIS :
• STANDARD DIALYSIS IS LIMITED IN ITS ABILITY TO REMOVE PHOSPHATE.
• THERE IS ONLY A SLOW EFFLUX OF PHOSPHATE FROM THE LARGE INTRACELLULAR
STORES INTO THE EXTRACELLULAR FLUID, WHICH IS UNDERGOING DIALYSIS.
• LENGTHENING DIALYSIS (WITHIN STANDARD DIALYSIS REGIMENS) OR USING
LARGER, HIGH-EFFICIENCY DIALYZERS IS LIKELY TO SUBSTANTIALLY INCREASE
PHOSPHATE REMOVAL.
• THE AVERAGE STANDARD DIALYSIS REMOVES APPROXIMATELY 900 MG OF
PHOSPHATE. BY COMPARISON, EXTREMELY LONG AND/OR FREQUENT DIALYSIS
CLEARS A LARGER AMOUNT OF PHOSPHATE.
• FOR PATIENTS WITH REFRACTORY HYPERPHOSPHATEMIA WHO ARE WILLING TO
ACCEPT THIS FORM OF DIALYSIS, THIS FORM OF DIALYSIS MAY BE THE BEST
APPROACH.
5/23/2014
34

• OBTAIN PHOSPHATE, CALCIUM, AND PARATHYROID HORMONE (PTH)
LEVELS INITIALLY AND THEN ON AN ONGOING BASIS.
• AMONG ALL PATIENTS WITH CKD, AVOID ALUMINUM HYDROXIDE
EXCEPT FOR SHORT-TERM THERAPY (FOUR WEEKS FOR ONE COURSE
ONLY) OF SEVERE HYPERPHOSPHATEMIA.
• AMONG DIALYSIS PATIENTS
• STAGE 3 TO 5 CKD NOT YET ON DIALYSIS

• AMONG DIALYSIS PATIENTS:
• MAINTAIN SERUM PHOSPHATE LEVELS BETWEEN 3.5 AND 5.5
MG/DL
1. RESTRICT DIETARY PHOSPHATE TO 900 MG/DAY.
2. PATIENTS REFRACTORY TO MAINTENANCE DIALYSIS THERAPY AND
DIET, RECOMMEND THE ADMINISTRATION OF PHOSPHATE-
BINDING AGENTS.
3. MORE FREQUENT AND MORE INTENSIVE DIALYSIS CAN ALSO
LOWER PHOSPHATE LEVELS, SUCH AS THAT PROVIDED BY
NOCTURNAL HEMODIALYSIS, CLEARS A LARGE AMOUNT OF
PHOSPHATE , IT IS AN OPTION AMONG THOSE WHO ARE
WILLING TO ACCEPT THIS FORM OF DIALYSIS. 5/23/2014Rehab Rayan & Doaa Hegy 37

• STAGE 3 TO 5 CKD NOT YET ON DIALYSIS :
1. RESTRICT DIETARY PHOSPHATE TO 900 MG/DAY.
2. SERUM PHOSPHATE LEVELS GREATER THAN TARGET LEVELS
DESPITE DIETARY PHOSPHORUS RESTRICTION AFTER ONE
MONTH, SUGGEST THE ADMINISTRATION OF PHOSPHATE
BINDERS.

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