hyperphosphatemia in ckd

HyperphosphatemiaIn Chronic Kidney Disease

04/13/2023Rehab Rayan & Doaa Hegy 2

TO BE DISCUSSED…INTRODUCTIONTHE CAUSES OF HYPERPHOSPHATEMIA, Acute or chronic kidney disease,

Phosphate RetentionGUIDELINE TARGET LEVELS, Treatment of Hyperphosphatemia1-Phosphate restriction 2-Phosphate binders

1.Aluminum hydroxide 2.Magnesium-containing antacids3.Calcium salts4.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


INTRODUCTION

• 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.


THE CAUSES OF HYPERPHOSPHATEMIA

• 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 CAUSES OF HYPERPHOSPHATEMIA


Acute or Chronic Kidney Disease

• 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/min

PO4 Retenti

on

↑

↓

↓ Hypo-Ca-

emia


Phosphate RetentionTumoral

collections of calcium

phosphate ↑mortality in

dialysiscoronary

atherosclerosis↓

parathyroidectomy


GUIDELINE TARGET LEVELS

• 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).


Treatment of Hyperphosphatemia

• 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).


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• 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.

Rehab Rayan & Doaa Hegy

• Treatment of HyperphosphatemiaPHOSPHATE BINDERS:

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• 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 .Rehab Rayan & Doaa Hegy



• 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


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• 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. Rehab Rayan & Doaa Hegy




• 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

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• 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.




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.


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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.




• 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

Managing Hyperphosphatemia

in CKD Patients’


• 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.



• 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.



References

• MURER H. HOMER SMITH AWARD. CELLULAR MECHANISMS IN PROXIMAL TUBULAR PI REABSORPTION: SOME ANSWERS AND MORE QUESTIONS. J AM SOC NEPHROL 1992; 2:1649.18.

• MURER H, LÖTSCHER M, KAISSLING B, ET AL. RENAL BRUSH BORDER MEMBRANE NA/PI-COTRANSPORT: MOLECULAR ASPECTS IN PTH-DEPENDENT AND DIETARY REGULATION. KIDNEY INT 1996; 49:1769.

• 12.MARTIN KJ, GONZÁLEZ EA. METABOLIC BONE DISEASE IN CHRONIC KIDNEY DISEASE. J AM SOC NEPHROL 12. 2007; 18:875.

• NATIONAL KIDNEY FOUNDATION. K/DOQI CLINICAL PRACTICE GUIDELINES FOR CHRONIC KIDNEY DISEASE: EVALUATION, CLASSIFICATION, AND STRATIFICATION. AM J KIDNEY DIS 2002; 39:S1.

• KATES DM, SHERRARD DJ, ANDRESS DL. EVIDENCE THAT SERUM PHOSPHATE IS INDEPENDENTLY ASSOCIATED WITH SERUM PTH IN PATIENTS WITH CHRONIC RENAL FAILURE. AM J KIDNEY DIS 1997; 30:809.

• HRUSKA KA, TEITELBAUM SL. RENAL OSTEODYSTROPHY. N ENGL 15. J MED 1995; 333:166.

• FOURNIER A, MORINIÈRE P, BEN HAMIDA F, ET AL. USE OF ALKALINE CALCIUM SALTS AS PHOSPHATE BINDER IN UREMIC PATIENTS. KIDNEY INT SUPPL 1992; 38:S50.


References

• LLACH F. SECONDARY HYPERPARATHYROIDISM IN RENAL FAILURE: THE TRADE-OFF HYPOTHESIS REVISITED. AM J KIDNEY DIS 1995; 25:663.

• FOURNIER A, MORINIÈRE P, BEN HAMIDA F, ET AL. USE OF ALKALINE CALCIUM SALTS AS PHOSPHATE BINDER IN UREMIC PATIENTS. KIDNEY INT SUPPL 1992; 38:S50.

• DELMEZ JA, SLATOPOLSKY E. HYPERPHOSPHATEMIA: ITS CONSEQUENCES AND TREATMENT IN PATIENTS WITH CHRONIC RENAL DISEASE. AM J KIDNEY DIS 1992; 19:303.

• MUCSI I, HERCZ G. CONTROL OF SERUM PHOSPHATE IN PATIENTS WITH RENAL FAILURE--NEW APPROACHES. NEPHROL DIAL TRANSPLANT 1998; 13:2457.

• BILLA V, ZHONG A, BARGMAN J, ET AL. HIGH PREVALENCE OF HYPERPARATHYROIDISM AMONG PERITONEAL DIALYSIS PATIENTS: A REVIEW OF 176 PATIENTS. PERIT DIAL INT 2000; 20:315.

• FOLEY RN, PARFREY PS, SARNAK MJ. CLINICAL EPIDEMIOLOGY OF CARDIOVASCULAR DISEASE IN CHRONIC RENAL DISEASE. AMJ KIDNEY DIS 1998; 32:S112.

• ISAKOVA T, XIE H, YANG W, ET AL. FIBROBLAST GROWTH FACTOR 23 AND RISKS OF MORTALITY AND END-STAGE RENAL DISEASE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. JAMA 2011; 305:2432.

• LEVIN A, BAKRIS GL, MOLITCH M, ET AL. PREVALENCE OF ABNORMAL SERUM VITAMIN D, PTH, CALCIUM, AND PHOSPHORUS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: RESULTS OF THE STUDY TO EVALUATE EARLY KIDNEY DISEASE. KIDNEY INT 2007;71:31.


References

• STEVENS LA, DJURDJEV O, CARDEW S, ET AL. CALCIUM, PHOSPHATE, AND PARATHYROID HORMONE LEVELS IN COMBINATION AND AS A FUNCTION OF DIALYSIS DURATION PREDICT MORTALITY: EVIDENCE FOR THE COMPLEXITY OF THE ASSOCIATION BETWEEN MINERAL METABOLISM AND OUTCOMES. J AM SOC NEPHROL 2004; 15:770.

• YOUNG EW, AKIBA T, ALBERT JM, ET AL. MAGNITUDE AND IMPACT OF ABNORMAL MINERAL METABOLISM IN HEMODIALYSIS PATIENTS IN THE DIALYSIS OUTCOMES AND PRACTICE PATTERNS STUDY (DOPPS). AM J KIDNEY DIS 2004; 44:34.

• KESTENBAUM B, SAMPSON JN, RUDSER KD, ET AL. SERUM PHOSPHATE LEVELS AND MORTALITY RISK AMONG PEOPLE WITH CHRONIC KIDNEY DISEASE. J AM SOC NEPHROL 2005; 16:520.

• KOVESDY CP, ANDERSON JE, KALANTAR-ZADEH K. OUTCOMES ASSOCIATED WITH SERUM PHOSPHORUS LEVEL IN MALES WITH NON-DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE. CLIN NEPHROL 2010; 73:268.

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• MENON V, GREENE T, PEREIRA AA, ET AL. RELATIONSHIP OF PHOSPHORUS AND CALCIUM-PHOSPHORUS PRODUCT WITH MORTALITY IN CKD. AM J KIDNEY DIS 2005; 46:455.

hyperphosphatemia in ckd

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