Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Medicationsandthe Nephron RonnieMoussaMD WichitaNephrologyGroup April10th,2015

Objectives • NSAIDs– KidneyFunction,Potassiumand Sodium • HeparinͲ Potassium • Sulfamethoxazole/Trimethoprim(Bactrim®)– PotassiumandCreatinine • Warfarin– KidneyFunction • GoutMedicationsandKidneyfunction Ͳ CertainmedicationsandUricAcidlevels

1

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

NSAIDs NonͲsteroidalantiͲinflammatorydrug PLEASE DONOTTAKE

Celecoxib (Celebrex®) Ibuprofen(Advil®),(Motrin®) Indomethacin (Indocin®) Meloxicam (Mobic®) Naproxen (Nasprosyn®),(Aleve®),(Anaprox®) Diclofenac (Voltaren®) Sulindac

2

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

NonͲsteroidalAntiͲinflammatory Drugs NSAIDs

• COXͲ1

– Expressedinmosttissues – Regulatesnormalcellularprocesses

• COXͲ2 – Expressionincreasedduringstatesof inflammation

NSAIDsandRenalEvents • • • • • •

HemodynamicKidneyInjury AcuteInterstitialNephritis NephroticSyndrome PapillaryNecrosis ElectrolyteAbnormalities Hypertension/Edema

3

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

NSAIDsandRenalEvents • Occursin1Ͳ5%ofNSAIDsusers • 2.5Millionincidentsayear – ~70millionprescriptions – 30billionOTCuses

• RiskFactors Age Hypercalcemia VolumeDepletion DecreaseKidneyperfusionformCHF,NephroticSyndromeor Cirrhosis – MedicationsspeciallyACEIandARB – TheaboveleadtoincreasedproductionofCOXͲ2 – – – –

NSAIDsandReducingGFR

4

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Afferent

STRESS

Glomerul ous

Efferent

ANGII

PGs

PGs

ANGII ACEI/A RB

COXͲ2I (NSAIDs)

NSAIDsandHyperkalemia

5

GFR

GFR

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

NSAIDsand Hyperkalemia Peritubular Blood

3Na +

A T P

P G

Principle Cell

Al d 2K+

P G

NSAIDs Lumen

URI NE

NSAIDsandHyperkalemia 50hospitalpts GivenIndomethacin 40%Î Kroseby0.5 mEq/L 34%Î Kroseby0.5Ͳ0.9 mEq/L 26%Î Kroseby1 mEq/L pts

BrMedJ(Clin ResEd).1985Jul13;291(6488):107Ͳ8.Incidenceofhyperkalaemia inducedbyindomethacininahospital population.ZimranA,KramerM,PlaskinM,HershkoC.

6

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

NSAIDsandHyponatremia • ADHisantiͲdiuretichormone • Itincreasesthepermeabilityofthecollecting ductinthekidneyforwaterretentionwhen needed • ProducedintheHypothalamusasresponseto Thirst,increaseserumosmolarityand Hypovolemia • ProducedinappropriatelyinCHFandSIADH

NSAIDsandHyperkalemia

7

NSAIDsandHyponatremia

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Peritubular Blood H2 O AD H

AqP

V2

Principle Cell

P G

NSAIDs Exacerbated in SIADH CHF Cirrhosis

URI NE

Lumen

NSAIDsandEdema • EdemaisduetoSaltreabsorption • PGcontributestoSaltWastingandBlocking theirproductionÎ SaltRetention – Studiesshowed0.5Ͳ 1kgweightgainwithchronic NSAIDsuse • EffectmostobviousinCHFandCirrhosis • ResistancetoDiuretics

– PGcausevasodilatationandblockingits productionÎ vasoconstrictionandincreasein afterloadinCHF

8

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

WhichNSAIDstoUse? • Noneifpossible • SomestudiesshowedthatSulindacisthe “safest’ • WhataboutAspirin? – Usuallyinlowdoses – StudieshaveshownthatASAhasaPartialand TransientglomerularPGinhibition

SomeNSAIDSEffects InSummary

• AcuteKidneyInjury – HemodynamicAKI – AcuteInterstitialNephritis – NephroticchangesinMinimalChangeDiseaseand Membranous

• Hyperkalemia • Hyponatremia • HypertensionandEdema

9

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Heparin

HeparinandHyperkalemia • Evenaprophylacticdoseof5000BIDSQcan leadtoelevatedPotassium • Thisoccursin7%ofpatients • SevereHyperkalemiainassociationwithother factorslikeAKI,ACEI/ARBandSpironolactone • LowMolecularWeightHeparinhasthesame effect

10

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

HeparinandHyperkalemia

NSAIDsandHyperkalemia

3N a+

Peritubular Blood A T P 2K

Principle Cell

Al d

+

Heparin

URI NE

Lumen

11

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Sulfamethoxazole/Trimethopri m(Bactrim®)

TRIMETHOPRIMandHYPERKALEMIA

12

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

TRIMETHOPRIMandHYPERKALEMIA • DoseDependent • Riskfactorsinclude: – TheElderly – AcuteKidneyInjury – ACEI,ARB,NSAIDsorSpironolactone

• Typically,Potassiumreaches5mEq/Lin4Ͳ5 days

Trimethoprim andHyperkalemia 3 N a

Peritubular Blood A T P 2 K

URI NE

Principle Cell

Al d

Trimethopr im Pentamidin e Lumen

Amiloride Trimamtere ne

13

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

TRIMETHOPRIM ANDELEVATED CREATININE • Likemanyotherdrugs,itcancauseAcute InterstitialNephritis • But…that’snotwhatIamtalkingabouthere

14

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Trimethoprim (inBactrim®) Cimetidine Dronedorone (Multaq®)

15-50% secreted

TrimethoprimandElevatedCreatinine

NSAIDsandHyperkalemia

Proximal Tubule

Cr

SerumCreatinineincreaseswithno effectonGFR 15

G

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Warfarin

WARFARINANDKIDNEYINJURY • WarfarinͲrelatedNephropathy • AcuteKidneyInjuryinpatientsonWarfarin (anyanticoagulation)withapersistentINR>3Ͳ 4

16

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

WARFARINANDKIDNEYINJURY • EPIDEMIOLOGYandONSET – Usuallyoccurs8weeksafterinitiationofWarfarin – VerydifficulttoassesstheEpidemiology – OnlyconfirmedbyBiopsythatisperformedlessin suchpatients • ReluctancetobiopsypatientswithhighINRs • AKIisattributedtootherEtiologies

– Approximately17% ofpatientsexperienceWRN andthepercentageincreaseswiththepresenceof certainriskfactors

WARFARINANDKIDNEYINJURY • RISKFACTORS – Chronickidneydisease – Heartdisease – Hypovolemia – Glomerulonephritis – Hypertension

17

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

PRESENTATIONOFWRN • 8weeksintotheinitiationofWarfarin • PatientsareHypertensive,volumeoverloaded withdecreasedUOP • RarelywithGrossHematuriaandmainly microscopichematuria – AbsenceofHematuriadoesnotexcludeWRN

18

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

TREATMENT&PROGNOSISOFWRN • Reversalofhypercoagulation – Quickreversalmightbeofbenefit

• Supportivecare • MostpatientsimprovetheirCreatininewithin thefirstfewweeksofnormalizedINR – SomepatientscontinuetohaveCKDandactually somestudiesshowedincreaseMortality

WARFARINͲRELATEDNEPHROPATHY • AKIinptsonWarfarin(orDabigatran)usually for8weekswithINRs>3Ͳ4leadingto GlomerularbleedingandRBCcast(withor withoutM.Hematuria)thatusuallyresolves withcessationofWarfarinandreversalof anticoagulationwiththeusualrecommended management

19

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

GOUTandKidney

GOUTTREATMENTinCKD • 98%ofGoutpatients,inGeneral,are undertreated

20

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

Beerx2Ͳ4

Obesity

Purine

Liquorx1Ͳ2

HTN

RedMeat,Sea Food HypoͲXanthine

Diuretics

Xanthine Oxidase

Xanthine 10,000 Patents OTC Cosmetics

Xanthine Oxidase

Uric acid

SmothesSkin

Uricaseinother Mammals

Wound Healing

Allantoin

AntiIrritant

Purine

HypoͲXanthine Xanthine Oxidase Allopurinol

Xanthine Febuxostat Xanthine Oxidase

Uric acid Rasburicase Uricase Pigloticase

Allantoin 21

Medicationa and the Nephron Ronnie Moussa, MD

Family Medicine Spring Symposium April 10, 2015

AllopurinolDose • Approvedforadoseupto800mgaday(keyistokeepUricacid levels30mL/min • NotwelldefinedforCrCl