1、Therapeutics in Renal DiseaseDr Michael ClarksonConsultant Renal Physician CUHChronic Kidney DiseaseCommonEasy to DiagnoseEffective Therapies AvailableCKD Care SuboptimalSerum Creatinine is a Poor Marker of GFRMDRD eGFR MDRD equation Complex log rhythmic equation Integrates key variablesAgeSexCreati
2、nineRace Urea Albumin GFR is the accepted measure of kidney function GFR is difficult to infer from serum creatinine alone Automatic reporting identifies CKD patients with apparently“normal”serum creatinine Reduces barrier to early detectionMDRD eGFRThree simple tests identify CKD in adults Dipstick
3、 Urinalysis Haematuria/Macroalbuminuria Urine PCR-Urine protein to creatinine ratio on a“spot”urine sample 24-hour urine collections are NOT needed eGFR-Estimated GFR from serum creatinine using the MDRD equationSpot Ratios!24 hour collections cumbersome Excretion of creatinine and protein is reason
4、ably constant throughout the day A random urine protein:creatinine ratio has been shown to correlate with a 24-hr estimation Expressed either as mg/mg(easy)or mg/mmol(multiply x 0.0088)Spot Ratios!24yo lady with ankle oedema,proteinuria and hypercholesterolaemia Spot urine protein 924mg/L Spot urine
5、 creatinine 3343mol/L Ratio=276mg/mmol(normal:0-45)Convert to mg/mg(276 x 0.0088)=2.4g/24hrIdentifying CKDBISHBASHBOSHStaging of Chronic Kidney DiseaseStageDescriptionGFREvaluation/Plan 0At risk 90Modify risk factors 1Kidney damage/90Diagnose/Treat cause.Slownormal GFRprogression and evaluate CV ris
6、k.2Mild 60-89Estimate progression 3 Moderate30-59 Evaluate and treat complications 4Severe15-29 Prepare for RRT 5ESRD Glomerular Disease Tubulointerstitial Disease Hypertensive NephrosclerosisInitiation FactorsProgression FactorsProgressive loss of renal functionwill occur even inthe absence of over
7、t activity of the primary renal disorderProgression Factors Hypertension Glomerular Hypertension Proteinuria Hyperlipidemia Genetic Factors Miscellaneous Exacerbating Effect of Risk Factor Clustering Maladaptive Response to Loss of Nephron MassInitial Renal InsultLoss of Nephron MassCompensatory Glo
8、merular Hypertrophy/HyperfiltrationMaximisation of GFR Intraglomerular HypertensionPodocyte Injury/MesangialMatrix ExpansionSecondary FSGS Proteinuria/HypertensionRAAS BlockadeBP ControlDietary ProteinRestrictionHypertension and CKDRole of Hypertension in CKD Progression50-75%of patients with CKD ha
9、ve BP 140/90mmHgGoals of therapy 1.Retard CKD progression2.Reduce overall cardiovascular riskRole of Hypertension in CKD Progression Strong association with poor renal outcomes esp.in diabetic nephropathy Microalbuminuria progression Morphologic injury Predicts loss of renal function in non-diabetic
10、 glomerular disorders and in APKD.Confounding effect of proteinuria make accurate assessment of independent effect difficultHypertension and CKDTarget Blood PressureRelationship between BP Control and Rate of Decline in GFR Bakris et al AJKD,2000.Decline in GFR and HTN:Stratification for Proteinuria
11、MDRD Study:Arch Int Med,1995Effective Control of Hypertension in CKD:Multiple Agents RequiredBakris et alAJKD,2000Effective Control of Hypertension Yields Major Benefit in CKDEarly treatment can make a difference100100No TreatmentDelayedTreatmentEarly Treatment47914Kidney FailureGFR(mL/min/1.732)283
12、Blood Pressure Goals in CKD Stratify According to Proteinuria Proteinuria 3g Goal 3gGoal 30-299mg/day300mg/dayRoutine DipstickNegativePositiveRenal SignificanceRisk MarkerMarker of progressionCardiovascular RiskIncreasedIncreasedMaladaptive Response to Loss of Nephron MassInitial Renal InsultLoss of
13、 Nephron MassCompensatory Glomerular Hypertrophy/HyperfiltrationMaximisation of GFR Intraglomerular HypertensionPodocyte Injury/MesangialMatrix ExpansionSecondary FSGS Proteinuria/HypertensionProteinuria and CKD Proteinuria evaluation mandatory in all patients with CKD Independent risk factor for CK
14、D progression Best predictor of ESRDAdverse Consequences of Proteinuria vs low eGFRAll-Cause Mortality(per 1000 patient yrs rate(95%CI)Normal Mild HeavyeGFR 602.7(2.6-2.8)5.8(5.5-6.0)7.2(6.6-7.8)eGFR 45-592.9(2.7-3.0)5.2(5.5-6.0)7.2(6.5-7.8)eGFR 30-444.0(3.7-4.2)5.8(5.4-6.2)7.5(6.8-8.2)eGFR 15-306.7
15、(6.2-7.3)9.1(8.2-10.0)10.4(9.3-11.6)Hemmelgarn et al.JAMA.2010;303(5):423-429.Proteinuria In CKDIntervention StudiesPharmacologic Approaches Dietary ApproachesReduction in proteinuria Reduction in proteinuria is key to successful renoprotective strategy.Anti-hypertensive regimens with better reducti
16、on in proteinuria afford greater renoprotective benefits.Benefit persists even when BP within the normal range.Proteinuria and CKDPharmacologic ApproachesACE-I Decrease Proteinuria More than Conventional Anti-Hypertensive Therapy Jafar et al,Meta AnalysisAnn Int Med2001RAAS Blockade in CKD-Mechanism
17、 of Action Reduction in intraglomerular hypertension Efferent arteriolar vasodilatation Improved glomerular permselectivity Attenuation of AII-stimulated growth factor and inflammatory cytokine secretion Prevention of extracellular matrix accumulationAfferentEfferentVasodilatorsProstaglandinsNitric
18、OxideVasoconstrictorsEndothelinCatecholaminesAdenosineVasoconstrictorsAngiotensin-IIAfferentEfferentVasodilatorsProstaglandinsNitric OxideVasoconstrictorsAngiotensin-IIPGc HyperfiltrationMechanical Strain2 FSGSEfferentRAAS BlockadePGc Hypertension ControlBPLower GFRReduction in ProteinuriaAngiotensi
19、n Recptor BlockadeMore Risk,More Benefit!Initiation of ACE-I or ARB“Although ACE inhibitors now have a specialised role in some forms of renal disease they also occasionally cause impairment of renal function which may progress and become severe in other circumstances”BNFInitiation of ACE-I or ARBCa
20、se Example 42 year old lady Hypertension Recurrent UTI Atrophic left kidney Pre-eclampsia x 2 BP=155/95 MAP=115 SeCr=145umol/L.MDRD GFR=50ml/min Urine Protein to Creatinine ratio:1.4Initiation of ACE-I or ARB Initiated on Ramipril 5mg qd+low salt diet Day 7.BP=145/90 Ramipril increased to 10mg qd Da
21、y 14 BP 140/85 Repeat Creatinine=175umol/L,K+5.4mmol/L Estimated GFR=42mls/minInitiation of ACE-I or ARB Clinical Dilemma Substantial fall in GFR following RAAS blockade Hyperkalaemia Do not suspect renovascular disease Withdraw ACE-I/ARB?Initiation of RAAS Blockade:Initial reduction in GFR predicts
22、 better outcomeAperloo et al,Kid Int,1997Initiation of ACEi/ARB10010047914Kidney FailureGFR(mL/min/1.732)283Initiation of ACE-I or ARB Continue RAAS Blockade.Accept 25%fall in GFR.Ensure it is not progressive.Goal 130/80 Review Medications Dietary K+Restriction Diuretic Add second agent Diuretic Non
23、-dihydroperidine CCB Beta BlockerGoal Proteinuria Independent Risk Marker Therefore Needs Independent Therapeutic Goal Irrespective of BP Control Proteinuria Dose Response to RAAS Blockade May Not Parallell That of BPGoal Proteinuria 300mg/24hours or Ratio of 0.3 RAAS Blockade BP Control Protein Res
24、trictionCase Example 56year old Bachelor Farmer Type II DMM x 2 years Retinopathy Proteinuria Living alone High salt intake Referred for management of rising serum creatinineCase Example Medications Basal Bolus Insulin Amlodipine 10mg daily 24 hour urinary sodium 160mmol/L01/200509/200601/200702/200
25、9Creat87120140247eGFR78564723PCRBP160/90165/95165/93170/95Case ExampleRelationship between BP Control and Rate of Decline in GFR Bakris et al AJKD,2000.Interventions:Tight salt restriction(100mmol/5g)No added salt No salt in cooking Minimise pre-prepared food Ramipril 5mg 40/3mmHg BP dropCase exampl
26、e01/200509/200601/200702/200904/200907/200902/201006/2010Creat87120140247268270260298eGFR7856472321212219PCR2.80.60.70.1BP160/90165/95165/93170/95160/75135/70130/70122/72Case ExampleNephrology ReferralCase ExampleGiving up the salt made an awful differenceSalt is a poison!By the way,Dr Horgan tells
27、me my eyes are way betterCase exampleSummary In proteinuric CKD ACE-inhibition+5g salt restriction Diuretic(thiazide or loop eGFR)Non-dihydropyridine CCB Others Goal 130/80mmHg at least ARB in Type II DM or if ACEi cough Summary In non-proteinuric CKD 5g salt restriction ACE-i not mandatory Diuretic(thiazide or loop eGFR)Non-dihydropyridine CCB Others Goal 130/80mmHg?Beware ARVDQUESTIONS?
