Therapeutics in Renal Disease

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Therapeutics in Renal Disease

• Dr Michael Clarkson
• Consultant Renal Physician CUH

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Chronic Kidney Disease

• Common
• Easy to Diagnose
• Effective Therapies Available
• CKD Care Suboptimal

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Serum Creatinine is a Poor Marker of GFR
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MDRD eGFR

• MDRD equation Complex log rhythmic equation
• Integrates key variables

Age Sex Creatinine Race
Urea Albumin
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MDRD eGFR

• 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 detection

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Three simple tests identify CKD in adults

• Dipstick 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 equation

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Spot Ratios!

• 24 hour collections cumbersome
• Excretion of creatinine and protein is reasonably
  constant throughout the day
• A random urine proteincreatinine ratio has been
  shown to correlate with a 24-hr estimation
• Expressed either as mg/mg (easy) or mg/mmol
  (multiply x 0.0088)

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Spot Ratios!

• 24yo lady with ankle oedema, proteinuria and
  hypercholesterolaemia
• Spot urine protein 924mg/L
• Spot urine creatinine 3343µmol/L
• Ratio 276mg/mmol (normal 0-45)
• Convert to mg/mg (276 x 0.0088) 2.4g/24hr

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Identifying CKD
BISH
BASH
BOSH
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Staging of Chronic Kidney Disease
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• Stage Description GFR Evaluation / Plan
• 0 At risk gt90 Modify risk factors
• 1 Kidney damage / gt90 Diagnose / Treat cause.
  Slow
• normal GFR progression and evaluate CV
  risk.
• 2 Mild 60-89 Estimate progression
  
• 3 Moderate 30-59 Evaluate and treat
  complications
• 4 Severe 15-29 Prepare for
  RRT
• 5 ESRD lt15 Initiate RRT

NKF, USA
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Factors Mediating Evolution of CKD

• Susceptibility Factors
• Initiation Factors
• Progression Factors

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Susceptibility Factors

• Male gender
• Hypertension
• Age
• 1ml/year loss normally
• Genetic Background
• ACE polymorphisms
• Reduced Nephron Mass at Birth

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Initiation Factors

• Diabetic Nephropathy gt Glomerular
• Disease gt Tubulointerstitial Disease gt
• Hypertensive Nephrosclerosis

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Progression Factors

• Progressive loss of renal function
• will occur even in
• the absence of overt activity
• of the primary renal disorder

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Progression Factors

• Hypertension
• Glomerular Hypertension
• Proteinuria
• Hyperlipidemia
• Genetic Factors
• Miscellaneous
• Exacerbating Effect of Risk Factor Clustering

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Maladaptive Response to Loss of Nephron Mass
Initial Renal Insult
Loss of Nephron Mass
Compensatory Glomerular Hypertrophy /
Hyperfiltration
Secondary FSGS ? Proteinuria / Hypertension
Maximisation of GFR ? Intraglomerular Hypertension
Podocyte Injury / Mesangial Matrix Expansion
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Hypertension and CKD
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Role of Hypertension in CKD Progression

• 50-75 of patients with CKD have
• BP gt140/90mmHg
• Goals of therapy
• Retard CKD progression
• Reduce overall cardiovascular risk

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Role 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
  glomerular disorders and in APKD.
• Confounding effect of proteinuria make accurate
  assessment of independent effect difficult

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Hypertension and CKD

• Target Blood Pressure

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Relationship between BP Control and Rate of
Decline in GFR
Bakris et al AJKD, 2000.
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Decline in GFR and HTN Stratification for
Proteinuria
MDRD Study Arch Int Med, 1995
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Effective Control of Hypertension in
CKDMultiple Agents Required
Bakris et al AJKD, 2000
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Effective Control of Hypertension Yields Major
Benefit in CKD
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Early treatment can make a difference
100
No Treatment DelayedTreatment Early Treatment
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GFR (mL/min/1.732)
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Kidney Failure
0
4
7
9
14
2
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Blood Pressure Goals in CKD

• Stratify According to Proteinuria
• Proteinuria lt3g Goal lt130/80
• Proteinuria gt3g Goal lt125/75
• Optimal Blood Pressure Unknown
• Diuretics Essential
• 120/80??

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Proteinuria and CKD
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Microalbuminuria and Macroalbuminuria

• Microalbuminuria Macroalbuminuria
• Definition gt30-299mg/day gt300mg/day
• Routine Dipstick Negative Positive
• Renal Significance Risk Marker Marker of
  progression
• Cardiovascular Risk Increased Increased

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Maladaptive Response to Loss of Nephron Mass
Initial Renal Insult
Loss of Nephron Mass
Compensatory Glomerular Hypertrophy /
Hyperfiltration
Secondary FSGS ? Proteinuria / Hypertension
Maximisation of GFR ? Intraglomerular Hypertension
Podocyte Injury / Mesangial Matrix Expansion
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Proteinuria and CKD

• Proteinuria evaluation mandatory in all patients
  with CKD
• Independent risk factor for CKD progression
• Best predictor of ESRD

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Adverse Consequences of Proteinuria vs low eGFR
All-Cause Mortality (per 1000 patient yrs rate (95 CI)) All-Cause Mortality (per 1000 patient yrs rate (95 CI)) All-Cause Mortality (per 1000 patient yrs rate (95 CI)) All-Cause Mortality (per 1000 patient yrs rate (95 CI))
Normal Mild Heavy
eGFR gt60 2.7 (2.6-2.8) 5.8 (5.5-6.0) 7.2 (6.6-7.8)
eGFR 45-59 2.9 (2.7-3.0) 5.2 (5.5-6.0) 7.2 (6.5-7.8)
eGFR 30-44 4.0 (3.7-4.2) 5.8 (5.4-6.2) 7.5 (6.8-8.2)
eGFR 15-30 6.7(6.2-7.3) 9.1 (8.2-10.0) 10.4 (9.3-11.6)
Hemmelgarn et al. JAMA. 2010303(5) 423-429.
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Proteinuria In CKD

• Intervention Studies
• Pharmacologic Approaches
• Dietary Approaches

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Reduction in proteinuria

• Reduction in proteinuria is key to successful
  renoprotective strategy.
• Anti-hypertensive regimens with better reduction
  in proteinuria afford greater renoprotective
  benefits.
• Benefit persists even when BP within the normal
  range.

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Proteinuria and CKD

• Pharmacologic Approaches

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ACE-I Decrease Proteinuria More than Conventional
Anti-Hypertensive Therapy
Jafar et al, Meta Analysis Ann Int Med 2001
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RAAS Blockade in CKD -Mechanism 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 accumulation

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Vasodilators Prostaglandins Nitric Oxide
Efferent
Afferent
Vasoconstrictors Endothelin Catecholamines Adenosi
ne
Vasoconstrictors Angiotensin-II
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PGc ?
Efferent
Afferent
Hyperfiltration Mechanical Strain ?2º FSGS
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BP
PGc ?
Efferent
Lower GFR Reduction in Proteinuria
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Angiotensin Recptor BlockadeMore Risk, More
Benefit!
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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
• BNF

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Initiation of ACE-I or ARB

• Case Example
• 42 year old lady
• Hypertension
• Recurrent UTI
• Atrophic left kidney
• Pre-eclampsia x 2
• BP155/95 MAP115
• SeCr 145umol/L. MDRD GFR 50ml/min
• Urine Protein to Creatinine ratio 1.4

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Initiation of ACE-I or ARB

• Initiated on Ramipril 5mg qd low salt diet
• Day 7. BP 145/90
• Ramipril increased to 10mg qd
• Day 14 BP 140/85
• Repeat Creatinine 175umol/L, K 5.4mmol/L
• Estimated GFR 42mls/min

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Initiation of ACE-I or ARB

• Clinical Dilemma
• Substantial fall in GFR following RAAS blockade
• Hyperkalaemia
• Do not suspect renovascular disease
• Withdraw ACE-I / ARB?

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Initiation of RAAS Blockade Initial reduction
in GFR predicts better outcome
Aperloo et al, Kid Int, 1997
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Initiation of ACEi / ARB
100
83
GFR (mL/min/1.732)
10
Kidney Failure
0
4
7
9
14
2
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Initiation of ACE-I or ARB

• Continue RAAS Blockade.
• Accept lt25 fall in GFR. Ensure it is not
  progressive.
• Goal 130/80
• Review Medications
• Dietary K Restriction ? Diuretic
• Add second agent
• Diuretic
• Non-dihydroperidine CCB
• Beta Blocker

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Goal Proteinuria

• Independent Risk Marker
• Therefore Needs Independent Therapeutic Goal
  Irrespective of BP Control
• Proteinuria Dose Response to RAAS Blockade May
  Not Parallell That of BP

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Goal Proteinuria

• lt300mg/24hours or Ratio of lt0.3
• RAAS Blockade
• BP Control
• Protein Restriction

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Case Example

• 56year old Bachelor Farmer
• Type II DMM x 2 years
• Retinopathy
• Proteinuria
• Living alone
• High salt intake
• Referred for management of rising serum creatinine

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Case Example

• Medications
• Basal Bolus Insulin
• Amlodipine 10mg daily
• 24 hour urinary sodium 160mmol/L

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Case Example
01/2005 09/2006 01/2007 02/2009
Creat 87 120 140 247

eGFR 78 56 47 23

PCR

BP 160/90 165/95 165/93 170/95
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Relationship between BP Control and Rate of
Decline in GFR
Bakris et al AJKD, 2000.
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Case example

• Interventions
• Tight salt restriction (100mmol / 5g)
• No added salt
• No salt in cooking
• Minimise pre-prepared food
• Ramipril 5mg
• 40/3mmHg BP drop

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Case Example
01/2005 09/2006 01/2007 02/2009 04/2009 07/2009 02/2010 06/2010
Creat 87 120 140 247 268 270 260 298

eGFR 78 56 47 23 21 21 22 19

PCR 2.8 0.6 0.7 0.1

BP 160/90 165/95 165/93 170/95 160/75 135/70 130/70 122/72
Nephrology Referral
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Case Example
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Case example

• Giving up the salt made an awful difference
• Salt is a poison!
• By the way, Dr Horgan tells me my eyes are way
  better

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Summary

• In proteinuric CKD
• ACE-inhibition 5g salt restriction
• Diuretic (thiazide or loop eGFR)
• Non-dihydropyridine CCB
• Others
• Goal lt130/80mmHg at least
• ARB in Type II DM or if ACEi ? cough

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Summary

• In non-proteinuric CKD
• 5g salt restriction
• ACE-i not mandatory
• Diuretic (thiazide or loop eGFR)
• Non-dihydropyridine CCB
• Others
• Goal lt130/80mmHg?
• Beware ARVD

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Questions?