Therapeutics in Renal
Disease
Dr Michael Clarkson
Consultant Renal Physician –
CUH
Chronic Kidney Disease
Common
Easy to Diagnose
Effective Therapies Available
CKD Care Suboptimal
Serum Creatinine is a Poor
Marker of GFR
MDRD eGFR
• MDRD equation – Complex log rhythmic
equation
• Integrates key variables
Age
Sex
Creatinine
Race
Urea
Albumin
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
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
Spot Ratios!
• 24 hour collections cumbersome
• Excretion of creatinine and protein is reasonably
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
• Spot urine creatinine
924mg/L
3343µmol/L
• Ratio = 276mg/mmol (normal: 0-45)
• Convert to mg/mg (276 x 0.0088) = 2.4g/24hr
Identifying CKD
BISH
BASH
BOSH
Staging of Chronic Kidney
Disease
Stage Description
GFR
Evaluation / Plan
>90
Modify risk factors
0
At risk
1
Kidney damage / >90
normal GFR
Diagnose / Treat cause. Slow
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
<15
Initiate RRT
NKF, USA
Factors Mediating Evolution of
CKD
• Susceptibility Factors
• Initiation Factors
• Progression Factors
Susceptibility Factors
• Male gender
– Hypertension
• Age
– 1ml/year loss normally
• Genetic Background
– ACE polymorphisms
• Reduced Nephron Mass at Birth
Initiation Factors
Diabetic Nephropathy > Glomerular
Disease > Tubulointerstitial Disease >
Hypertensive Nephrosclerosis
Progression Factors
Progressive loss of renal function
will occur even in
the absence of overt activity
of the primary renal disorder
Progression Factors
•
•
•
•
•
•
Hypertension
Glomerular Hypertension
Proteinuria
Hyperlipidemia
Genetic Factors
Miscellaneous
• Exacerbating Effect of Risk Factor
Clustering
Maladaptive Response to Loss of
Nephron Mass
Initial Renal Insult
BP Control
Loss of Nephron Mass
RAAS Blockade
Dietary Protein
Restriction
Secondary FSGS 
Proteinuria / Hypertension
Compensatory Glomerular
Hypertrophy / Hyperfiltration
Podocyte Injury / Mesangial
Matrix Expansion
Maximisation of GFR 
Intraglomerular Hypertension
Hypertension and CKD
Role of Hypertension in CKD
Progression
•
50-75% of patients with CKD have
BP >140/90mmHg
Goals of therapy
1. Retard CKD progression
2. Reduce overall cardiovascular risk
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 nondiabetic glomerular disorders and in APKD.
• Confounding effect of proteinuria make
accurate assessment of independent
effect difficult
Hypertension and CKD
Target Blood Pressure
Relationship between BP Control
and Rate of Decline in GFR
Bakris et al AJKD, 2000.
Decline in GFR and HTN: Stratification
for Proteinuria
MDRD Study:
Arch Int Med, 1995
Effective Control of Hypertension in
CKD:
Multiple Agents Required
Bakris et al
AJKD, 2000
Effective Control of Hypertension
Yields Major Benefit in CKD
Early treatment can
make a difference
100
No Treatment
DelayedTreatment
Early Treatment
GFR (mL/min/1.732)
83
10
Kidney Failure
0
2
4
7
9
14
Blood Pressure Goals in CKD
• Stratify According to Proteinuria
– Proteinuria <3g
– Proteinuria >3g
Goal <130/80
Goal <125/75
– Optimal Blood Pressure Unknown
– Diuretics Essential
– 120/80??
Proteinuria and CKD
Microalbuminuria and Macroalbuminuria
Microalbuminuria
Macroalbuminuria
Definition
>30-299mg/day
>300mg/day
Routine Dipstick
Negative
Positive
Renal Significance
Risk Marker
Marker of
progression
Cardiovascular Risk
Increased
Increased
Maladaptive Response to Loss of
Nephron Mass
Initial Renal Insult
Loss of Nephron Mass
Secondary FSGS 
Proteinuria / Hypertension
Compensatory Glomerular
Hypertrophy / Hyperfiltration
Podocyte Injury / Mesangial
Matrix Expansion
Maximisation of GFR 
Intraglomerular Hypertension
Proteinuria and CKD
• Proteinuria evaluation mandatory in all
patients with CKD
• Independent risk factor for CKD
progression
• Best predictor of ESRD
Adverse Consequences of
Proteinuria vs low eGFR
All-Cause Mortality
(per 1000 patient yrs – rate (95% CI))
Normal
Mild
Heavy
eGFR >60
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. 2010;303(5): 423-429.
Proteinuria In CKD
Intervention Studies
Pharmacologic Approaches
Dietary Approaches
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’.
Proteinuria and CKD
Pharmacologic Approaches
ACE-I Decrease Proteinuria More
than Conventional AntiHypertensive Therapy
Jafar et al,
Meta Analysis
Ann Int Med
2001
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
Vasodilators
Prostaglandins
Nitric Oxide
Afferent
Vasoconstrictors
Endothelin
Catecholamines
Adenosine
Efferent
Vasoconstrictors
Angiotensin-II
Vasodilators
Prostaglandins
Nitric Oxide
Afferent
Hyperfiltration
Mechanical Strain
2º FSGS
PGc 
Efferent
Vasoconstrictors
Angiotensin-II
Hypertension
Control
BP
PGc 
Lower GFR
Reduction in Proteinuria
Efferent
RAAS Blockade
Angiotensin Recptor Blockade
More 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”
BNF
Initiation of ACE-I or ARB
Case 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: 1.4
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
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?
Initiation of RAAS Blockade :
Initial reduction in GFR predicts better
outcome
Aperloo et al,
Kid Int, 1997
Initiation of ACEi /
ARB
100
GFR (mL/min/1.732)
83
10
Kidney Failure
0
2
4
7
9
14
Initiation 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-dihydroperidine CCB
• Beta Blocker
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
Goal Proteinuria
• <300mg/24hours or Ratio of <0.3
• RAAS Blockade
• BP Control
• ± Protein Restriction
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
Case Example
• Medications
– Basal Bolus Insulin
– Amlodipine 10mg daily
• 24 hour urinary sodium 160mmol/L
Case Example
01/2005
09/2006
01/2007
02/2009
Creat
87
120
140
247
eGFR
78
56
47
23
160/90
165/95
165/93
170/95
PCR
BP
Relationship between BP Control
and Rate of Decline in GFR
Bakris et al AJKD, 2000.
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
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
2.8
0.6
0.7
0.1
160/75
135/70
130/70
122/72
PCR
BP
160/90
165/95
165/93
170/95
Nephrology Referral
Case Example
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’
Summary
• 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 ARVD
QUESTIONS?