Myths and facts in Nephrology, 2016

Sheffield Kidney Institute
Myths and Legends in Nephrology
Jordanian Society of Nephrology 2016
Prof Meguid El Nahas, MD, PhD, FRCP
Professor of Nephrology & Chairman
Global Kidney Academy
Sheffield, UK

The Nephrology Herd Mentality

Critical Thinking

Nephrology
Publications

Nephrologist
CKD
Proteinuria
ACEi
BP

CKD Prevalence is rising
KDIGO CKD Classification is useful
eGFR is useful
Maximum BP reduction slows Progression
Proteinuria reduction slows Progression
ACE inhibition Slows Progression

CKD Prevalence is rising in Community

An increasing number of people are
suffering from CKD…

CKD Prevalence in UK

UK CKD
eGFRKDOQI
Classification
CKD Prevalence in UK

What is CKD Prevalence?
a. 5%
b. 10%
c. 20%
d. 40%

What is CKD Prevalence
in the over 65?
a. 5%
b. 10%
c. 20%
d. 40%

McCullough et al, 2012

Prevalence of CKD
NHANESIII
0%
5%
10%
15%
20%
25%
30%
35%
40%
Prevalenc
e (%)
20-39 40-59 60-69 70+
Age Group (years)
<2%
>30%

Population Profile

eGFR Decline with Age

Population Profile
GFR = 120 GFR = 100 GFR = 90

IS AGEING A DISEASE?

Medicalisation of Normality
cCKD in the Aged

eGFR & RAAS Prescribing
Jain et al, 2012

Deviation from Normality <60 Years
3 Moderate renal insufficiency 59-30
4 Severe renal insufficiency 29-15
5 Kidney Failure/ERF/ESRD <15
60
120

Deviation from Normality >60 Years
90

A
G
E
M
O
R
T
A
L
I
T
Y

Deviation from Normality >60 Years
45
90

CKD Classification <60years
Stage Description GFR
1 Kidney damage/normal GFR >90ml/min
2 Mild renal insufficiency 89-60
3 Moderate renal insufficiency
A 59-45*
B 44-30 (p)
• * * = not applicable >60 unless proteinuria (p) present
2014 Revised Classification

2014 Revised Classification
CKD Classification>60
Stage Description GFR
1 Kidney damage/normal GFR >90ml/min*
2 Mild renal insufficiency 89-45*

CKD3a
US = 5m
China: 20m
Age Related “CKD3a”

CKD3a
US = 5m
China: 20m
Age Related “CKD3a”
3.6 1

Is CKD rising in the Community

eGFR is useful

Sheffield Kidney Institute 19
LDL-cholesterol (mg/dl) 137.0 (41.6)
Table 2 – eGFR levels and CKD by estimating method, in the overall sample and by age
strata.
Method
Overall sample age <65 age 65+
eGFR
ml/min/1.73m2
CKD:
eGFR <60
ml/min/1.73m2
No. of
individuals with
eGFR <30
ml/min/1.73m2
eGFR ml/min/1.73m2
mean (SD)
mean (SD) N
Prevalence
% (95%CI)
MDRD-4 84.7 (16.2) 69 5.8 (4.5-7.2) 1 86.8 (15.3) 74.3 (16.3)
MDRD-6 87.0 (16.1) 46 3.8 (2.8-5.1) 1 89.6 (15.0) 74.4 (15.1)
CKD-EPI 92.8 (16.8) 43 3.6 (2.6-4.8) 0 96.6 (14.9) 74.4 (13.3)
Virga 99.2 (20.9) 21 1.8 (1.1-2.7) 0 102.7 (19.7) 82.3 (18.2)
Cystatin C 103.9 (24.6) 52 4.3 (3.3-5.6) 2 110.0 (20.7) 74.6 (20.2)
Cystatin / Creatinine 98.6 (19.8) 33 2.8 (1.9-3.8) 1 103.1 (17.1) 76.9 (17.4)
Pattaro et al, 2013
CKD Classification

Spanaus et al, MMKD 2010
CKD Detection

KDIGO 2012
ESRD Risk: An Early Detection
sCr

fils, M., Nivez, M. P., Isaac, R., Mayaud, C., Sraer,
olec. Med. 1975, 49, 301.
. P., Piamba, G., Fillastre, J. P., Ardaillou, R. Nephro-
.
, J. A., Earnshaw, M., Russell, R. G. G., Woods, C. G.
Transpl. Ass. (in the press).
nshaw, M., Heynen, G., Ledmgham, J. G. G., Oliver,
Russell, R. G. G., Woods, C. G. ibid. (in the press).
rson, R. G., Heynen, G., Ledingham, J. G. G., Russell,
R., Walton, R. J. Archs dis. Childh, (in the press).
on, J. L. E. Israel. J. med. Sci. 1971, 7, 488.
ith, R., Ledingham, J. G. G., Oliver, D. O. Proc. eur.
ss. 1971, 8, 122.
nenko, P., Meyner, A., Vallee, G., Beaugas, C. J. clin. In-
345.
53226, U.S.A.
In 31 of 34 patients with chronic renal
insufficiency caused by various diseases,
um-creatinine concentration declined
inine concentration rose from a mean of
ot;8 mg/dl over an average of 71 months.
indicate that in most cases reciprocal
e declines linearly with time as chronic
gresses. Analysis of this relation in indi-
gives an estimate of the progression of
help to determine the effects of therapy,
ed to predict when dialysis will become
Introduction
enal failure develops, serum-creatinine
easingly more rapidly. (This prediction
e well known inverse relation between
nd serum concentration of substances
-rate is constant.l If this were the case,
m-creatinine might fall linearly with
ned this hypothesis in patients who had
ilure with various causes.
Methods
ecords of all patients with chronic renal fail-
n followed in a renal clinic for at least a year
here were 34 patients in whom 7 or more cre-
tions had been performed and in whom there
a threefold increase in creatinine concentra-
r of determinations over a period of at least
sen as sufficient to determine whether there
trend in serum-creatinine with time in indi-
he reciprocal of serum-creatinine concentra-
at the Annual Meeting of the American Federation
h, Atlantic City, N.J., May 2-5, 1976, and pub-
rm (Clin. Res. 1976, 24, 407).
accompanying table. The average of the correlation
coefficients was 0.954 (excluding the patients who had
a non-linear decline in reciprocal serum-creatinine). The
95% confidence limits of the slopes averaged 17.1% of
the individual slopes, with a range of 5.6 to 32.0%.
These limits indicate the smallest change in the rate of
progression that would be detectable by this method.
Discussion
These results indicate that in most patients reciprocal
serum-creatinine concentration declines linearly as
chronic renal failure progresses. There appear to be few
Composite plot of reciprocal serum-creatinine concentration (in
mg/dl) versus months of observation in 6 patients with
chronic renal failure.
Final value for reciprocal of serum-creatinine concentration is
shown for each patient. Ordinate has uniform divisions of 0.1 dl/mg.
Diagnoses in these patients are indicated.
CKD Progression
Mitch et al 1976
1:sCr

Prediction of CKD Progression

sCr >148umol/lGFR <54ml/min
sCR and GFR Prognostic value

KDIGO 2010

Chang and Kramer, 2011

Mantra: “Early Detection…Better Prevention…”
O’Hare et al, 2013

sCr = eGFR
eGFR = mGFR

Maximum BP Reduction Slows Progression

CKD progression and BP control
MDRD Study – BP and long term outcomes
Sarnak M et al , 2005

CKD Progression and BP Meta-Analysis
Jafar et al, 2003

Clinical Trials

HOPE Study
Svensson et al, 2001

Proteinuria Reduction Slows Progression

Reducing Proteinuria Slows CKD Progression

Loss AutoRegulation
Afferent arteriolar
Vasodilatation
AII
Glomerular Hyperfiltration

Reduction of Proteinuria

Reduction in Albuminuria
• Benazapril + Hydrochlorothiazide: - 63.8%
• Benazapril + Amlodipine: - 29%

• Albuminuria Reduction
Aliskiren: -16%
• Control: - 5%

Renal outcomeswithtelmisartan, ramipril, or both, in
peopleat high vascular risk (the ONTARGETstudy):
amulticentre, randomised, double-blind, controlled trial
JohannesFEMann,RolandESchmieder ,MatthewMcQueen,LeanneDyal,Helmut Schumacher ,JanicePogue,Xingyu Wang,AldoMaggioni,
Andrzej Budaj,Suphachai Chaithiraphan,Kenneth Dickstein, MatyasKeltai, Kaj Metsärinne,Ali Oto,Alexander Parkhomenko, LeopoldoSPiegas,
TageLSvendsen, KoonKTeo,SalimYusuf, onbehalf of theONTARGETinvestigators
Summary
Background Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to
reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for
comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE
inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established
atherosclerotic vascular disease or with diabetes with end-organ damage.
MethodsThe trial ran from 2001 to 2007. After a 3-week run-in period, 25620 participants were randomly assigned to
ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median
follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a
composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is
registered with ClinicalTrials.gov, number NCT00153101.
Findings784 patientspermanently discontinued randomised therapy during the trial because of hypotensive symptoms
(406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of eventsfor the composite primary
outcome was similar for telmisartan (n=1147 [13· 4%]) and ramipril (1150 [13· 5%]; hazard ratio [H R] 1· 00, 95% CI
0· 92–1· 09), but was increased with combination therapy (1233 [14.5%]; H R 1· 09, 1· 01–1· 18, p=0· 037). The secondary
renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2· 21%]) and ramipril (174
[2· 03%]; H R 1· 09, 0· 89–1· 34) and more frequent with combination therapy (212 [2· 49%]: H R 1· 24, 1· 01–1· 51,
p=0· 038). Estimated glomerular ﬁltration rate (eGFR) declined least with ramipril compared with telmisartan
(–2· 82 [SD 17· 2] mL/ min/ 1· 73 m² vs −4· 12 [17· 4], p<0· 0001) or combination therapy (−6· 11 [17· 9], p<0· 0001). The
increase in urinary albumin excretion was less with telmisartan (p=0· 004) or with combination therapy (p=0· 001) than
with ramipril.
Interpretation In people at high vascular risk, telmisartan’s effects on major renal outcomes are similar to ramipril.
Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major
renal outcomes.
Funding Boehringer-Ingelheim.
Introduction
Clinical trials of angiotensin-converting enzyme (ACE)
inhibitors and angiotensin receptor blockers (ARB) have
shown that these drugs reduce albuminuria, as well as
renal risk—ie, loss of glomerular ﬁltration rate (GFR) and
need for dialysis in those with advanced renal disease.1
progressive renal insufficiency.3
Further reduction of
proteinuria by combined ACE inhibitor and ARB therapy
could theoretically protect the kidney from chronic kidney
failure compared with either agent alone.3
Proteinuria has
also been linked with increased cardiovascular morbidity .4
Combining ACE inhibitors with an ARB might also lead
5

Susantitahong et al, 2013

ACE inhibition Slows Progression better
than other anti-hypertensive agents

Giatras et al, 1997

Casas et al, 2005

BP LTTC, BMJ, 2014

BP LTTC 2014

Ahmed et al, 2011
Older CKD
STOP ACE

CKD Prevalence is rising
eGFR is useful
Proteinuria reduction slows Progression

Critical Thinking
A Good Nephrologist

Myths and facts in Nephrology, 2016

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