CKD Natural History 2014

Sheffield Kidney Institute
Global Kidney Academy
CKD Natural History
Professor Meguid El Nahas, PhD, FRCP
Chairman, Global Kidney Academy
Sheffield, UK
Nephrology Online Courses

CKD Natural History
Learning Objectives
1. Distinguish between cCKD and rCKD
2. Know Factors influencing CKD Progression
3. Know Patterns of CKD Progression
4. Know Predictors of CKD Progression (Biomarkers)

CKD Natural History
Distinguish:
cCKD
(community Acquired/Detected CKD)
From
rCKD
(Referred CKD with primary or secondary nephropathies)

Table 7: Susceptibility, initiation and progression risk factors in CKD
Susceptibility factors Initiation factors Progression factors
Age (older) Systemic hypertension Age (older)
Race/ethnicity (non-white) Diabetes mellitus Gender (male)
Genetics Cardiovascular disease Race/ethnicity (non-white)
Birth weight (low) Dyslipidemia Genetics
Low socioeconomic status Obesity/metabolic syndrome Hypertension
Hyperuricemia Hyperglycaemia
Smoking Proteinuria
Low socioeconomic status Cardiovascular disease
Nephrotoxins exposure:
NSAIDs, analgesics,
traditional herbal use, heavy
metals, exposure (such as
lead)
Low socioeconomic status
Acute kidney injury
CKD
cCKD rCKD

C-K-D & Progression of cCKD

El Nahas, KI 2010
Cardio-Kidney-Damage (C-K-D)

Risk of developing CKD with Ageing
Kshirsagar et al, 2008

Estimated GFR in “Healthy” Caucasian Females
0
20
40
60
80
100
120
140
160
18-
24
25-
29
30-
34
35-
39
40-
44
45-
49
50-
54
55-
59
60-
64
65-
69
70-
74
75-
79
80-
84
85+
Age (years)
eGFR(mL/min/1.73m2)
95th Percentile
50th Percentile
5th Percentile
Nijmegen Biomedical Study, 2008

Baltimore
Longitudinal
Study on Aging
446 men; >5 years
observational period
Subjects with edema
and proteinuria
Subjects with hypertension & DM
Subjects without co-morbidity
Creatinine clearance (ml/min)

Figure 2.
Association of Subclinical Cardiovascular Disease Measures with Kidney Function Decline
Shlipak et al. Page 11
NIH-PAAuthorManuscriptNIH-PAAuthorManuscript
Predicting cCKD Development

Figure 1.
Association of Clinical Cardiovascular Disease with Kidney Function Decline
Shlipak et al. Page 10
NIH-PAAuthorManuscriptNIH-PAAuthorManuscript
Shlipak et al, 2009
Predicting cCKD Progression

Age impacts on outcomes in CKD
O’Hare A et al. 2007
210,000 subjects, eGFR<60mls/minute/1.73m², outcomes at 3.5 years

CKD and Outcomes
Oregon #27,998
CKD stages Progression to
ESRD
Death
2 1.1% 19.5%
3 1.3% 24.3%
4 19.9% 45.7%
Keith DS et al, 2004

CKD Natural History
Distinguish:
cCKD
(community Acquired/Dectected CKD)
From
rCKD
(Referred CKD with primary or secondary nephropathies)

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).
shaw, 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).
n, J. L. E. Israel. J. med. Sci. 1971, 7, 488.
th, R., Ledingham, J. G. G., Oliver, D. O. Proc. eur.
s. 1971, 8, 122.
nenko, P., Meyner, A., Vallee, G., Beaugas, C. J. clin. In-
345.
In 31 of 34 patients with chronic renal
nsufficiency caused by various diseases,
m-creatinine concentration declined
inine concentration rose from a mean of
t;8 mg/dl over an average of 71 months.
ndicate that in most cases reciprocal
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,
-creatinine might fall linearly with
ned this hypothesis in patients who had
lure with various causes.
Methods
cords of all patients with chronic renal fail-
followed in a renal clinic for at least a year
here were 34 patients in whom 7 or more cre-
ions 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-
t the Annual Meeting of the American Federation
h, Atlantic City, N.J., May 2-5, 1976, and pub-
rm (Clin. Res. 1976, 24, 407).
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.
1/sCr Slopes and CKD Progression
Mitch et al 1976

m creatinine
ariability of
o estimate
um creati-
ce between
GFR versus
ations[22].
wo slopes is
art can vary
echangein
zed percent
ectory. The
used abso-
all of apa-
method of
Proteinuria/albuminuria
Protein reduction
AKI
Diabetescontrol
Alkali therapy
Multidisciplinary
follow-up
Age/race/diet
ACE/ARB
Fig. 1. Factorsaffectingrenal function trajectory.
Colorversionavailableonline

Risk Models for CKD Progression
Cheugui and Kengne, 2012

Validation of Risk Models for CKD Progression
Cheugui and Kengne, 2012

Locatelli et al 1996
Hypertension and CKD Progression

BP Target
BP < 140/90mmHg
BP <130/80mmHg

CKD progression and BP control
MDRD Study – BP and long term outcomes
Sarnak M et al Ann Intern Med. 2005

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

Proteinuria Target
Proteinuria <1g/24h
uPCR< 1000mg/g
uACR< 500mg/g

Proteinuria and CKD Progression

REIN: ACE inhibition and CKD Progression

Renaloutcomeswithtelmisartan,ramipril,orboth,in
peopleat highvascularrisk(theONTARGETstudy):
amulticentre,randomised, double-blind,controlledtrial
JohannesFEMann,RolandESchmieder,MatthewMcQueen,LeanneDyal,Helmut Schumacher,JanicePogue,XingyuWang,AldoMaggioni,
AndrzejBudaj,SuphachaiChaithiraphan,KennethDickstein,MatyasKeltai,KajMetsärinne,AliOto,AlexanderParkhomenko,LeopoldoSPiegas,
TageLSvendsen,KoonKTeo,SalimYusuf,onbehalfoftheONTARGETinvestigators
Summary
Background Angiotensin receptor blockers(ARB) andangiotensin convertingenzyme(ACE) inhibitorsareknown 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
atheroscleroticvascular diseaseor with diabeteswith end-organ damage.

Glycemia Target
HbA1c <8%
(between 6.5-8%)

AKI and CKD

in eGFRof 0.1ml/min/1.73m2
per year) followingangio-
graphy, whereasthosewith mild AKI showed adecline
in kidney function at arateof 0.8ml/min/1.73m2
per
year and thosewith moderateor severeAKI showed a
declinein kidneyfunction at arateof 2.6ml/min/1.73m2
per year (Figure 1). Notably, in patientswithout AKI or
with mild AKI, theseratesof eGFRdeclinein thepost-
underway to confirm the results o
studies.27,64
Although even prospe
studiescannot proveacausal relatio
and CKD, AKI isincreasingly cons
ated with abroad spectrum of kidne
ing progressiveCKD and ESRD. T
important clinical implications.27,65
If AKI does cause CKD progre
prevent AKI might also help to prev
and its consequences, including
vascular events.6
However, even if
CKD, recognition of theprognostic
for subsequent progression toCKD h
cations.66
The2012 KDIGO guideli
mend that patientswho haveexperi
AKI should beevaluated 3 months
recovery, new onset of CKD, devel
CKD or worseningof pre-existingC
guidelinessuggest that patientswith
vived AKI should bemanaged accor
CKD guidelines, whereasthosewith
considered at increased risk for futu
in arecent observational studyof 3,9
with eGFR<60ml/min/1.73m2
,only
had an outpatient nephrologyreferra
atingdialysisor experiencingimprov
tion during a1-year follow-up per
demonstratethat only asmall prop
of AKI receivenephrology follow-u
Importantly, not all patientswith
to advanced CKD or ESRD and m
recover kidney function after AKI.
observational studydescribed above
–15 0 3
Time (months)
MeaneGFR(ml/min/1.73m2
)
24
60
50
40
70
0
21 2718151296–3–6–9–12
No AKI
Mild AKI
Moderate or severe AKI
Coronary
angiogram
Figure 1 | Rate of change in eGFR in patients before and after coronary
angiography, according to AKI status. Patients with no AKI or mild AKI showed no
difference in the rate of eGFR decline before and after angiography. However,
among patients with moderate or severe AKI, the rate of eGFR decline increased by
1.8 ml/ min/ 1.73 m2
per year between the preangiography and postangiography
periods. Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular
filtration rate. Permission obtained from Nature Publishing Group Ltd ©
James, M. T. et al. Kidney Int. 78, 803–809 (2010).
REVIEWS
Leung et al, 2013

Chawla and Kimmel, 2012

Acute on CKD Deterioration

Contrast-Induced Nephrotoxicity

CKD Outcomes Prediction

Lind et al, 2013
Serum Cystatin C and Outcomes Prediction in CKD

2012

Tangri et al, 2011
CKD Progression Predictive Models

Natural History of CKD
Important to distinguish the nature and natural history of
cCKD and rCKD
Early Detection of underlying causes of CKD and its progression may
lead to improved control
CKD progression is associated with increased overall complications,
morbidity and mortality

CKD Natural History
Recommended Reading
1. http://www.ncbi.nlm.nih.gov/pubmed/?term=Mitch+W%2C+Lancet+1976
2. http://www.ncbi.nlm.nih.gov/pubmed/22305758

http://www.ncbi.nlm.nih.gov/pubmed/19231760
CKD Natural History
Assignment
Critically Appraise
The Conceptual Model of CKD put forward by AS Levey in 2009

CKD Natural History
MCQ1
Development of community CKD is linked primarily in the West to:
1. Ageing
2. Development of CVD
3. Herbal nephrotoxicity
4. NSAIDs Nephrotoxicity

CKD Natural History
MCQ2
The progression of CKD in the Community depends on:
1. Severity of proteinuria
2. Progression of underlying CVD
3. Severity of dyslipidemia
4. Levels of serum CystatinC

CKD Natural History
MCQ3
The best predictor of referred CKD progression is:
1. Albuminuria
2. Hypertension
3. Circulating levels of CRP
4. Serum Bicarbonate levels

CKD Natural History 2014

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