Introduction to CKD

POSTGRADUATE
SCHOOL OF MEDICINE
INTRODUCTION TO CHRONIC KIDNEY
DISEASE
Dr Michael Schulz
MDSC175: Transplantation Science for Transplant Clinicians
(Online)
A MEMBER OF THE RUSSELL GROUP
CONTINUING PROFESSIONAL DEVELOPMENT
Introduction to CKD
2
Chronic Kidney Disease (CKD) Definition
CKD is defined as abnormalities of kidney structure or function, present for
more than 3 months
•
In 2002 the US National Kidney Foundation kidney disease initiative (NKFKDOQI) introduced a 5 stage classification of CKD based on estimated
Glomerulofiltration Rate (eGFR)
•
In 2012 this classification was revised and published in the Kidney Disease:
Improving Global Outcomes (KDIGO) guidelines
•
Now it includes the subdivision of CKD 3 but also included 3 ACR categories in order
to stratify better according to the risk of progression
Introduction to CKD
Key Facts
CKD describes
Considerable overlap
abnormal kidney
between CKD, Diabetes
function and/or
Mellitus and
structure
Cardiovascular disease
Common, frequently
unrecognised and
usually asymptomatic
3
Introduction to CKD
Key Facts
Advanced CKD carries an
increased risk of other
significant adverse outcomes
Risk of CKD increases with
such acute kidney injury,
increasing age
more severe co-morbidities
and increased mortality
4
Introduction to CKD
5
Key Facts
CKD cannot be cured but
treatment can prevent or delay
the progression of CKD, reduce
or prevent the development of
complications, and reduce the
risk of cardiovascular disease
CKD progresses to end-stage
renal disease (ESRD) only in
a small but significant
percentage of people
Introduction to CKD
CKD Public Health
6
Introduction to CKD
7
Paradigm Shift In Nephrology
Recent change in focus in renal medicine from treatment of
established kidney disease to earlier identification and
prevention of kidney disease
Why?
Late presentation of people with kidney failure increases
morbidity, mortality and associated healthcare costs
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8
Paradigm Shift In Nephrology
In 2005 the Department of Health in UK published the Renal National Service
Framework (NSF) (-designed to help the NHS carry on improving the quality of
healthcare)
In order to improve early diagnosis of kidney disease NSF came up with one
key recommendation:
Whenever creatinine was measured the Laboratory has to report eGFR
(estimated Glomerulofiltration rate) using the MDRD equation
Introduction to CKD
Why MDRD Equation?
9
Introduction to CKD
10
Why MDRD Equation?
Levey and colleagues derived a predictive equations for
eGFR using 4 variables (serum creatinine, age, sex, and
race) from the 1628 patients included in the modification
of diet in renal disease (MDRD) study and undergoing
renal clearance of 125I Iothalamate as a reference method
Introduction to CKD
Renal Function
After NS Bricker et al, in BM
Brenner (ed): Brenner and
Rector's The Kidney, 6th ed.
Philadelphia, Saunders, 2000.
Curve A - substances such as
creatinine and urea
Curve B - urate, PO4, and K+
Curve C – Na+
11
Introduction to CKD
12
Renal Function Assessment vs. Screening for
Renal Disease
•
A gold standard marker for directly measuring GFR should be
•
Freely filtered by the glomerulus,
•
Should not be bound to plasma proteins,
•
Must be excreted unchanged and not be subject to either tubular secretion (unlike Creatinine)
or absorption
•
Inulin clearance and other exogenous markers such as radiolabeled isotopes (51Cr EDTA, 99mTc
DTPA or 125I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol)
•
These methods of measuring GFR are unsuitable for widespread identification of
CKD in the ‘at risk’ population
Introduction to CKD
13
Estimating GFR
Current practice is to estimate GFR from serum creatinine
•
This is calibrated to the internationally standardised isotope dilution mass
spectrometry (IDMS) methodology using the IDMS-related Modification of Diet
in Renal Disease (MDRD) equation
eGFR (mL/min/1.73 m2) =
GFR = 175 x SerumCr-1.154 * age-0.203 * 1.212 (if patient is black) * 0.742 (if female)
Introduction to CKD
14
Why MDRD Equation?
• The normal serum creatinine reference interval does
not necessarily reflect a normal GFR for a patient
•
MDRD Study equation employs age, gender, and race
therefore CKD can be detected despite a “normal” serum
creatinine concentration
Introduction to CKD
15
Limitations Of The MDRD Equation
•
Non-Adults
•
Individuals with unstable creatinine concentrations
•
Persons with extremes in muscle mass and diet
•
? eGFR > 60ml/min !!!
•
? Older patients
•
? Asians
•
? Transplant patients
eGFR (mL/min/1.73 m2) =
175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
Introduction to CKD
Limitations Of The MDRD Equation
Non-adults
Individuals with unstable
creatinine concentrations
Persons with extremes in muscle
mass and diet
eGFR >60ml/min
Older patients
Asians
Transplant patients
16
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17
‘A New Kid On The Block’
•
The Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation is a new equation,
•
Published in 2009
•
Estimates glomerular filtration rate (GFR) from serum
creatinine, age, sex, and race for adults age ≥ 18 years
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular
filtration rate. Ann Intern Med. 2009;150(9):604-12
Introduction to CKD
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CKD-EPI Vs. MDRD Equation
The CKD-EPI equation is based on the same four variables as the MDRD
Study equation but uses a 2-slope "spline" to model the relationship
between GFR and serum creatinine, age, sex, and race.
(hence applies different coefficients to the same 4 variables used in the MDRD Study equation)
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black]
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1
Introduction to CKD
19
CKD-EPI Vs. MDRD Equation
The CKD-EPI equation classified
fewer individuals as having CKD
and more accurately categorized
the risk for mortality and ESRD
than did the MDRD Study
equation across a broad range
of populations
Kunihiro Matsushita et al, Comparison of Risk Prediction Using the CKD-EPI Equation and the MDRD Study Equation for Estimated
Glomerular Filtration Rate, JAMA. 2012;307(18):1941-1951
Introduction to CKD
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To Complicate Further
To make matters even more complicated there is another Biomarker for renal
function:
Cystatin C
•
A protein containing a chain of 120 amino acids
•
A member of the cysteine proteinase inhibitor family
•
Produced at a constant rate by all nucleated cells
•
Found in virtually all tissues and body fluids
Serum levels of cystatin C are a more precise test of kidney function than serum
creatinine levels
(Cystatin C levels are less dependent on age, sex, race and muscle mass compared to creatinine and are not tubular secreted)
Introduction to CKD
21
New Recommendations
Clinical labs should use:
•
The Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI)
•
Consider using eGFR cystatinC to confirm the diagnosis of
CKD in people with :
•
An eGFR creatinine of 45–59 ml/min/1.73 m2,
•
For at least 90 days and
•
No proteinuria (albumin:creatinine ratio)
•
ACR less than 3mg/mmol
Introduction to CKD
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New Recommendations
• Do not diagnose CKD in people with:
•
An eGFR creatinine of 45–59ml/min/1.73m2
•
An eGFR cystatinC of more than 60 ml/min/1.73 m2
•
With no other marker of kidney disease
Introduction to CKD
Limitations Of The MDRD Equation
Non-adults
Individuals with
unstable creatinine
concentrations
Persons with
extremes in muscle
mass and diet
eGFR >60ml/min !!!
Older patients
Asians
Transplant patients
23
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24
Can any of the eGFR equations reliably be used in
Transplant patients ?
Not really…
•
eGFR unreliable in patients with significant change in renal function in short period
of time
•
greater heterogeneity in creatinine generation among all transplant recipients
(length of time spent on dialysis, number of acute rejections or cumulative steroid
dose seem to be a predictors of muscle mass index in transplant recipients
independent of BW and what about nephron mass transplanted to the recipient ?)
•
few studies found that the predicting equations were less accurate within the first
year of transplantation and that they were quite limited in assessing GFR decline
over time
Introduction to CKD
25
Why Do We Need eGFR?
To diagnose, classify and stage CKD
•
eGFR is an independent predictor of all-cause and cardiovascular
mortality and kidney failure in a wide range of populations
•
Level of eGFR provides a guide to management, including
stratification of risk for progression and complications of CKD
•
Risk stratification is used to inform appropriate treatments and the
intensity of monitoring and patient education
Introduction to CKD
Classifying CKD
26
Introduction to CKD
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CV mortality risk increases with declining
renal function1
4.35
Relative risk of CV death*
4.38
5
3.01
4
2.36
3
2.19
2.42
2
1.48
2.18
15–59
1
0
1.00
Macroalbuminuria
≥90
Microalbuminuria
eGFR
(ml/min/1.73m2)
60–89
Normal
NHANES III 1988–2000
*
Adjusted for age, sex, race/ethnicity, previous CV disease, blood pressure category, use of antihypertensive medication, diabetes mellitus, smoking status, body
mass index, physical activity level, low density lipoprotein and high density lipoprotein cholesterol, log triglyceride level, and C-reactive protein category
1. Adapted from: Astor BC, et al. Am J Epidemiol 2008;167:1226–34.
Introduction to CKD
28
CV mortality risk increases with declining
renal function1
Relative risk of CV death*
4.35
4.38
5
3.01
4
2.36
3
2.42
2.18
2
1.48
2.19
15–59
1
1.00
0
Macroalbuminuria
≥90
Microalbuminuria
eGFR
(ml/min/1.73m2)
60–89
Normal
NHANES III 1988–2000
*
Adjusted for age, sex, race/ethnicity, previous CV disease, blood pressure category, use of antihypertensive medication, diabetes mellitus, smoking status, body mass index,
physical activity level, low density lipoprotein and high density lipoprotein cholesterol, log triglyceride level, and C-reactive protein category
1. Adapted from: Astor BC, et al. Am J Epidemiol 2008;167:1226–34.
Introduction to CKD
29
Risk Marker of CKD
•
Degree of renal impairment and proteinuria are regarded as an
independent marker for worsening of renal function and
cardiovascular disease hence considered to be a risk markers for CKD
•
Risk of adverse outcomes from CKD, including progression of CKD, is
substantially increased below a GFR of 45 ml/min/1.73 m2
irrespective of urine ACR
•
Urine ACR >30 mg/mmol suggests increased risk of adverse
outcome, irrespective of GFR, including progression of CKD
Introduction to CKD
Classification of CKD
30
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CKD Progression And Risk Categories
Group GFR and albuminuria categories with similar relative risk for CKD progression
into risk categories
Introduction to CKD
CKD Incidence and Prevalence
32
Introduction to CKD
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NHANES 2005-2010
Distribution of NHANES 2005–2010 participants with diabetes, cardiovascular
disease and single-sample markers of CKD
NHANES participants 2005–2010, age 20 & older; single-sample estimates of
eGFR & ACR
USRDS ADR 2013
Introduction to CKD
34
Prevalence of CKD In USA
•
•
•
14% of adults ≥ 20 years old
•
6.7% with estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2
•
9.4% with albumin to creatinine ratio ≥ 30 mg/g
Prevalence by age (any stage)
•
5.7% at age 20-39 years
•
9.1% at age 40-59 years
•
35% at age ≥ 60 years
Based on National Health and Nutrition Examination Survey (NHANES)
2005-2010
United States Renal Data System 2013 Atlas of Chronic Kidney Disease
Introduction to CKD
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CKD In England
In an age standardised cross sectional point prevalence study of over
130,000 adults from Kent, Surrey and Manchester
•
Prevalence of people with an estimated GFR <60 ml/min/1.73 m2 (CKD
stages 3-5) was 8.5%,
•
Those with CKaD were more likely to have hypertension, diabetes and
cardiovascular disease compared to people with GFR>60 ml/min/1.73
m2,
•
Prevalence of CKD rose with age and female gender
Stevens PE, O'donoghue DJ, de LS, Van VJ, Klebe B, Middleton R et al. Chronic kidney disease management in
the United Kingdom: NEOERICA project results. Kidney International. 2007; 72(1):92-99
Introduction to CKD
36
CKD In England
CKD Stage
Male
Female
1
3%
3%
2
6%
3%
3-5
5%
7%
Total
14%
13%
Health Survey for England: Adult CKD prevalence
www.ic.nhs.uk/statistics-and-data-collections/health-and-lifestyles-related-surveys/health-survey-for-england
Introduction to CKD
CKD Causes
37
Introduction to CKD
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NHANES 2005-2010
Distribution of markers of CKD in NHANES participants with diabetes and
hypertension, 2005–2010
NHANES 1988–1994 & 2005–2010 participants age 20 & older; single sample estimates of eGFR & ACR. eGFR calculated using the
CKD-EPI equation.
USRDS ADR 2013
Introduction to CKD
39
NHANES 2005-2010
Distribution of markers of CKD in NHANES participants with diabetes and
hypertension, 2005–2010
NHANES 1988–1994 & 2005–2010 participants age 20 & older; single sample estimates of eGFR & ACR. eGFR calculated using the
CKD-EPI equation.
USRDS ADR 2013
Introduction to CKD
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Cardiovascular Risk in CKD: Chicken or Egg?
Relationship between
metabolic syndrome risk
factors and prevalence rate
of CKDs in the NHANES III
survey (1988-94, USA sample
of 33,994 persons)
Introduction to CKD
AGE and CKD
41
Introduction to CKD
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Cause of CKD
To keep it simple: it seems
• 2/3 of patients have ischaemic and/or hypertensive
nephropathy (“Arteriopath patients”)
• 1/3 of patients have “other” renal disease (e.g ADPKD,
Glomerulonephritis, Obstructive Nephropathy, renal
vascular disease, drug induced renal disease)
Introduction to CKD
Outcomes of CKD
43
Introduction to CKD
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Life expectancy of NHANES participants
with or without CKD, 1999–2004
NHANES 1999–2004 participants age 20 & older; single sample estimates of eGFR & ACR. eGFR calculated using the
CKD-EPI equation.
USRDS ADR 2013
Introduction to CKD
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CKD Prognosis
Summary of continuous meta-analysis (adjusted relative risk (RR)) for general population cohorts with albumin-to-creatinine ratio (ACR). The three lines
represent urine ACR of <30 mg/g or dipstick negative and trace (blue), urine ACR 30–299 mg/g or dipstick 1+ positive (green), and urine ACR greater than or
equal to300 mg/g or dipstick greater than or equal to2+ positive (red). All results are adjusted for covariates and compared with reference point of eGFR of
95 ml/min per 1.73 m2 and ACR of <30 mg/g or dipstick negative (diamond). Each point represents the pooled relative risk from a meta-analysis. Solid circles
indicate statistical significance compared with the reference point (P<0.05); triangles indicate non-significance. Red arrows indicate eGFR of 60 ml/min per
1.73 m2, threshold value of eGFR for the current definition of chronic kidney disease (CKD). HR, hazards ratio; OR, odds ratio.
Introduction to CKD
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Take Home Messages
•
Older CKD patients are far more likely to die from CVD event than to
approach ESRD
•
The risk of cardiovascular event/death dwarfs the risk of eventually requiring renal
replacement therapy.
•
This risk varies with age and other factors: older patients with less severe CKD are more
likely to die (usually due to cardiovascular disease) before needing renal replacement
therapy, while younger patients are more likely to ultimately need renal replacement
therapy
•
Both decreased GFR and increased proteinuria increase the risk of
cardiovascular disease
Introduction to CKD
CKD Costs
47
Introduction to CKD
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CKD Costs in USA Per Person Per Year
$8,245 per year
for those without
CKD
•
$11,103 for the
average Medicare
patient
$27,715 Patients
with CKD of Stages
4–5 and other
complications,
$23,128 average
CKD patient
In 1993, total costs for Medicare patients age 65 and older with CKD accounted for just 3.8 % of overall
Medicare expenditures.
•
In 2011, costs for these patients reached $45.5 billion, 18 % of total Medicare dollars
www.usrds.org/2013/view/v1_07.aspx
Introduction to CKD
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Overall PPPY costs in CKD patients,
by CKD diagnosis code, dataset, & year
585.1 CKD Stage 1
585.2 CKD Stage 2 (mild)
585.3 CKD Stage 3 (moderate)
585.4 CKD Stage 4 (severe)
585.5 CKD Stage 5 (requires chronic dialysis)
Point prevalent Medicare patients age 65 &
older (5 percent Medicare sample, 7.2–4) &
Truven Health MarketScan patients age 50–64
(7.2). Includes Part D.
http://www.usrds.org/2013/view/v1_07.aspx
Introduction to CKD
Overall expenditures for CKD in the
Medicare population age 65 & older
Point prevalent Medicare CKD patients age 65 & older; costs are total expenditures per
calendar year
http://www.usrds.org/2013/view/v1_07.aspx
50
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CKD Costs UK
•
The total cost of CKD in England in 2009–10 was estimated at £1.44 - £1.45 billion
•
Approximately 1.3% of all NHS spending in that year
> 50% of this amount was spent on renal replacement therapy for the 2% of people with
CKD that progresses to kidney failure
•
Approximately 7000 excess strokes and 12,000 excess myocardial infarctions
occurred in people with CKD in 2009–10 (relative to an age- and gender-matched
population without CKD), with an estimated cost of between £174 and £178 million
Kerr M, Bray B, Medcalf J et al. (2012) Estimating the financial cost of chronic kidney disease to the
NHS in England. Nephrology Dialysis Transplantation. 27 (Suppl. 3): iii73–80
Introduction to CKD
Management of CKD
52
Introduction to CKD
Management of CKD
Treatment of
reversible
causes of
renal failure
Preventing or
slowing the
progression of
renal disease
Treatment of
the
complications
of renal
failure
53
Introduction to CKD
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Treatment of reversible causes of renal failure
Avoid nephrotoxic drugs
Improve renal perfusion (e.g.
Cardio renal syndrome)
Treat urinary tract obstruction
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Preventing or slowing the progression of renal
disease
Optimise treatment of
the underlying disease
(e.g. Diabetes mellitus)
Blood pressure control
Lifestyle modification (vicious circle
Obesity, physical inactivity, smoking
and Diabetes/hypertension)
Aim to reduce
Proteinuria
Diet restriction
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Treatment of the complications of renal failure
Reducing cardiovascular
disease
Treating hypertension
Preventing
Hyperkalaemia,
Metabolic Acidosis
Preventing/Treating
Mineral and Bone
Disease and sHPTH
Managing volume
overload
Renal Anaemia
Introduction to CKD
57
References
•
Levey et al (2011) Kidney International 80, 17–28
•
Shah et al (2015) Recent Advances in Understanding the Pathogenesis of
Atherosclerosis in CKD Patients, J. Ren. Nutr., S1051-2276
•
Mazzaferro et al (2014) News on Biomarkers in CKD-MBD, Semin. Nephrol., 34 (6),
598-611
•
Stevens et al (2014) Integrating Guidelines, CKD, Multimorbidity, and Older Adults,
Am. J. Kidney Dis., S0272-6386
•
Matsushita K et al (2010) Association of estimated glomerular filtration rate and
albuminuria with all-cause and cardiovascular mortality in general population
cohorts: a collaborative meta-analysis, Lancet, 375 (9731), 2073
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A MEMBER OF THE RUSSELL GROUP