Introduction to Chronic Kidney Disease (CKD).

Report
CHRONIC KIDNEY
DISEASE (CKD)
Dr Michael Schulz, MD FRCP
CKD definition
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 (NKF-KDOQI) 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
KDIGO
defines chronic kidney disease (CKD) as
either of the following for > 3 months
• glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2
• kidney damage as evidenced by ≥ 1 of
• albuminuria
• urine sediment abnormalities
• electrolyte or other abnormalities due to tubular disorders
• abnormal histology
• abnormal structure detected by imaging
• history of kidney transplant
CKD Key Facts
Key facts CKD
• CKD describes abnormal kidney function and/or structure
• Common, frequently unrecognised and usually
asymptomatic
• considerable overlap between CKD, Diabetes Mellitus
and Cardiovascular disease
Key facts CKD
• Advanced CKD carries an increased risk of other
significant adverse outcomes such acute kidney injury,
more severe co-morbidities and increased mortality
• Risk of CKD increases with increasing age
Key facts CKD
• 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
CKD Public health
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
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
Why MDRD equation?
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
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+
Renal Function Assessment vs.
Screening for Renal Disease
• A gold standard marker for 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) are considered gold standard for a
direct GFR determination
• These methods of measuring GFR are unsuitable for
widespread identification of CKD in the ‘at risk’ population
Current practice is to estimate GFR from serum
creatinine 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)
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
Limitations of the MDRD Equation
eGFR (mL/min/1.73 m2) =
175 × (Scr)-1.154 × (Age)-0.203 ×
(0.742 if female) × (1.212 if
African American)
• Non-adults
• Individuals with unstable creatinine concentrations
• Persons with extremes in muscle mass and diet
• ? eGFR >60ml/min !!!
• ? old patients
• ? Asians
• ? Transplant patients
Limitations of the MDRD Equation
eGFR (mL/min/1.73 m2) =
175 × (Scr)-1.154 × (Age)-0.203 ×
(0.742 if female) × (1.212 if
African American)
• Non-adults
• Individuals with unstable creatinine concentrations
• Persons with extremes in muscle mass and diet
•? eGFR >60ml/min !!!
• ? old patients
• ? Asians
• ? Transplant patients
“a new kid on the block”
• The Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation is a new equation, published in 2009,
to estimate 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
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
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
• Comparison of Risk Prediction Using the CKD-EPI Equation and the
MDRD Study Equation for Estimated Glomerular Filtration Rate Kunihiro
Matsushita et al JAMA. 2012;307(18):1941-1951. doi:10.1001/jama.2012.3954
• 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
To make matters even more complicated….
another Biomarker for renal function: Cystatin C
• 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)
New recommendation
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, sustained for at least 90 days and no
proteinuria (albumin:creatinine ratio)ACR less than
3mg/mmol)
CONT…
• Do not diagnose CKD in people with: an eGFR
creatinine of 45–59ml/min/1.73m2and an eGFR
cystatinC of more than 60 ml/min/1.73 m2 and no
other marker of kidney disease
Limitations of the MDRD Equation
eGFR (mL/min/1.73 m2) =
175 × (Scr)-1.154 × (Age)-0.203 ×
(0.742 if female) × (1.212 if
African American)
• Non-adults
• Individuals with unstable creatinine concentrations
• Persons with extremes in muscle mass and diet
• ? eGFR >60ml/min !!!
• ? old patients
• ? Asians
•? Transplant patients
Excurse:
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
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
CKD Classification
CV mortality risk increases with declining
renal function1
Relative risk of CV death*
4.35
4.38
5
3.01
4
2.36
3
2.19
2.42
2
1.48
2.18
15–59
1
0
Macroalbuminuria
≥90
Microalbuminuria
eGFR
(ml/min/1.73m2)
60–89
1.00
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.
30
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.
31
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
Classification of CKD
group GFR and albuminuria categories with similar
relative risk for CKD progression into risk categories
CKD Incidence/prevalence
Distribution of NHANES 2005–2010 participants
with diabetes, cardiovascular disease
& single-sample markers of CKD
NHANES participants 2005–2010, age 20 & older; single-sample
estimates of eGFR & ACR
USRDS ADR 2013
Prevalence of CKD in United States
• 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
Reference - United States Renal Data System
2013 Atlas of Chronic Kidney Disease
CKD in England 1
• In a cross sectional point prevalence study of over
130,000 adults from Kent, Surrey and Manchester the age
standardised prevalence of people with an estimated GFR
<60 ml/min/1.73 m2 (CKD stages 3-5) was 8.5%, those
with CKD were more likely to have hypertension, diabetes
and cardiovascular disease compared to people with
GFR>60 ml/min/1.73 m2, the 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
CKD in England 2
What causes CKD?
-Hen or Egg?
Distribution of markers of CKD in
NHANES participants with diabetes
& 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
Distribution of markers of CKD in
NHANES participants with cardiovascular
disease & obesity, 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
• Relationship between
metabolic syndrome
risk factors
and prevalence rate of
CKDs in the NHANES
III survey
(1988-94, USA sample of
33,994 persons)
Age and CKD
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)
Outcomes of CKD
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
CKD Prognosis
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. However, 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
• “Association of estimated glomerular filtration rate and albuminuria with all-cause and
cardiovascular mortality in general population cohorts: a collaborative meta-analysis”
Matsushita K et al. Lancet. 2010;375(9731):2073
CKD costs
CKD costs in USA
• CKD patients incur per person per year (PPPY) costs of
$23,128 compared to $11,103 for the average Medicare
patient and to $8,245 per year for those without CKD,
diabetes, CHF, or ESRD Patients with CKD of Stages 4–5
have yearly expenditures of $27,715, demonstrating the
impact of more advanced disease and its increasing
complications.
• 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
• The hemodialysis population (with the exception of some
populations with rare diseases) is the most expensive in
the Medicare system
• Source http://www.usrds.org/2013/view/v1_07.aspx
Overall PPPY costs in CKD patients,
by CKD diagnosis code, dataset, & year
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
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
CKD costs UK
• The total cost of CKD in England in 2009–10 was
estimated at between £1.44 and £1.45 billion, which was
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
• It was estimated in the economic model that 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
Management of CKD
MANAGEMENT OF CKD
3 cornerstones:
• Treatment of reversible causes of renal failure
• Preventing or slowing the progression of renal disease
• Treatment of the complications of renal failure
Treatment of reversible causes of renal failure
• Avoid nephrotoxic drugs
• Improve renal perfusion (e.g. Cardio renal syndrome)
• Treat urinary tract obstruction
Preventing or slowing the progression of renal
disease
• Optimise treatment of the underlying disease (e.g. Diabetes
mellitus)
• Blood pressure control
• Aim to reduce Proteinuria
• Lifestyle modification
• (vicious circle Obesity, physical inactivity, smoking and
Diabetes/hypertension)
• (Diet restriction)
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
Thank you for your attention

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