Dr Michael Schulz, MD FRCP

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

•
• glomerular filtration rate (GFR) < 60 mL/minute/1.73 m 2 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

• CKD describes abnormal kidney function and/or structure
• Common, frequently unrecognised and usually asymptomatic
• considerable overlap between CKD, Diabetes Mellitus and Cardiovascular disease

• 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

• 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

• 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

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

• 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 125 I 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+

• 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 ( 51 Cr EDTA, 99m Tc DTPA or 125 I
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 m 2 ) =
GFR = 175 x SerumCr -1.154
* age -0.203
* 1.212 (if patient is black) * 0.742 (if female)

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

eGFR (mL/min/1.73 m 2 ) =
175 × (S cr
) -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

eGFR (mL/min/1.73 m 2 ) =
175 × (S cr
) -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
• ? old patients
• ? Asians
• ? Transplant patients

• 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

• 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 (S cr
/κ, 1) α × max(S
1.018 [if female] × 1.159 [if black] cr
S cr 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 S cr
/κ or 1, and max indicates the maximum of S cr
/κ or 1
/κ, 1) -1.209
× 0.993
Age ×

• 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 (S cr
/κ, 1) α × max(S
1.018 [if female] × 1.159 [if black] cr
S cr 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 S cr max indicates the maximum of S cr
/κ or 1, and
/κ or 1
/κ, 1) -1.209
× 0.993
Age ×

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)

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)

• 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

eGFR (mL/min/1.73 m 2 ) =
175 × (S cr
) -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

• 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

• 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 function 1
4.38
4.35
5
3.01
4 2.36
3
2.42
2.19
2
2.18
1.48
1
0
1.00
Macroalbuminuria
Microalbuminuria Normal
NHANES III 1988 –2000
15 –59
60 –89 eGFR
(ml/min/1.73m
2 )
≥90
* 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 function 1
4.35
4.38
5
3.01
4
2.36
3
2.42
2.18
1.48
2
2.19
1
0
1.00
15 –59
60 –89
(ml/min/1.73m
2 )
≥90 eGFR
Macroalbuminuria
Microalbuminuria 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

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

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

• 14 % of adults ≥ 20 years old
•
•
6.7% with estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73 m 2
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

• 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

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)

To keep it simple: it seems
• 2/3 of patients have ischaemic and/or hypertensive n ephropathy (“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

NHANES 1999 –2004 participants age 20 & older; single sample estimates of eGFR & ACR. eGFR calculated using the CKD-EPI equation.
USRDS ADR 2013

• (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 metaanalysis”
Matsushita K et al. Lancet. 2010;375(9731):2073

CKD costs

•
•
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

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

Point prevalent Medicare CKD patients age 65 & older; costs are total expenditures per calendar year http://www.usrds.org/2013/view/v1_07.aspx

• 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

• Treatment of reversible causes of renal failure
• Preventing or slowing the progression of renal disease
• Treatment of the complications of renal failure

• Avoid nephrotoxic drugs
• Improve renal perfusion (e.g. Cardio renal syndrome)
• Treat urinary tract obstruction

• 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)

• 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