Chronic Kidney Disease - A medical or Public health Disease? - an update

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1 Chronic Kidney Disease - A medical or Public health Disease? - an update Dr Michael Schulz, MD Consultant Nephrologist & Physician Royal Liverpool University Hospital Senior Associate Lecturer University of Liverpool & Faculty of Health, Edge Hill University

2 Paradigm shift in Nephrology change in focus in renal medicine from treatment 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

3 CKD costs UK The total cost of CKD in England in 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 (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

4 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

5 After NS Bricker et al, in BM Brenner (ed): Brenner and Rector's The Kidney, 6th ed. Philadelphia, Saunders, Curve A - substances such as creatinine and urea Curve B - urate, PO4, and K+ Curve C Na+

6 CKD- new Diagnosis or Old vine in new bottles

7 CKD definition

8 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

9 KDIGO defines chronic kidney disease (CKD) as either of the following for > 3 months 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

10

11 CKD Classification

12 Relative risk of CV death* CV mortality risk increases with declining renal function Macroalbuminuria Microalbuminuria 1.00 Normal egfr (ml/min/1.73m 2 ) 90 NHANES III * 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:

13 Relative risk of CV death* CV mortality risk increases with declining renal function Macroalbuminuria Microalbuminuria Normal NHANES III 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 Adapted from: Astor BC, et al. Am J Epidemiol 2008;167:

14

15 Risk markers of 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

16 Staging patients with CKD according to cause, egfr, and albuminuria enhances risk stratification for the major complications of CKD

17 Classification of CKD

18

19 CKD- Classification- Referral

20 CKD- Classification- Monitor

21 a step backwards..

22 Why MDRD equation?

23 After NS Bricker et al, in BM Brenner (ed): Brenner and Rector's The Kidney, 6th ed. Philadelphia, Saunders, Curve A - substances such as creatinine and urea Curve B - urate, PO4, and K+ Curve C Na+

24 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 ( 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

25 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

26 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 125 I Iothalamate as a reference method

27 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 * age * (if patient is black) * (if female)

28 Limitations of the MDRD Equation egfr (ml/min/1.73 m 2 ) = 175 (S cr ) (Age) (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

29 Limitations of the MDRD Equation 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 ) (Age) (0.742 if female) (1.212 if African American)

30 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

31 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 (S cr /κ, 1) α max(s cr /κ, 1) Age [if female] [if black] S cr is serum creatinine in mg/dl, κ is 0.7 for females and 0.9 for males, α is for females and for males, min indicates the minimum of S cr /κ or 1, and max indicates the maximum of S cr /κ or 1

32

33 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): doi: /jama >> declassification of patients wrongly labelled with CKD 1-3

34 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)

35 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 ml/min/1.73 m2, sustained for at least 90 days and no proteinuria (albumin:creatinine ratio)acr less than 3mg/mmol)

36 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

37 CKD Incidence/prevalence

38

39 Distribution of markers of CKD in NHANES participants with diabetes & hypertension, NHANES & participants age 20 & older; single sample estimates of egfr & ACR. egfr calculated using the CKD-EPI equation. USRDS ADR 2013

40 Distribution of markers of CKD in NHANES participants with cardiovascular disease & obesity, NHANES & participants age 20 & older; single sample estimates of egfr & ACR. egfr calculated using the CKD-EPI equation. USRDS ADR 2013

41 Relationship between metabolic syndrome risk factors and prevalence rate of CKDs in the NHANES III survey ( , USA sample of 33,994 persons)

42 What causes CKD? -Hen or Egg?

43

44 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)

45 Age and CKD Natural renal function (GFR) declines by approximately 10% (10ml/min) per decade..

46 Age and CKD

47 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

48 CKD Key Facts

49 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

50 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

51 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

52 Management of CKD

53 MANAGEMENT OF CKD 3 (5) cornerstones: Treatment of reversible causes of renal failure Preventing or slowing the progression of renal disease Treatment of the complications of renal failure Adjusting drug doses when appropriate for the level of estimated glomerular filtration rate (egfr) Identification and adequate preparation of the patient in whom renal replacement therapy will be required

54 Treatment of reversible causes of renal failure Avoid nephrotoxic drugs Improve renal perfusion (e.g. Cardio renal syndrome) Treat urinary tract obstruction

55 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)

56 Pharmacotherapy for CKD Choice of antihypertensive agent Offer a low-cost renin-angiotensin system antagonist to people with CKD and: diabetes and an ACR of 3 mg/mmol or more hypertension and an ACR of 30 mg/mmol or more an ACR of 70 mg/mmol or more (irrespective of hypertension or cardiovascular disease)

57 Cont.. Do not offer a combination of renin-angiotensin system antagonists to people with CKD And do not offer a renin-angiotensin system antagonist to people if pretreatment serum potassium is >5.0mmol/litre taking at least one (non-diuretic) antihypertensive medication at night

58 Cont.. Vitamin D supplements in the management of CKD-mineral and bone disorders Do not routinely offer vitamin D supplementation to manage or prevent CKD-mineral and bone disorders. Offer cholecalciferol or ergocalciferol to treat vitamin D deficiency in people with CKD and vitamin D deficiency. If vitamin D deficiency has been corrected and symptoms of CKD-mineral and bone disorders persist, offer alfacalcidol (1-alpha-hydroxycholecalciferol) or calcitriol (1-25-dihydroxycholecalciferol) to people with stage 4 or 5 CKD.

59 Oral bicarbonate supplements in management of metabolic acidosis Consider oral sodium bicarbonate supplementation for people with both: Stage 4 or 5 CKD and A serum bicarbonate concentration of less than 20 mmol/litre.

60 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

61 Thank you for your attention

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