Management of Stage 3 Chronic Kidney Disease (CKD) in General Practice Dr. Valli Manickam Renal Physician

Objectives: Statistical data about CKD Target values in ESKD When to Refer patients

Why worry about CKD & ESKD? Projected annual ESKD costs 400 500 600 700 800 900 1000 ESKD services ($millions) Steady state Linear growth 559.9 640.1 688.0 724.5 754.5 782.3 811.3 652.5 712.9 763.8 808.6 852.5 899.1 2004 5 6 7 8 9 2010 Cass et al Kidney Health Australia Report 2006

ESKD has a life expectancy between that of Colon Cancer & Lung Cancer USRDS 2001

ESKD and Cardiovascular Mortality Foley et al AJKD 1996

Why be interested? – Slowing progression Creatinine Clearance (ml/min) Residual Renal Function Timely Start ? 25 30 20 10 15 5 Late Referral Early Referral

CKD Definitions 1 2 3 4 5 Stage Description GFR (ml/min/1.73 m2) Kidney Damage with Normal or  GFR >90 (with proteinuria) 2 Kidney Damage with Mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5 Kidney Failure <15 or (or dialysis) Adapted from Am J Kidney Dis 2002; 39 (2, Suppl. 1): S17-S31 and using AusDiab data

Kidney Disease in Australia The titanic/iceberg model   Adults over 25 years of age Stage 5 – kidney failure Stage 1-3 Stage 4 – GFR <30 1.7 MILLION 30,000 4.5+ MILLION AT RISK Hypertension or diabetes 16,000 AusDiab data, 2005

CKD and the risk of death,CV events and hospitalisation All cause mortality Cardiovascular mortality N = 1,120,295 Go et al N Engl J Med 2004; 351:1296-1305 Kaiser Permanente Renal Registry

Outcomes in patients with CKD Kaiser Permanente Longitudinal Study n = 27988, FU = 66 mo Patients with CKD are 20 times more likely to die from cardiovascular events than survive to reach dialysis Keith et al Arch Int Med 2004

Estimated GFR (MDRD) Median and interquartile range GFR and Ageing Estimated GFR (MDRD) Median and interquartile range Prevalence of eGFR < 60 ml/min in popn GFR declines by 5-8mL/min/1.73m2 each decade NHANES III

Bruce the Battler With CKD 12

Bruce the Battler Oral hypoglycaemics Mr Bruce Battams seen 02/08 74 yo, retired Smoker – 20 / day, alcohol - 30 g/day Hypertension – 20 years DM2 – 5 years Oral hypoglycaemics Diverticular disease Infra-renal AAA – 4 cm Incidental finding on CT for abdo pain Stress echo - no inducible ischaemia Medications: amlodipine, pravastatin, gliclazide, aspirin (low-dose) 13

Bruce the Battler BP 190 / 84 mmHg Peripheral pulses present Murmur Aortic Sclerosis eGFR mL/min/1.73m2 Creatinine 160 umol/L 37 [on 02/08] 115 umol/L 57 [on 09/07] Chol - 6.7 mmol/L: TG - 4.05 mmol/L FBC normal UA trace protein, no RBC, no WBC 14

Question 1: Answer True or False The absence of significant proteinuria makes diabetic kidney disease extremely unlikely Quantitation of proteinuria will give important prognostic information He should not be started on an RAS inhibitor* to slow progression of kidney disease as he has worsening kidney function His smoking will worsen his kidney function Lipid lowering therapy has been proven to slow progression of kidney disease *ACE/ARB 15

Question 1 Mechanism not well understood The absence of significant proteinuria makes diabetic kidney disease extremely unlikely FALSE 20-30% of diabetic patients may have chronic kidney disease without evidence of proteinuria Mechanism not well understood Likely to progress with time Minerva Endocrinol. 2005 Sep;30(3):161-77 16

Question 1 Quantitation of proteinuria will give important prognostic information TRUE Increasing degrees of proteinuria lead to increasing risk of ESKD Proteinuria a stronger marker of risk of progression to ESRD than baseline GFR But eGFR strong predictor of morbidity and mortality Reduction of proteinuria in proteinuric disease predicts reduced mortality and reduced progression to ESKD 17

Risk of ESKD related to baseline proteinuria (dipstick) over 18 year period Iseki et al, Kidney Int 2003;63:1468-1476 18

Macroalbuminuria is a better marker than GFR in predicting loss of kidney function N=8952 – F/U 4yrs Reduced GFR – mean 45 mL/min/1.73m2 General Population + RBC urine Macroalbuminuria PREVEND Study J Am Soc Nephrol 2006; 17:2582–2590. 19

Mechanism not well understood Recommended Targets in CKD Proteinuria and ESRD: 20-30% of diabetic patients may have chronic kidney disease without evidence of proteinuria Mechanism not well understood Likely to progress with time Minerva Endocrinol. 2005 Sep;30(3):161-77

But eGFR strong predictor of morbidity and mortality Increasing degrees of proteinuria lead to increasing risk of ESKD Proteinuria a stronger marker of risk of progression to ESRD than baseline GFR But eGFR strong predictor of morbidity and mortality Reduction of proteinuria predicts reduced mortality and reduced progression to ESKD

Albuminuria and  GFR predict mortality and morbidity (RR) Normal Macroalbuminuria  GFR Mortality (RR) CV non CV 1 2.6 1.5 3.4 3.0 Morbidity (RR) 1.4 2.3 PREVEND Study J Am Soc Nephrol 2006;17: 2582–2590. 22

Question 1 He should not be started on an RAS inhibitor to slow progression of kidney disease as he has worsening kidney function FALSE RAS inhibitors beneficial in decreasing mortality in those with GFR < 60 mL/min RAS preferred agent for BP control in CKD, particularly in those with significant proteinuria 23

Risk Stratification - BP 10 mmHg  SBP results in 10.9% increase in RR of ESRD (RENAAL STUDY) SBP = PP < DBP in prediction of ESRD PP > SBP > DBP in prediction of mortality PP > 70 mmHg   risk mortality in SHEP, FHS 24

RAS inhibitors beneficial in decreasing mortality in those with GFR < 60 mL/min RAS preferred agent for BP control in CKD, particularly in those with significant proteinuria

Treatment of BP in CKD - ? which agent ACEi / ARB independent effect over BP alone Multiple trials DM CTS – ACEi RENAAL – ATII IDNT – ATII Non-DM GISEN REIN Bakris Et al AJKD 2000;36:646-661

Target blood pressure < 140/90 mmHg <130/80 mmHg Adults  65 years (unless there is diabetes and/or renal insufficiency and/or proteinuria 25 g/day) < 140/90 mmHg Adults <65 years and/or Adults with diabetes and/or Adults with renal insufficiency and/or Adults with proteinuria 0.25-1.0 g/day <130/80 mmHg Adults with proteinuria >1 g/day (in people with and without diabetes) < 125/75 mmHg

Question 1 Smoking is associated with kidney damage in the population AusDiab Study Smoking increases proteinuria and accelerates loss of GFR Am J Med Sci 2005;330:111-119

Question 1 Lipid lowering therapy has been proven to slow progression of kidney function FALSE 29

Does treating lipids affect CKD progression? No specific randomised trials Post hoc analysis of CVD trials CARE Pravastatin vs placebo Fall in GFR 0.6 mL/min/1.73m2/yr if GFR < 50 mL/min 2.7 mL/min/1.73m2/yr if GFR < 40 mL/min greater effect with increasing proteinuria HPS 40 mg simvastatin vs placebo attenuation in rise of serum creatinine GREACE atorvastatin vs placebo Atorvastatin increased CrCl 12% placebo decrease in CrCl 5 % Summary slides of what is known about effect of lipid lowering on renal function in humans all post hoc subgroup analysis of CVD trials CARE Cholesterol And Recurrent Events HPS Heart Protection Study GREACE Greek Atorvastatin and Coronary heart disease Evaluation No trials in GFR <40 mL/min/1.73m2 30

Pravastatin reduces Absolute RR for CV events in DM & CKD – similar benefit seen in all-cause mortality Median F/U 64m Tonelli et al JASN 2005;16:3748 31

Bruce the Battler Commenced on perindopril/indapamide Seen 2 weeks later and reassessed: BP 150 / 76 mmHg Creatinine 189 umol/L (eGFR : 30 mL/min/1.73m2) – Previously Creat 160 umol/L and GFR 37 mls/mt in Feb 2008. K 5.8 mmo/L Urine ACR 9 mg/mmol 32

Question 2 Cease the ACEi and commence another drug Do you : Cease the ACEi and commence another drug Cease the ACEi and check for a renal artery stenosis Continue the ACEi and check for a renal artery stenosis Add another drug for better BP control 33

My answer: Add another drug for better blood pressure control Rationale: A rise in creatinine of <30% is not unexpected after BP lowering and is a result of decreased perfusion Target BP in CKD is <130/80 mmHg ACEi may have particular benefit for kidney disease K+ needs watching but not a concern at this level (? Give low K+ diet) 34

Bruce the Battler Seen 1 month later BP 134 / 68 mmHg Creatinine 245 umol/L eGFR 23 mL/min Ca 2.05 mmol/L PO4 1.54 mmol/L Hb 98 g/L normocytic/normochromic Urine dipstick normal 35

Question 3 What would you do? Refer for erythropoietin treatment Check iron studies Check Vit B12 and folate levels Check Vitamin D and PTH All of the above 36

Bruce the Battler My Answer: e. All of the above Results: Ferritin 996 Tsat 55% B12 and folate Normal TSH Normal PTH 18 pmol/L (N <8 pmol/L) Vit D 25 nmo/L (mod deficiency) 37

CKD progression - Anaemia Anaemia due to CKD begins at GFR < 60 mL/min common when GFR < 30 mL/min (30-40%) CKD anaemia is a diagnosis of exclusion Need to ensure not Fe deficient or B12/folate deficient, or hypothyroid Different reference range for Fe stores if on Erythropoietin Ferritin > 300 ng/ml Tsat >20% May respond to iv iron if stores low without need for erythropoietin I.v. iron gives quicker and higher response than oral (and is better tolerated) Gouva et al, Kidney Int 2004;66:753-760

Anaemia is associated with mortality in dialysis patients Adjusted RR of death due to any cardiac cause, according to Hct. n= 50,579 Multiple observational studies show lower Hb associated with adverse outcome Li & Collins, Kidney International 2004;65:626–633 39

The target Hb for anaemia in CKD Optimal Hb level not known Observational – 110 – 120 g/L RCT – no benefit above 120 g/L

CKD & Anaemia Summary Common and important to correct Can’t start EPO till Hb <100g/L (PBS) Need to have nephrologist endorsement to start Ensure not iron deficient All respond – need to dose titrate Most self administer SC each 2- 4wks All will need extra iron (oral or i.v.) 41

Bruce the Battler Seen 1 month later BP 134 / 68 mmHg Creatinine 245 umol/l eGFR 23 mL/min Ca 2.05 mmol/L PO4 1.54 mmol/L Hb 98 g/L normocytic/normochromic Urine dipstick normal 42

Why worry about Ca & PO4 in CKD Stages 3-5? All patients develop Ca/PO4 disturbance (by CKD Stage 5) Onset of Ca changes is early in CKD Ca/PO4 disturbance causes Bone disease Soft tissue calcification (coronaries & valves) Pruritus Proximal myopathy Premature death

Increased PO4 is associated with increased mortality even in normal Kidney Function Hazard ratio S. PO4 mg/dL Tonelli et al, Circulation 2006

PO4 and mortality in Dialysis 45

Mechanisms of Ca/PO4 disturbance Phosphate retention with reduced GFR results in increased s PO4 and suppresses Vit D3 production Reduced Vit D3 leads to reduced Ca absorption and this plus high s PO4 leads to low s Ca Ca x PO4 increases favouring tissue deposition PTH stimulated by low Ca, high PO4 & low Vit D3 Clinical effects: Low s Ca High s PO4 High s PTH Low Vit D3 [1,25 (OH)2D3 = calcitriol] 46

Changes in serum levels Changes Ca/PO4 parameters with reducing GFR Changes in serum levels CKD Stage GFR (mL/min/1.73m2) 1,25D Phosphate Calcium PTH 60-90 2     2-fold 3 30-59     2-fold 15-30 4     4-fold <15 5     8-fold 47

Assessment of Ca/PO4 disturbance* (CKD Mineral and Bone disorder) What to measure Calcium (corrected for albumin) Phosphate Alkaline phosphatase Bicarbonate PTH (Vitamin D3) How often? 12 monthly in CKD Stage 3 3 monthly in CKD Stage 4 *KDIGO position statement. Kid Intern 2006;69:1945 48

Goals of therapy for Ca/PO4 disturbance Control s PO4 to <1.65 mmol/L Keep s Ca in normal range (2.2-2.6 mmol/L) Keeps Ca x PO4 <4mmol/L Keep s PTH to ~2-3 times normal

Therapy for Ca/PO4 disturbance Control s PO4 Dietary restriction Phosphate binders (prevent uptake) Control s Ca Adequate calcium intake Calcitriol (increases uptake) Control s PTH Calcitriol Cinacalcet Parathyroidectomy

Ca++ / PO42- / PTH / Vit D in CKD Changes by Stage of CKD Clinical effects 51

Mechanism for Vit D effect on CVS Fig. 7. Various mechanisms for how vitamin D and its metabolites 25(OH)D and 1,25(OH)2D and active analogs may affect the cardiovascular system. 52

Who may be considered for referral to a nephrologist? Anyone with eGFR <30mL/min/1.73m2 Unexplained decline in kidney function (>15% drop in GFR over 3 months) Proteinuria >1g/24hrs (protein:creatinine ratio of 100 mg/mmol @ 1g/24hrs) Glomerular haematuria (particularly if proteinuria present) CKD and hypertension that is hard to get to target Diabetes with eGFR <60mL/min/1.73m2 Unexplained anaemia (<100g/L) with eGFR <60mL/min/1.73m2 Clinical tip When referring to a nephrologist ensure patient has had a recent kidney ultrasound, current blood chemistry and quantification of proteinuria Anyone with an acute presentation and signs of acute nephritis should be regarded as a medical emergency and referred without delay

Who does not usually need to be referred to a nephrologist? Don’t refer CKD Stage 2-3 if: Stable eGFR 30-89 mL/min/1.73m2 Minor proteinuria (<0.5g/d with no haematuria) Controlled blood pressure In CKD Stages 2-3 Don’t refer to nephrologist if targets of therapy are achieved Pay attention to CVD risk reduction Use ACE/ARB Monitor 3-6 monthly The decision to refer or not must always be individualised. In younger patients the indications for referral may be less stringent e.g. minor proteinuria and in older patients they may be more selective.

Conclusion Early CKD is so common that it must be mainly managed in general practice Therapy overlaps significantly with best practice in CV risk reduction and diabetes care Key CKD management tasks Lifestyle – Healthy diet & exercise, no smoking, weight control Reduce CV risk BP at target with ACE/ARB Reduce proteinuria with ACE/ARB Optimise haemoglobin, Ca/P and glycemia

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