Renoprotective Strategies in Clinical Practice. Dr Michael Clarkson

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1 Renoprotective Strategies in Clinical Practice Dr Michael Clarkson

2 The Silent Epidemic? ESRD CKD 5% of a UK population

3 Staging of Chronic Kidney Disease

4 Stage Description GFR Evaluation / Plan 0 At risk >90 Modify risk factors 1 Kidney damage / >90 Diagnose / Treat cause. Slow normal GFR progression and evaluate CV risk. 2 Mild Estimate progression 3 Moderate Evaluate and treat complications 4 Severe Prepare for RRT 5 ESRD <15 Initiate RRT NKF, USA

5 Shared Care in Chronic Kidney Disease 0 Modify risk factors Primary Care 1 Diagnose / Treat cause. Slow progression and evaluate CV risk. 2 Estimate progression 3 Evaluate and treat complications 4 Prepare for RRT 5 Initiate RRT GFR 30-60cc/min Specialty Care

6 Clinical Signs and Symptoms of CKD According to Stage

7 Estimation of GFR Cockcroft-Gault Equation (140-age) x Serum creatinine X (0.8 in Women) Body Weight

8 Estimation of GFR MDRD Equation Online Calculator

9 Three simple tests identify CKD in adults Dipstick Urinalysis Haematuria / Macroalbuminuria Urine PCR - Urine protein to creatinine ratio on a spot urine sample 24-hour urine collections are NOT needed egfr - Estimated GFR from serum creatinine using the MDRD equation

10 Identifying CKD BISH BASH BOSH

11 Factors Mediating Evolution of CKD Susceptibility Factors Initiation Factors Progression Factors

12 Susceptibility Factors Male gender Hypertension Age 0.5ml/year loss Genetic Background ACE polymorphisms Reduced Nephron Mass at Birth

13 Initiation Factors Diabetic Nephropathy > Glomerular Disease > Tubulointerstitial Disease > Vascular Nephropathy

14 Progression Factors Progressive loss of renal function will occur even in the absence of overt activity of the primary renal disorder

15 Progression Factors Hypertension Glomerular Hypertension Proteinuria Hyperlipidemia Genetic Factors Miscellaneous Exacerbating Effect of Risk Factor Clustering

16 Maladaptive Response to Loss of Initial Renal Insult Nephron Mass BP Control Loss of Nephron Mass RAAS Blockade Dietary Protein Restriction Secondary FSGS Proteinuria / Hypertension Compensatory Glomerular Hypertrophy / Hyperfiltration Podocyte Injury / Mesangial Matrix Expansion Maximisation of GFR Intraglomerular Hypertension

17 Hypertension and CKD

18 Role of Hypertension in CKD Progression 50-75% of patients with CKD have BP >140/90mmHg Goals of therapy 1. Retard CKD progression 2. Reduce overall cardiovascular risk

19 Role of Hypertension in CKD Progression Strong association with poor renal outcomes esp. in diabetic nephropathy Microalbuminuria progression Morphologic injury Predicts loss of renal function in non-diabetic glomerular disorders and in APKD. Confounding effect of proteinuria make accurate assessment of independent effect difficult

20 Hypertension and CKD Target Blood Pressure

21 Relationship between BP Control and Rate of Decline in GFR Bakris et al AJKD, 2000.

22 Decline in GFR and HTN: Stratification for Proteinuria MDRD Study: Arch Int Med, 1995

23 Effective Control of Hypertension Yields Major Benefit in CKD

24 Effective Control of Hypertension in CKD: Multiple Agents Required Bakris et al AJKD, 2000

25 Blood Pressure Goals in CKD Stratify According to Proteinuria Proteinuria <3g Goal <130/80 Proteinuria >3g Goal <125/75 Optimal Blood Pressure Unknown 120/80??

26 Blood Pressure Goals in DM Nilsson PM. Swedish National Diabetes Register (NDR) Blood Pressure, 2012

27 Proteinuria and CKD

28 Microalbuminuria and Macroalbuminuria Microalbuminuria Macroalbuminuria Definition >30-299mg/day >300mg/day Routine Dipstick Negative Positive Renal Significance Risk Marker Marker of progression Cardiovascular Risk Increased Increased

29 Maladaptive Response to Loss of Initial Renal Insult Nephron Mass Loss of Nephron Mass Secondary FSGS Proteinuria / Hypertension Compensatory Glomerular Hypertrophy / Hyperfiltration Podocyte Injury / Mesangial Matrix Expansion Maximisation of GFR Intraglomerular Hypertension

30 Proteinuria and CKD Proteinuria evaluation mandatory in all patients with CKD Independent risk factor for CKD progression Best predictor of ESKD

31 Proteinuria Evaluation Dipstick affected by urine concentration 24 hour collections cumbersome Morning spot urine protein:creatinine ratio

32 Spot Urine Protein to Creatinine Ratio When expressed in mg and g respectively the urine protein to creatinine ratio accurately predicts 24hr excretion Conversion Factor required for SI units Protein (mg) / (UCr x 0.001) X

33 Spot Urine Protein to Creatinine Ratio 52 yo female. Type II DM x 10years Dipstick ranges from trace to 2+ Spot Urine Protein 626mg/L Spot Urine Creatinine 7763umol/L 626 / = 81 mg/mmol (0-44) x = 0.7 Consistent with overt proteinuria of 0.7g/24hours

34 Degree of Proteinuria Predicts Loss of Renal Function Aperloo et al, Kidney Int, 1994.

35 Proteinuria In CKD Intervention Studies Pharmacologic Approaches Dietary Approaches

36 Reduction in proteinuria Reduction in proteinuria is key to successful renoprotective strategy. Anti-hypertensive regimens with better reduction in proteinuria afford greater renoprotective benefits. Benefit persists even when BP within the normal range.

37 Short Term Anti-Proteinuric Response Predicts Long Term Outcomes in Non- Diabetic CKD Aperloo et al, Kidney Int, 1994.

38 Proteinuria and CKD Pharmacologic Approaches

39 ACE-I Decrease Proteinuria More than Conventional Anti-Hypertensive Therapy Jafar et al, Meta Analysis Ann Int Med 2001

40 Benefit of ACE-I in Non-Diabetic Renal Disease Meta Analysis Jafar et al, Ann Int Med 2001

41 RAAS Blockade in CKD - Mechanism of Action Reduction in intraglomerular hypertension Efferent arteriolar vasodilatation Improved glomerular permselectivity Attenuation of AII-stimulated growth factor and inflammatory cytokine secretion Prevention of extracellular matrix accumulation

42 Vasodilators Prostaglandins Nitric Oxide Afferent Efferent Vasoconstrictors Endothelin Catecholamines Adenosine Vasoconstrictors Angiotensin-II

43 Vasodilators Prostaglandins Nitric Oxide Afferent PGc Efferent Hyperfiltration Mechanical Strain 2º FSGS Vasoconstrictors Angiotensin-II

44 Hypertension Control BP PGc Efferent Lower GFR Reduction in Proteinuria RAAS Blockade

45 Angiotensin Recptor Blockade More Risk, More Benefit!

46 Initiation of ACE-I or ARB Although ACE inhibitors now have a specialised role in some forms of renal disease they also occasionally cause impairment of renal function which may progress and become severe in other circumstances BNF

47 Initiation of ACE-I or ARB Case Example 42 year old lady Hypertension Recurrent UTI Atrophic left kidney Pre-eclampsia x 2 BP=155/95 MAP=115 SeCr = 145umol/L. MDRD GFR = 50ml/min Urine Protein to Creatinine ratio: 1.4

48 Initiation of ACE-I or ARB Initiated on Ramipril 5mg qd + low salt diet Day 7. BP = 145/90 Ramipril increased to 10mg qd Day 14 BP 140/85 Repeat Creatinine = 175umol/L, K + 5.4mmol/L Estimated GFR = 42mls/min

49 Initiation of ACE-I or ARB Clinical Dilemma Substantial fall in GFR following RAAS blockade Hyperkalaemia Do not suspect renovascular disease Withdraw ACE-I / ARB?

50 Initiation of RAAS Blockade : Initial reduction in GFR predicts better outcome Aperloo et al, Kid Int, 1997

51 GFR (ml/min/ ) Effect of ACEi / ARB on GFR in Proteinuric CKD 100 No Treatment Standard anti-hypertensive 83 ACEi or ARB Kidney Failure

52 Initiation of ACE-I or ARB Continue RAAS Blockade. Accept <25% fall in GFR. Ensure it is not progressive. Goal 130/80 Review Medications Dietary K + Restriction Diuretic Add second agent Diuretic Non-dihydroperidine CCB Beta Blocker

53 Post hoc analysis of RENAAL and IDNT Trials Renoprotection only with salt restriction Lambers Heerspink et al. Kidney International, 2012) 82,

54 Slan Study: Dietary Salt Intake in Ireland Method Mean (g/day) Questionnaire 8.1(M) 7.6 (F) Spot urine hr collection Perry IJ et al (2010). Dietary salt intakeand related risk factors in the Irish population. A report for Safefood Ireland.

55 Slan: Food Groups contributing to salt intake Salt (g) % overall intake Cereals, breads, and potatoes Meat, fish and poultry Soups, sauces, spreads Vegetables Dairy products and fats Sweets, savoury snacks Drinks Fruits Milk Perry IJ et al (2010). Dietary salt intakeand related risk factors in the Irish population. A report for Safefood Ireland.

56 Slan Conclusion Dietary salt intakes in the Irish population remain high with the overwhelming majority of the population consuming salt at levels well in excess of the current target of six grams per day. Perry IJ et al (2010). Dietary salt intakeand related risk factors in the Irish population. A report for Safefood Ireland.

57 Patient BC 62yo Farmer The Bachelor Farmer Referred for progressive CKD Past Medical History Type II DM: Retinopathy / Proteinuria Hypertension Meds: Losartan-Hctz 100/25mg daily Doxasocin 4mg daily Amlodipine 10mg daily

58 The Bachelor Blood Pressure in Clinic 160/75 Spot urine protein to creatinine ratio 2.8mg/mg Creatinine 250µmol/L Cooks for himself

59 Creatinine Trend 01/ / / / / / / /2010 Creat egfr PCR BP 160/75 135/70 130/70 122/72

60 egfr Creatinine Trend Category 1

61 The Bachelor Interventions: Tight salt restriction (100mmol / 5g) No added salt No salt in cooking Minimise pre-prepared food / sauces Bisoprolol 5mg 40/3mmHg BP drop

62 And I quote... Giving up the salt made an awful difference Salt is a poison! By the way, Dr Horgan tells me my eyes are way better

63 Combined ACE-I / ARB Therapy Advocated for Maximal RAAS blockade. Initial studies suggested benefit Not confirmed in later studies

64 Bad Combinations Combined ACEi and ARB No additional benefit Lots of additional risk Hyperkalaemia Swings in egfr in elderly Haemodynamic AKI

65 OnTarget N Engl J Med 2008; 358:

66 ACEi + ARB Combination

67 ARB + Direct Renin Inhibitor AVOID Study Parving H et al. N Engl J Med 2008;358:

68 Proteinuria and CKD Dietary Modification

69 Dietary Protein Intake Protein loading increases RBF and GFR Evolutionary adaptation Hunter Gatherer Maladaptive in setting of reduced renal reserve Glomerular hypertension Accelerated glomerulosclerosis in animal models

70 MDRD Study: Effect of Dietary Protein Restriction on CKD Progression Klahr et al NEJM, 1994

71 Goal Proteinuria Independent Risk Marker Therefore Needs Independent Therapeutic Goal Irrespective of BP Control Proteinuria Dose Response to RAAS Blockade May Not Parallell That of BP

72 Degree of Proteinuria Predicts Loss of Renal Function Goal GFR Decline Aperloo et al, Kid Int, 1994.

73 Goal Proteinuria <300mg/24hours or Ratio of <0.45 RAAS Blockade BP Control ± Protein Restriction

74 Risk Factor Clustering in CKD When sorrows come, they come not single spies, but in battalions. William Shakespeare

75 CV Mortality in ESRD CVD mortality is high on Dialysis CVD mortality in dialysis patients (USRDS) compared to the general population (NCHS) Foley et. al., 1998 Am J Kid Disease 32

76 CV Risk Factors in ESRD Uremia-Related Anemia ECV Expansion Homocysteine Oxidative Stress Divalent Ion Disarray Traditional Hypertension Diabetes Smoking Dyslipidemia LVH

77 Divalent Ion Disarray CKD Hypovitaminosis D Hyperphosphatemia Hyperparathyroidism Osseous Calcium + Phosphate Mobilisation Vitamin D Rx Raised Ca x Phos Enhanced Ca 2+ Product Intake Vascular Calcification

78 Divalent Ion Disarray

79 Divalent Ion Disarray What to do? Address in mid-late stage 3 Nutrition input Restrict dietary phosphate Monitor PTH 1 vitamin D? Phosphate binders Calcium based vs. non-calcium-based controversial

80 Hyperlipidemia in CKD Experimental Data support pathogenic role HDL Cholesterol predicts progression in CKD (MDRD) Statins effectively lower lipids in CKD Outcome data in progression lacking Consider CV risk factor clustering!! Goal Total Chol <5.0, LDL <2.5

81 Obesity and CKD Morbid obesity assoc. with FSGS Mechanism Exacerbation of other risk factors HTN / DM / Lipids / Sodium Intake Hyperfiltration Clinical outcomes data available Goal BMI < 30

82 Smoking and CKD Smoking is independently associated with the development of nephropathy in Type II DM. Exacerbates overall CV risk factor profile Stop!

83 Anaemia and CKD Anaemia may accelerated CKD progression Hypoxia-induced increased tubulointerstitial fibrosis Anti-apoptotic effects on tubular cells Small scale studies suggest benefit Consider CV risks: LVH Goals Maintain Hb g/dL EPO Fe supplements (po/iv) Nurse Specialist. Industry / CUH / KGH

84 Framework for Renoprotection Identify patients at risk Establish individual risk factor profile Intervention Non-pharmacological / pharmacological

85 Framework for Renoprotection Monitor Therapeutic Efficacy BP Proteinuria Optimise Therapy If therapy resistant consider causes and reevaluate

The hypertensive kidney and its Management

The hypertensive kidney and its Management Dr H0 Chung Ping Hypertension Management Seminar 20061124 Hypertensive kidney Kidney damage asymptomatic till late stage Viscous cycle to augment renal damage