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Therapeutics in Renal Disease

Therapeutics in Renal Disease. Dr Michael Clarkson Consultant Renal Physician – CUH. Chronic Kidney Disease. Common Easy to Diagnose Effective Therapies Available CKD Care Suboptimal. Serum Creatinine is a Poor Marker of GFR. MDRD eGFR. MDRD equation – Complex log rhythmic equation

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Therapeutics in Renal Disease

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  1. Therapeutics in Renal Disease Dr Michael Clarkson Consultant Renal Physician – CUH

  2. Chronic Kidney Disease Common Easy to Diagnose Effective Therapies Available CKD Care Suboptimal

  3. Serum Creatinine is a Poor Marker of GFR

  4. MDRD eGFR • MDRD equation – Complex log rhythmic equation • Integrates key variables Age Sex Creatinine Race Urea Albumin

  5. MDRD eGFR • GFR is the accepted measure of kidney function • GFR is difficult to infer from serum creatinine alone • Automatic reporting identifies CKD patients with apparently “normal” serum creatinine • Reduces barrier to early detection

  6. 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

  7. Spot Ratios! • 24 hour collections cumbersome • Excretion of creatinine and protein is reasonably constant throughout the day • A random urine protein:creatinineratio has been shown to correlate with a 24-hr estimation • Expressed either as mg/mg (easy) or mg/mmol (multiply x 0.0088)

  8. Spot Ratios! • 24yo lady with ankle oedema, proteinuria and hypercholesterolaemia • Spot urine protein 924mg/L • Spot urine creatinine 3343µmol/L • Ratio = 276mg/mmol (normal: 0-45) • Convert to mg/mg (276 x 0.0088) = 2.4g/24hr

  9. Identifying CKD BISH BASH BOSH

  10. Staging of Chronic Kidney Disease

  11. 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 60-89 Estimate progression 3 Moderate 30-59 Evaluate and treat complications 4 Severe 15-29 Prepare for RRT 5 ESRD <15 Initiate RRT NKF, USA

  12. Factors Mediating Evolution of CKD • Susceptibility Factors • Initiation Factors • Progression Factors

  13. Susceptibility Factors • Male gender • Hypertension • Age • 1ml/year loss normally • Genetic Background • ACE polymorphisms • Reduced Nephron Mass at Birth

  14. Initiation Factors Diabetic Nephropathy > Glomerular Disease > Tubulointerstitial Disease > Hypertensive Nephrosclerosis

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

  16. Progression Factors • Hypertension • Glomerular Hypertension • Proteinuria • Hyperlipidemia • Genetic Factors • Miscellaneous • Exacerbating Effect of Risk Factor Clustering

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

  18. Hypertension and CKD

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

  20. 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

  21. Hypertension and CKD Target Blood Pressure

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

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

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

  25. Effective Control of Hypertension Yields Major Benefit in CKD

  26. Early treatment can make a difference 100 No Treatment DelayedTreatment Early Treatment 83 GFR (mL/min/1.732) 10 Kidney Failure 0 4 7 9 14 2

  27. Blood Pressure Goals in CKD • Stratify According to Proteinuria • Proteinuria <3g Goal <130/80 • Proteinuria >3g Goal <125/75 • Optimal Blood Pressure Unknown • Diuretics Essential • 120/80??

  28. Proteinuria and CKD

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

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

  31. Proteinuria and CKD • Proteinuria evaluation mandatory in all patients with CKD • Independent risk factor for CKD progression • Best predictor of ESRD

  32. Adverse Consequences of Proteinuria vs low eGFR Hemmelgarn et al. JAMA. 2010;303(5): 423-429.

  33. Proteinuria In CKD Intervention Studies Pharmacologic Approaches Dietary Approaches

  34. 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’.

  35. Proteinuria and CKD Pharmacologic Approaches

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

  37. 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

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

  39. Vasodilators Prostaglandins Nitric Oxide Vasoconstrictors Angiotensin-II PGc  Efferent Afferent Hyperfiltration Mechanical Strain 2º FSGS

  40. Hypertension Control RAAS Blockade BP PGc  Efferent Lower GFR Reduction in Proteinuria

  41. Angiotensin Recptor BlockadeMore Risk, More Benefit!

  42. 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

  43. 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

  44. 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

  45. 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?

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

  47. Initiation of ACEi / ARB 100 83 GFR (mL/min/1.732) 10 Kidney Failure 0 4 7 9 14 2

  48. 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

  49. 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

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