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 through the renin-angiotensin system Rate of damage predictable Adequate treatment can reduce rate of progression 1
Primary Renal Disease of new patients DM 34% 7% Others 20% Unknown 7% HT / renal vascular 3% Obstructive / 3% Urolithiasis Inherited congenital 2% Infection / reflux 25% GN Hypertensive Kidney Underlying pathology Vascular damage Renin- angiotensin activation Glomerular damage Hyperfiltration and proteinuria Glomerulosclerosis 2
Endothelial damage One of the markers of endothelial damage is urine microalbumin In a hypertensive patient develop microalbuminuria, chance of cardiovascular events increased. Microalbuminuria Normal urine contains albumin of 20 mg/litre. Dipsticks can only detect albumin of 150 mg/litre Albumin excretion between 20 150 mg/litre (30 300 mg/day) is called microalbuminuria. Reversible at this stage 3
Microalbuminuria Can be performed in spot urine, need to determine the urine creatinine concentration to correct for urine dilution Urine albumin/creatinine ratio in MA: >30 mg/g or 3.4 mg/mmol 4
5
6
7
Hypertensive Kidney Underlying pathology Vascular damage Renin- angiotensin activation Glomerular damage Hyperfiltration and proteinuria Glomerulosclerosis 8
Ramipril and Renoprotection Part 1, slide 7 ACE inhibition and glomerular function (I) Afferent Arteriole BP Glomerulus Bowman s Capsule GCP Filtered Proteins EAR Efferent Arteriole Lewis E. Contrib Nephrol 1996;118:206-213. 9
Aims of HKD treatment Prevent the development of renal disease Delay the progression of renal disease Prevent the development of cardiovascular events many HKD patients died of cardio-vascular events before ESRD SHAPE UP program Management of hypertensive kidney disease - SHAPE UP program S Staging of renal failure, stop smoking H high BP, BS, cholesterol, high PO4 Rx A Anaemia management P Proteinuria management E Evaluation for renal transplantation U Undo nephrotoxins P Preservation of veins 10
Hypertensive Kidney Disease Chronic Kidney Disease renal damage sustained for more than 2 months Divided into 5 stages according to creatinine clearance Hypertensive kidney disease and diabetic nephropathy are major causes 11
Renal Function Tests blood urea (normal < 6 mmol/l) affected by the protein intake serum creatinine (normal <120 umol/l) more reliable because less affected by the protein intake affected by muscle mass, remain low despite poor renal function. when the serum creatinine is twice normal, 50% renal function is gone. creatinine clearance 12
Creatinine Clearance Test Most accurate measure of renal function Need to collect 24 hour urine NOT all laboratories in HK can do this test accurately Can also be calculated from BW, age and serum creatinine Interpretation of CCr Normal around 100 ml/minute When CCr falls below 40 ml/minute, started to have symptoms Once CCr falls below 40/minute, downhill course inevitable When falls below 15 ml/minute, dialysis or transplant needed Computer program to calculate CCr and suggest treatment 13
14
15
Management of hypertensive kidney disease - SHAPE UP program S Staging of renal failure, stop smoking H high BP, BS, cholesterol, high PO4 Rx A Anaemia management P Proteinuria management E Evaluation for renal transplantation U Undo nephrotoxins P Preservation of veins Blood pressure Control BP highest in the early morning, lowest at night time Cardio-vascular events highest in the morning Ideal to control 24 hour BP to within target level 24 hour BP recording useful 16
Blood Pressure in Diabetic Nephropathy Each 10 mm Hg systolic reduce complications by 12% (UKPDS) Complications lowest at systolic BP 120 mm Hg Each 10 mm Hg increase in systolic blood pressure associated with 6.7% ESRD (RENNAL ) Summary of Studies on Nephropathy Progression GFR (ml/min/year) SBP (mm Hg) 130 134 138 142 146 150 154 170 180 0-2 -4-6 -8 r = 0.69; P < 0.05 Untreated HTN -10-12 -14 Parving HH et al. Br Med J, 1989 Viberti GC et al. JAMA, 1993 Klahr S et al. N Eng J Med, 1993* Hebert L et al. Kidney Int, 1994 Lebovitz H et al. Kidney Int, 1994 Maschio G et al. N Engl J Med, 1996* Bakris GL et al. Kidney Int, 1996 Bakris GL. Hypertension, 1997 GISEN Group, Lancet, 1997* Bakris GL et.al.am J Kidney Dis, Sept. 2000 17
Target for blood pressure control With ACEI or ARB, reduce blood pressure to 130/80 mm Hg If urine protein >1 g/day, 120/75 mm Hg In type 2 diabetics, renal protection more clearly proven with ARB Angiotensin converting enzymes inhibitor For the same degree of BP reduction, also reduce proteinuria Preservation of renal function (small study) Lisinopril (Zestril) slows renal deterioration Can be combined with verapamil or diltiazem 18
Angiotensin Receptor Blocker Irbesartan Diabetic nephropathy Trial RENAAL Trial (Reduction of end-points in NIDDM with AA Losartan) Clear renoprotection in diabetic nephropathy in type 2 diabetics No head to head comparison with ACEI IDNT: Time to Doubling of Serum Creatinine Subjects (%) 70 60 50 40 30 Irbesartan 300 mg/d Amlodipine 10 mg/d Control RRR= 37% P<.001 P= NS RRR= 33% P=.003 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (mo) Lewis EJ et al. N Engl J Med. 2001;345:851-860. 860. 19
RENAAL Time to ESRD from Doubling of Serum Creatinine % with event 80 60 40 20 Risk Reduction: 30% p=0.013 P 0 0 6 12 18 24 Months P (+CT) 198 111 48 11 4 L (+CT) 162 104 43 19 3 L K/DOQI Clinical practice guidelines Target Reduction of proteinuria <1 g/day blood pressure <130/80 mm Hg Start with ACEI/ARB Add Diuretics Add non-dihydropyridine (verapamil or diltiazem) Add ARB/ACEI 20
Drug combinations To reach the target blood pressure, more than one anti-hypertensive drugs need to be used. Drug combination may be convenient ACEI and verapamil both can reduce BP and proteinuria Combination of ACEI and ARB therapy Candesartan and Lisinopril Microalbuminuria Study (CALM) 199 hypertensive type 2 diabetic patients with microalbuminuria, randomly assigned first to ACEI or ARB therapy and then, after 12 weeks, to combination therapy or continued monotherapy Combination therapy afforded greater reductions in blood pressure and albuminuria than either treatment alone. 21
Phosphate control Hyper-phosphataemia is a potent cause of coronary calcification and vascular event Preventable with phosphate binder Calcium based phosphate binder can cause hypercalcaemia Aluminum phosphate binder may cause Al accumulation Hyperlipidaemia High blood lipid level accelerate glomerulosclerosis Albumin excretion falls by 25% according to one study The lower the lipid level the better Target cholesterol level 3.5 mmol/l 22
Management of hypertensive kidney disease - SHAPE UP program S Staging of renal failure, stop smoking H high BP, BS, cholesterol, high PO4 Rx A Anaemia management P Proteinuria management E Evaluation for renal transplantation U Undo nephrotoxins P Preservation of veins 23
Erythropoietin Major site of production is in the kidneys Produced by interstitial fibroblasts in? Proximal tubular cells Production stimulated by hypoxia (hypoxia inducible factor HIF) Use of Erythropoietin Previously used in end-stage renal failure patients Useful also in patients with moderate renal failure when Hb is low Part of the uraemic symptoms are in fact anaemic symptoms correctable by EPO injection 24
EPO and its benefits Correct the anaemia, target Hb level 10 to 11 g/dl Increase exercise tolerance Prevent left ventricular hypertrophy a risk factor for cardiac mortality Improved quality of life vitality and sleep Principle of EPO administration Response is dose dependent SC route generally more effective, dose 1/3 less compared with IV route. Response limited by iron store, inflammation, bone marrow fibrosis Hypertension as chief complication Headache (15%), flu like syndrome and seizures rare 25
The cardio-renal syndrome Hypertension caused heart failure and renal failure Heart failure aggravate renal failure Control of heart failure and anemia caused an improvement in renal function Management of hypertensive kidney disease - SHAPE UP program S Staging of renal failure, stop smoking H high BP, BS, cholesterol, high PO4 Rx A P Anaemia management Proteinuria management E Evaluation for dialysis/renal transplantation U Undo nephrotoxins P Preservation of veins 26
RENAAL data revisited Compare degree of proteinuria and occurrence of renal end-points (doubling of serum creatinine, ESRD or death) Compare degree of proteinuria and ESRD De Zeeuuw et al, 2004, Kidney International 27
28
New findings Albuminuria is the most powerful marker for renal progression in DN Suppression of albuminuria an independent predictor of renal protection Renal protection by losartan explained by anti-proteinuria effect in addition to hypotensive effect. Baseline proteinuria Patient with proteinuria >3.0 g/g creatinine showed 5.2 fold increased risk to renal end-point and 8.1 fold increase risk to ESRD Measurement of urine protein important. Urine protein a measure of glomerular hyperfiltration 29
Urine protein measurement In early stage, check for urine microalbumin reversible stage At macro-albumin stage, proteinuria a measure of glomerular pressure Proteinuria proportional to renal risk Reduction of proteinuria proportional to renal protection Proteinuria Estimation Ordinary urine dipstix affected by urine dilution, inaccurate ($0.20) 24 hour urine measurement accurate but expensive ($150) Early morning urine albumin/creatinine ratio ($150) Ho s dry state analysis ($0.75) 30
Urine albumin: creatinine ratio ($150/test) Check urine creatinine in addition to albumin, cancel out dilution effect If urine albumin 3 g/l and creatinine 1 g/l, the ratio is 3 g/g 24 hour urine protein excretion= 3 g/day Use early morning urine Useful for progress follow up. Ho s dry state analysis ($0.75/test) Instead of using urine creatinine, use SG instead Done on common urine dipstix Urine albumin expressed as mg/l Probability of significant proteinuria obtained from a curve 31
32
33
Low protein diet 0.6 g/kg/day slow GFR decline (12 ml/minute/year to 3 ml/minute/yr) At risk of protein malnutrition Effect modest 34
When to start dialysis? In diabetic patients, start dialysis when CCr around 15 ml/minute Other renal failure patients, start dialysis around 10 ml/minute Nephrologist needs 2 months to prepare patients for dialysis Management of hypertensive kidney disease - SHAPE UP program S Staging of renal failure, stop smoking H high BP, BS, cholesterol, high PO4 Rx A Anaemia management P Proteinuria management E Evaluation for dialysis/renal transplantation U Undo nephrotoxins P Preservation of veins 35
Predicting the date of endstage renal failure Creatinine clearance falls linearly with time 1/creatinine falls linearly We can use a computer program to predict the change computer simulation program 36
37