Hypertension Control and Progression of Renal Disease

1. Hypertension Control and Progression of Renal Disease • In clinical trials, a slower rate of decline in GFR is noted in those who achieved a BP of 130/80 or less • In the MDRD study (nondiabetics), a subset analysis found that in those with proteinuria >1 gram/day had a slower rate of progression when BP was <125/75 (MAP 92) • To achieve this will require multiple medications (>2 on average)

2. Relationship Between Achieved BP in Clinical Trials and Decline in GFR From Bakris et al AJKD 2000

3. Blood Pressure Goals *Caution advised if creatinine >3mg/dl

4. MDRD and BP Control on Progression of Renal Disease • In addition to the protein restriction arm, there was an arm to look at 2 levels of BP (MAP  107 vs  92) • In both Blacks and Whites, higher protein excretion was associated with a greater effect from tighter BP control • Overall, the lower BP treatment arm was associated with a greater benefit in Blacks (11.87.3 difference between 2 treatment groups in Blacks vs 0.31.3 in Whites) Hebert et al, Hypertens 1997

5. AASK trial • Study of African Americans, age 18-70, with renal insufficiency secondary to hypertension • GFR (by iothalamate) between 25-70 ml/min/1.73m2 • Designed to compare (2x3 design) • 2 levels of BP (MAP  92 vs usual Map of 102-107) • 3 initial antihypertensive regimens (enalapril (ACEI), amlodipine (calcium-channel blocker), atenolol (beta-blocker)) • Rate of decline in GFR

6. AASK • Trial is still on-going, but the amlodipine arm has been discontinued • Amlodipine led to an initial improvement in GFR and then a faster decline compared to enalapril • This difference was mainly seen in those with a urine protein excretion >1 gram/day • Overall, the group with a urine protein excretion > 1 gram/day was a higher risk subgroup • This suggests that for those with significant proteinuria and hypertension, ACEI are the first drug of choice and that African Americans benefit from ACEI

7. ACEI • ACEI are effective in diabetic and nondiabetic renal disease in slowing progression of renal disease • The effect of ACEI appears to be in addition to their blood pressure lowering effect • Their effect is greater in those with proteinuria • They should be the first line agent in any patient with hypertension and proteinuria • Would consider use in normotensive patients with proteinuria

8. ACEI in Diabetic Renal Disease • ACEI decrease progression from microalbuminuria to overt proteinuria in Type 1 diabetes • All Type 1 diabetics with microalbuminuria should be on an ACEI, irregardless of BP • There is less data in Type 2 DM with microalbuminuria, however ACEI decrease mortality in high risk individuals with DM (HOPE study) and slow progression once overt nephropathy has developed • In my opinion, all Type 2 DM with nephropathy should be on an ACEI (or ARB) unless not tolerated

9. ACEI in Nondiabetic Renal Disease • Recent meta-analysis (Jafar et al) • 11 studies in English language • 1860 subjects (941 ACEI, 919 control) • 92% hypertensive • Baseline creatinine (mean) 2.31.2 mg/dl • Baseline proteinuria (mean) 1.8 2.3 g/day • Follow-up duration mean 2.2 years • Pooled analysis of individual patient data Annals Int Med 2001

10. ACEI in Nondiabetic Renal Disease: Jafar et al Results • Those in ACEI group did have a greater mean decrease in systolic and diastolic BP • 5.5 mm systolic (95% CI 3.0 to 6.1) • 2.3 mm diastolic (CI 1.4 to 3.2) • ACEI decreased proteinuria to a greater degree • After adjustment for baseline characteristics, BP and proteinuria during follow-up, ACEI decreased progression to end-stage renal disease (7.4% ACEI, 11.6% control; RR 0.69, CI 0.51-0.94)

11. Angiotensin Receptor Blockers and Progression of Diabetic Nephropathy • 3 recently published randomized trials examining the effect of ARB on progression of nephropathy in Type 2 diabetes (NEJM 2001) • All 3 studies aimed for equivalent BP control in all groups • Compared to other antihypertensive regimes, ARB’s slowed progression from microalbuminuria to overt proteinuria (Parving et al) and slowed progression to ESRD (Lewis et al, Brenner et al) • There isn’t data on head-to-head comparison of ACEI and ARB on progression of renal disease

12. Diabetes Control • Tighter glucose control decreases the development of microalbuminuria and overt proteinuria • There is not convincing data that it delays progression of renal disease once overt nephropathy develops • Unclear whether this reflects the relative importance of various risk factors in each stage of diabetic nephropathy or whether no trial has been of long enough duration

13. Control of Diabetes on Diabetic Nephropathy: DCCT • Intensive therapy decreased the development of sustained microalbuminuria by 60% (95% CI 37 to 74) • Intensive therapy decreased the risk of developing sustained overt albuminuria by 51% (CI 2 to 75%) • There were too few patients with a decline in GFR to evaluate Kidney Int 1995

14. Intensive Glucose Control in Type II DM on Diabetic Nephropathy: UKDPS • Intensive control was associated with a decrease in the development of microalbuminuria and proteinuria • Not a significant difference in the development of renal failure (RR 0.45, 95% CI 0.25-2.14)

15. Lipids and Progression of Renal Disease • Mesangial cells resemble smooth muscle cells and respond to many of the same stimuli • In many, but not all, epidemiologic studies, hyperlipidemia predicts decline in renal function • In animal studies, treatment of hyperlipidemia ameliorates damage from renal disease (e.g. diabetic models, other renal disease models) • Treatment trial data is sparse

16. Meta-analysis of Lipid Reduction on Progression of Renal Disease • Randomized trials >3 months • 13 trials found, able to obtain individual patient data from 5 • 11/13 used statins • Most short term and small • Examined change in GFR and proteinuria/albuminuria Fried et al, Kidney Int 2001

17. Effect of Lipid Reduction on Loss of GFR Treatment Worse Treatment Better Smulders (15) Aranda (16) Rayner (16) Thomas (17) Nielsen (18) Tonolo (19) Buemi (21) Hommel (21) Scanferla (24) Lam (34) Olbricht (43) Nishimura (118) Total (362) p = 0.008

18. Effect of Lipid Reduction on Protein Excretion Treatment Better Treatment Worse Smulders(15) Aranda (16) Rayner (16) Nielsen (18) Tonolo (19) Zhang (20) Hommel (21) Buemi (21) Thomas (23) Lam (34) Olbricht (43) Total (246) p = 0.068

19. Lipid Reduction in Early Diabetic Nephropathy • Pilot Study in 39 Type 1 diabetics with normal or microalbuminuria • Randomized trial of simvastatin + diet (n=19) /placebo +diet (n=20) in those with LDL 100-160 mg/dl • LDL decline by at least 25% by un-blinded pharmacist • Planned as 2-year study, but discontinued early, when recommendation of LDL threshold for starting medication lowered Fried et al, JDC 2001

20. Effect of Lipid Reduction on Albuminuria Data are medians and interquartile range

21. Poor Control of Hypertension and Low Use of ACEI in Renal Disease • In NHANES III, 75% of those with an elevated creatinine ( 1.6 in men or 1.4 in women) and hypertension were on medication • Only 27% had a BP <140/90 • Only 11% had a BP <130/85 (JNC VI target) • In a recent study, 33% of nondiabetics and less than 50% of diabetics with CRI, in a large HMO, were on ACEI Coresh et al, Arch Intern Med 2001; Nissenson et al JASN 2000

22. Use of Cardioprotective Medications in Chronic Renal Disease: Tonelli et al* *Prospective Study of Patients seen by Nephrologists in 4 Canadian centers

23. Summary • Renal Failure is a growing public health problem that disproportionately affects the elderly and minorities • Early identification is possible by screening people for proteinuria or a mildly elevated creatinine • In current practice, many people with renal disease are diagnosed late and are under-treated • Early identification would allow greater attention at risk factors to decrease both progression of renal disease and cardiovascular disease, as similar risk factors are involved in the progression of both