Review
Paper
Implications of Albuminuria on Kidney Disease Progression George L. Bakris, MD
Albuminuria is recognized in all hypertension guideline statements as a cardiovascular risk factor and indicator of kidney disease. Recent data also demonstrate a strong association between the presence of microalbuminuria and elevations in C-reactive protein. Thus, the increased membrane permeability that generates microalbuminuria may be secondary to an inflammatory process. Progression from microalbuminuria (>30 and ≤300 mg albumin/g creatinine) to macroalbuminuria (>300 mg albumin/g creatinine) indicates a worsening of vascular disease and the presence of kidney disease. Recent outcome trials of kidney disease progression have demonstrated the best results among those with reductions in albuminuria in concert with blood pressure (BP) reduction. Thus, use antihypertensive agents that not only lower BP but also lower or normalize albuminuria levels. All recent guideline statements support the use of agents that block the renin-angiotensin-aldosterone system as part of a regimen to achieve the BP goal. Further lowering of albuminuria may be achieved by adding either a nondihydropyridine calcium antagonist such as verapamil or diltiazem, or aldosterone receptor blockers. Use of an angiotensin receptor blocker added to an angiotensin-converting enzyme inhibitor or vice versa can further lower albuminuria by an additional 30%– 40%, which is not true of the additional lowering of BP. (J Clin Hypertens. 2004;6(11 suppl 3):18–22) ©
2004 Le Jacq Communications, Inc.
From the Rush University Hypertension/Clinical Research Center, Department of Preventive Medicine, Rush University Medical Center, Chicago, IL Address for correspondence: George Bakris, MD, Rush University Hypertension Center, Rush University Medical Center, 1700 West Van Buren Street, Suite 470, Chicago, IL 60612 E-mail:
[email protected]
www.lejacq.com 18
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here are no outcomes trials in people with stage 1 or stage 2 nephropathy, i.e., glomerular filtration rates >60 mL/min that are positive with regard to slowing the progression of kidney disease, as defined by the doubling of creatinine, development of end-stage renal disease, or death. There are, however, many trials in people with advanced kidney disease (stages 3 and 4) secondary to either diabetic or nondiabetic causes demonstrating a marked slowing of kidney disease in concert with a reduction in proteinuria (macroalbuminuria) (Table I).1–6 The definitions of microalbuminuria and macroalbuminuria (proteinuria) are discussed in the paper by Toto7 in this issue, so the reader is referred to that paper for an in-depth discussion of this topic. Microalbuminuria is a urinary finding that results from a generalized injury to the endothelium along the vascular tree that includes the kidney.8 It is indicative of an inflammatory process in that transient microalbuminuria occurs in settings such as exercise, fevers, heart failure, and poor glycemic control.9 Thus any value obtained for albuminuria must be evaluated in the context of a stable disease process and absence of the aforementioned factors. The urinary test should also be repeated after 1–2 weeks as per the new recommendations.9 Proper evaluation to assess whether any level of albuminuria or proteinuria is present is summarized in Figure 1.10 KIDNEY DISEASE PROGRESSION: FOCUS ON PROTEINURIA It should be remembered that all studies focused on renal outcomes were carried out in people usually with >300 mg/d of proteinuria and a glomerular filtration rate of 177 μmol/L (2.0 mg/dL) and >3.0 g/d of proteinuria and were treated in the ACE inhibitor group had a 62% reduction in renal disease progression while individuals with microalbuminuria
had only a 22% reduction in renal disease progression over the same 42-month follow-up period. In this trial, the greatest benefit was observed in those with the greatest reduction in proteinuria, which occurred in those with the highest levels of proteinuria at the start of the study. The third trial is in African Americans with renal disease, who have a higher likelihood of developing progressive renal disease and who derive additional renoprotection from blockade of the renin-angiotensin system (RAS) if adequate blood pressure (BP) lowering is achieved. In the African-American Study of Kidney Disease and Hypertension (AASK),6 the primary end point was the rate of change in glomerular filtration rate (GFR) (GFR slope), clinical composite outcome of reduction in GFR by ≥50% (≥25 mL/min/1.73 m2) from the baseline, end-stage renal disease, or death. A group treated with ramipril plus other medications manifested a risk reduction in clinical composite outcomes of 22% (95% confidence
Evaluation for proteinuria Not at
Risk
At
Standard dipstick
≥1+
Risk
Albumin-specific dipstick
Negative/Trace
Negative
Positive
Albumin/creatine ratio
Total protein/creatine ratio
>200 mg/g
≤200 mg/g
≤300 mg/g
>30 mg/g
Recheck at periodic health evaluation
Diagnostic evaluation
Treatment
Consultation
Figure 1. Annual evaluation of albuminuria SUPPL. 3 VOL. VI NO. XI NOVEMBER 2004
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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
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Table I. A Summary of Studies Demonstrating Positive Outcomes in Concert With Reductions in Proteinuria/Macroalbuminuria BASELINE GFR
BASELINE ALBUMINURIA LEVEL
40 52 56 46
>300 mg/d* >300 mg/d* >300 mg/d* ≈300 mg/d
68 51 59 62 ≈40 ≈40
>300 mg/d >300 mg/d >300 mg/d* >300 mg/d* >500 mg/d* >300 mg/d*
Nondiabetic MDRD20 AIPRI4 REIN5 AASK6 Diabetic Captopril study3 Hannedouche et al.21 Bakris et al.22 Bakris et al.23 IDNT2 RENAAL1
GFR=glomerular filtration rate; MDRD=Modification of Diet in Renal Disease study group; AIPRI=Angiotensin-Converting enzyme Inhibition in Progressive Renal Insufficiency trial; REIN=Ramipril Efficacy In Nephropathy trial; AASK=African-American Study of Kidney Disease and Hypertension; IDNT=Irbesartan Diabetic Nephropathy Trial; RENAAL=Reduction of Endpoints in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan study; *more than half the patients had close to a gram or more of proteinuria (macroalbuminuria) per day. Clearly all patients had stage ≥3 kidney disease, stage 5 being the initiation of dialysis.
interval, 1%–38%; p=0.04) as compared with a metoprolol-based treatment group and 38% (95% confidence interval, 14%–56%; p=0.004) when compared with an amlodipine group. In this trial, prognostic signs that correlated with a slowing of kidney disease progression included: 1) goal BP
