- Email: [email protected]
Albuminuria reduction: The Holy Grail for Kidney Protection
co m m e nt a r y
see original article on page 879
Albuminuria reduction: The Holy Grail for Kidney Protection KR Tuttle1,2 Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease. Observational analyses have raised a strong hypothesis that albuminuria reduction should be a clinical treatment target. Bakris et al. report further exploration of albuminuria-lowering capabilities of intensified renin–angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease. Kidney International (2007) 72, 785–786. doi:10.1038/sj.ki.5002505
Holy Grail: a distant, ultimate goal
Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease (CKD). Reduction of albuminuria/proteinuria (referred to as ‘albuminuria’ from here forward) has been associated with decreased risk of major clinical events (death, end-stage renal disease, or 50% loss of kidney function) in both diabetic and nondiabetic forms of CKD.1–3 The most commonly studied treatments for albuminuria reduction are the renin–angiotensin system inhibitors, angiotensin-converting enzyme inhibitor, and angiotensin receptor blockers. Observational analyses from studies of renin–angiotensin system inhibitors have been performed to examine relationships between albuminuria change and clinical events. The first of these analyses from a large randomized trial of angiotensin receptor blockade in diabetic kidney disease characterized by macroalbuminuria showed that reduction in albuminuria at 6 months strongly predicted improved 1Providence Medical Research Center at Sacred
Heart Medical Center, Spokane, Washington, USA; and 2University of Washington School of Medicine, Spokane, Washington, USA Correspondence: KR Tuttle, Providence Medical Research Center, 122 W. 7th Avenue, Suite 230, Spokane, Washington 99224, USA. E-mail: [email protected] Kidney International (2007) 72
kidney and cardiovascular outcomes, whereas an increase in albuminuria predicted the opposite.1,4 Another more recent analysis from the same study suggests that predictive ability of albuminuria change for kidney outcomes can largely be dissociated from blood pressure changes in diabetic kidney disease.5 In addition, observational analyses from clinical trials of renin–angiotensin system inhibition in hypertensive African Americans with CKD and hypertensive patients with left ventricular hypertrophy have also shown relationships between albuminuria change, or achieved level of albuminuria, during the trials and kidney and cardiovascular outcomes.3,6 In the latter two studies, most patients had microalbuminuria, which potentially extends the spectrum of albuminuria amenable to treatment. This emerging body of data has led to the suggestion that treatment with renin–angiotensin system inhibitors should target reduction of albuminuria as well as blood pressure. In other words, increasing the dosage or intensity of treatment with renin–angiotensin system inhibition to reduce albuminuria should be considered even if blood pressure is at goal. Either prespecified secondary or post hoc analyses of clinical trials have raised a strong hypothesis that albuminuria reduction should be a clinical treatment
target. In further support of the hypothesis, experimental studies have shown biologic rationale for the clinical observations. Urinary albumin appears to be proinflammatory to the tubulointerstitium in particular and could contribute to progressive kidney damage and loss of function.7 However, caution is in order before this hypothesis, or any other, is accepted as fact. First, although scientific inquiry begins with a hypothesis, the conclusion should not be presumed before it has been rigorously tested. Second, alternate hypotheses should also be considered. For example, albuminuria may be a marker of patient responsiveness to therapy rather than a causal mechanism for kidney and cardiovascular disease. Third, obsession with a single risk factor or marker may lead to missed opportunities to find therapies that work through different pathways. Bakris et al.8 (this issue) now report further exploration of albuminurialowering capabilities of intensified renin–angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease: the Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events (IMPROVE) trial.8 Renin–angiotensin system inhibition was intensified by dual blockade, ramipril plus irbesartan, in comparison with treatment with the angiotensinconverting enzyme inhibitor alone. Because of unanticipated and substantial variability in albuminuria, particularly among the majority of participants who had microalbuminuria (70%), the study was underpowered for the primary end point of change in albuminuria over 20 weeks. However, despite significantly lower systolic and diastolic blood pressures in the dual-blockade group, the degree of albuminuria reduction was no different from that in the group treated with ramipril alone. Indeed, both groups had considerable decreases in albuminuria that approached 50%. When analyzed by quantity of albuminuria, those with macroalbuminuria (≥200 µg/min) 785
co mmentar y
The Holy Grail.
tended to have a greater response to dual blockade, but the between-group difference was not statistically significant. Albuminuria responsiveness to dual blockade versus ramipril alone also did not differ by diabetes status. Besides low power, the IMPROVE study was limited by short duration and lack of additional kidney outcome measures such as estimates of glomerular filtration rate or other markers of damage. The IMPROVE results stand in contrast to a prior short-term study of dual renin–angiotensin system blockade compared with single-agent therapy in diabetic patients with microalbuminuria, the Candesartan and Lisinopril Microalbuminuria (CALM) study. In CALM, albuminuria reduction was enhanced by the combination of angiotensin-converting enzyme inhibition and angiotensin receptor blockade compared with either agent alone.9 The CALM study enrolled patients with a narrower range of albuminuria, which may have reduced variability and provided a clearer result. On the other hand, publication bias for positive results is also a legitimate concern. Initial impressions may not remain as optimistic as first reported after more studies are completed. Irrespective of
786
whether albuminuria is a disease mechanism or marker, it has a fairly reliable association with clinical outcomes. If the IMPROVE results are viewed from the perspective of greater versus lesser blood pressure lowering, they appear consistent with some larger long-term studies of hypertensive patients with early-stage CKD or non-CKD, wherein clinical events, loss of kidney function, or albuminuria did not differ by a higher or lower blood pressure goal.10,11 The IMPROVE study leads to still more questions in the context of current understanding of increased albuminuria and its clinical correlates. Importantly, studies with albuminuria reduction as the specific treatment target are needed to validate the recommendation that such treatments be titrated to urinary albumin. Studies should also carefully specify the population and outcomes of interest. For example, do renin–angiotensin system inhibitors reduce kidney events in patients with diabetic kidney disease when dose is titrated to targets for albuminuria and blood pressure? Does targeting albuminuria reduction in hypertensive patients reduce cardiovascular events? What is the proper albuminuria target? Can achieving the albuminuria target be sustained? Do treatments to reduce albuminuria other than renin–angiotensin inhibition — for example, novel agents for CKD or intensive glycemic control in diabetes — have the same or similar relationships to clinical outcomes? Do relationships between albuminuria change and clinical outcome vary by cause of CKD? In order to improve on confidence in surrogates of CKD, even better biomarkers than albuminuria are urgently needed. This is an area of active investigation that spans a wide range from new markers of kidney function to cytokines, fibrosis molecules, and novel indicators of kidney damage and disease identified by rapidly moving scientific advances in genomics and proteomics. The existing state of knowledge has led to a strong hypothesis that albuminuria reduction may be an important clinical treatment target for various disease
states. However, we should not presume the answers before the questions have been properly addressed by thorough scientific inquiry. Hypotheses, no matter how well founded, are not yet confirmed facts. We must continue to ask legitimate questions in order to move from a state of hypothesis to one of clinical evidence in the quest for the Holy Grail of optimal approaches to preventing and treating CKD. REFERENCES 1.
de Zeeuw D, Remuzzi G, Parving H-H et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309–2320. 2. Atkins RC, Briganti EM, Lewis JB et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45: 281–287. 3. Lea J, Greene T, Herbert L et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease. Arch Intern Med 2005; 165: 947–953. 4. de Zeeuw D, Remuzzi G, Parving H-H et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–927. 5. Eijkelkamp WBA, Zhang Z, Remuzzi G et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007; 18: 1540–1546. 6. Ibsen H, Olsen MH, Wachtell K et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2005; 45: 198–202. 7. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006; 116: 288–296. 8. Bakris GL, Ruilope L, Locatelli F et al. Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007; 72: 879–885. 9. Mogensen CE, Neldam S, Tikkanen I et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and noninsulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 321: 1440–1444. 10. Estacio RO, Jeffers BF, Gifford N et al. Effect of blood pressure control on diabetic microvascul ar complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23: B54–B64. 11. Wright JT Jr., Bakris G, Greene T et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease [published erratum appears in JAMA 2006; 295: 2726]. JAMA 2002; 288: 2421–2431.
Kidney International (2007) 72
see original article on page 879
Albuminuria reduction: The Holy Grail for Kidney Protection KR Tuttle1,2 Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease. Observational analyses have raised a strong hypothesis that albuminuria reduction should be a clinical treatment target. Bakris et al. report further exploration of albuminuria-lowering capabilities of intensified renin–angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease. Kidney International (2007) 72, 785–786. doi:10.1038/sj.ki.5002505
Holy Grail: a distant, ultimate goal
Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease (CKD). Reduction of albuminuria/proteinuria (referred to as ‘albuminuria’ from here forward) has been associated with decreased risk of major clinical events (death, end-stage renal disease, or 50% loss of kidney function) in both diabetic and nondiabetic forms of CKD.1–3 The most commonly studied treatments for albuminuria reduction are the renin–angiotensin system inhibitors, angiotensin-converting enzyme inhibitor, and angiotensin receptor blockers. Observational analyses from studies of renin–angiotensin system inhibitors have been performed to examine relationships between albuminuria change and clinical events. The first of these analyses from a large randomized trial of angiotensin receptor blockade in diabetic kidney disease characterized by macroalbuminuria showed that reduction in albuminuria at 6 months strongly predicted improved 1Providence Medical Research Center at Sacred
Heart Medical Center, Spokane, Washington, USA; and 2University of Washington School of Medicine, Spokane, Washington, USA Correspondence: KR Tuttle, Providence Medical Research Center, 122 W. 7th Avenue, Suite 230, Spokane, Washington 99224, USA. E-mail: [email protected] Kidney International (2007) 72
kidney and cardiovascular outcomes, whereas an increase in albuminuria predicted the opposite.1,4 Another more recent analysis from the same study suggests that predictive ability of albuminuria change for kidney outcomes can largely be dissociated from blood pressure changes in diabetic kidney disease.5 In addition, observational analyses from clinical trials of renin–angiotensin system inhibition in hypertensive African Americans with CKD and hypertensive patients with left ventricular hypertrophy have also shown relationships between albuminuria change, or achieved level of albuminuria, during the trials and kidney and cardiovascular outcomes.3,6 In the latter two studies, most patients had microalbuminuria, which potentially extends the spectrum of albuminuria amenable to treatment. This emerging body of data has led to the suggestion that treatment with renin–angiotensin system inhibitors should target reduction of albuminuria as well as blood pressure. In other words, increasing the dosage or intensity of treatment with renin–angiotensin system inhibition to reduce albuminuria should be considered even if blood pressure is at goal. Either prespecified secondary or post hoc analyses of clinical trials have raised a strong hypothesis that albuminuria reduction should be a clinical treatment
target. In further support of the hypothesis, experimental studies have shown biologic rationale for the clinical observations. Urinary albumin appears to be proinflammatory to the tubulointerstitium in particular and could contribute to progressive kidney damage and loss of function.7 However, caution is in order before this hypothesis, or any other, is accepted as fact. First, although scientific inquiry begins with a hypothesis, the conclusion should not be presumed before it has been rigorously tested. Second, alternate hypotheses should also be considered. For example, albuminuria may be a marker of patient responsiveness to therapy rather than a causal mechanism for kidney and cardiovascular disease. Third, obsession with a single risk factor or marker may lead to missed opportunities to find therapies that work through different pathways. Bakris et al.8 (this issue) now report further exploration of albuminurialowering capabilities of intensified renin–angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease: the Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events (IMPROVE) trial.8 Renin–angiotensin system inhibition was intensified by dual blockade, ramipril plus irbesartan, in comparison with treatment with the angiotensinconverting enzyme inhibitor alone. Because of unanticipated and substantial variability in albuminuria, particularly among the majority of participants who had microalbuminuria (70%), the study was underpowered for the primary end point of change in albuminuria over 20 weeks. However, despite significantly lower systolic and diastolic blood pressures in the dual-blockade group, the degree of albuminuria reduction was no different from that in the group treated with ramipril alone. Indeed, both groups had considerable decreases in albuminuria that approached 50%. When analyzed by quantity of albuminuria, those with macroalbuminuria (≥200 µg/min) 785
co mmentar y
The Holy Grail.
tended to have a greater response to dual blockade, but the between-group difference was not statistically significant. Albuminuria responsiveness to dual blockade versus ramipril alone also did not differ by diabetes status. Besides low power, the IMPROVE study was limited by short duration and lack of additional kidney outcome measures such as estimates of glomerular filtration rate or other markers of damage. The IMPROVE results stand in contrast to a prior short-term study of dual renin–angiotensin system blockade compared with single-agent therapy in diabetic patients with microalbuminuria, the Candesartan and Lisinopril Microalbuminuria (CALM) study. In CALM, albuminuria reduction was enhanced by the combination of angiotensin-converting enzyme inhibition and angiotensin receptor blockade compared with either agent alone.9 The CALM study enrolled patients with a narrower range of albuminuria, which may have reduced variability and provided a clearer result. On the other hand, publication bias for positive results is also a legitimate concern. Initial impressions may not remain as optimistic as first reported after more studies are completed. Irrespective of
786
whether albuminuria is a disease mechanism or marker, it has a fairly reliable association with clinical outcomes. If the IMPROVE results are viewed from the perspective of greater versus lesser blood pressure lowering, they appear consistent with some larger long-term studies of hypertensive patients with early-stage CKD or non-CKD, wherein clinical events, loss of kidney function, or albuminuria did not differ by a higher or lower blood pressure goal.10,11 The IMPROVE study leads to still more questions in the context of current understanding of increased albuminuria and its clinical correlates. Importantly, studies with albuminuria reduction as the specific treatment target are needed to validate the recommendation that such treatments be titrated to urinary albumin. Studies should also carefully specify the population and outcomes of interest. For example, do renin–angiotensin system inhibitors reduce kidney events in patients with diabetic kidney disease when dose is titrated to targets for albuminuria and blood pressure? Does targeting albuminuria reduction in hypertensive patients reduce cardiovascular events? What is the proper albuminuria target? Can achieving the albuminuria target be sustained? Do treatments to reduce albuminuria other than renin–angiotensin inhibition — for example, novel agents for CKD or intensive glycemic control in diabetes — have the same or similar relationships to clinical outcomes? Do relationships between albuminuria change and clinical outcome vary by cause of CKD? In order to improve on confidence in surrogates of CKD, even better biomarkers than albuminuria are urgently needed. This is an area of active investigation that spans a wide range from new markers of kidney function to cytokines, fibrosis molecules, and novel indicators of kidney damage and disease identified by rapidly moving scientific advances in genomics and proteomics. The existing state of knowledge has led to a strong hypothesis that albuminuria reduction may be an important clinical treatment target for various disease
states. However, we should not presume the answers before the questions have been properly addressed by thorough scientific inquiry. Hypotheses, no matter how well founded, are not yet confirmed facts. We must continue to ask legitimate questions in order to move from a state of hypothesis to one of clinical evidence in the quest for the Holy Grail of optimal approaches to preventing and treating CKD. REFERENCES 1.
de Zeeuw D, Remuzzi G, Parving H-H et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65: 2309–2320. 2. Atkins RC, Briganti EM, Lewis JB et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis 2005; 45: 281–287. 3. Lea J, Greene T, Herbert L et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease. Arch Intern Med 2005; 165: 947–953. 4. de Zeeuw D, Remuzzi G, Parving H-H et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–927. 5. Eijkelkamp WBA, Zhang Z, Remuzzi G et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 2007; 18: 1540–1546. 6. Ibsen H, Olsen MH, Wachtell K et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: Losartan Intervention for Endpoint Reduction in Hypertension Study. Hypertension 2005; 45: 198–202. 7. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006; 116: 288–296. 8. Bakris GL, Ruilope L, Locatelli F et al. Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007; 72: 879–885. 9. Mogensen CE, Neldam S, Tikkanen I et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and noninsulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000; 321: 1440–1444. 10. Estacio RO, Jeffers BF, Gifford N et al. Effect of blood pressure control on diabetic microvascul ar complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000; 23: B54–B64. 11. Wright JT Jr., Bakris G, Greene T et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease [published erratum appears in JAMA 2006; 295: 2726]. JAMA 2002; 288: 2421–2431.
Kidney International (2007) 72