Microalbuminuria: target for renoprotective therapy PRO

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http://www.kidney-international.org & 2014 International Society of Nephrology

Microalbuminuria: target for renoprotective therapy PRO Sara S. Roscioni1,2, Hiddo J. Lambers Heerspink1,2 and Dick de Zeeuw1 1

Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/ markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients. Kidney International (2014) 86, 40–49; doi:10.1038/ki.2013.490; published online 23 April 2014 KEYWORDS: diabetic nephropathy; diabetes mellitus; end-stage renal disease; microalbuminuria; randomized controlled trial

Correspondence: Hiddo J. Lambers Heerspink, Department of Clinical Pharmacology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan, 1, Groningen 9713 AV, The Netherlands. E-mail: [email protected] 2

These two authors contributed equally to this work.

Received 15 June 2013; revised 19 August 2013; accepted 22 August 2013; published online 23 April 2014 40

Despite the availability of effective treatments to delay the progression of renal function loss, the prevalence of end-stage renal disease (ESRD) continues to rise.1 Novel strategies are needed to lessen the burden of this devastating condition. Health campaigns have focused on early detection of chronic kidney disease on the basis of the rationale that early intervention and appropriate treatment has a greater impact in delaying the progression of renal function loss compared with late intervention. To study the efficacy of new drugs, clinically meaningful outcomes that directly affect the well-being of patients are needed. ESRD is a commonly used hard clinical end point in drug trials in nephrology. However, the progression of kidney disease to ESRD takes many years if not decades. Clinical trials enrolling patients at early stages of disease would therefore require a long follow-up and/or an impractical large sample size to establish drug efficacy toward ESRD. The use of a surrogate end point may be a solution to this problem. A surrogate end point of a clinical trial is a laboratory measurement or a physical sign that measures the effect of a certain treatment and is intended to substitute for the clinical end point.2 Although such a surrogate end point does not directly measure how a patient feels, functions, or survives, it is associated with clinically meaningful outcomes so that changes in the marker level are expected to predict benefit or harm. The use of surrogate end points in clinical trials is tempting as it may reduce sample size requirements, shorten the follow-up time of clinical trials, and allow the performance of early intervention trials to be carried out. The presence of microalbuminuria is an early sign of renal damage and predicts an accelerated loss of renal function.3 Clinicians currently use microalbuminuria to diagnose renal damage and establish the prognosis of an individual. Moreover, the change in albuminuria after treatment initiation with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is frequently used to monitor renal and/or cardiovascular -protective response to therapy. Microalbuminuria could therefore be used as target for treatment and as a surrogate end point in clinical trials. However, there is growing awareness that surrogate end points should be used in clinical trials only after they have been sufficiently validated and reflect a true clinical end point. In the past, a number of promising potentially valid surrogate end points (e.g., hemoglobin) have failed to reflect a true clinical end Kidney International (2014) 86, 40–49

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Figure 1 | Higher albuminuria associates with faster decline in renal function in different populations. The annual decline in glomerular filtration rate (GFR) relative to the levels of baseline albuminuria in patients with (a) type 2 diabetes, (b) hypertension, and in the (c) general population. Data on type 2 diabetes patients are from the Irbesartan Microalbuminuria-2 (IRMA-2) study,90 data on hypertensive patients are from Bigazzi et al,14 and data on the general population are from Prevention of Renal and Vascular End-stage Disease (PREVEND).16 eGFR, estimated GFR.

point.4,5 Therefore, rigorous validation of a surrogate end point is necessary before it can be implemented in clinical practice. The criteria for validation of surrogacy have been described in the ‘statistical principles for clinical trials’ of the International Conference on Harmonization.6 First, prognostic evidence of the surrogate end point with patient outcome must be available. Second, a biologically plausible relationship between the surrogate and outcome should exist, and third, clinical trial data must demonstrate that the effect of interventions that change the surrogate end point is directly associated with the same change in clinical outcomes. Herein, we provide new updates that support the concept that microalbuminuria is a valid surrogate renal end point and a target for treatment in renal disease. MICROALBUMINURIA IS ASSOCIATED WITH RENAL OUTCOMES

Twenty-four-hour urine collection represents the gold standard method for determining the presence of microalbuminuria. However, as 24-hour urine collection is an inconvenient procedure for patients, more practical alternatives have been proposed, such as measurement of the albumin:creatinine ratio (UACR) derived from a first morning void or a spot urine sample. Of these, the measurement of UACR in a first morning void appears to be the most reliable alternative to the 24-hour urinary albumin excretion (UAE) in determining the presence of microalbuminuria and also in predicting the progression of disease.7,8 For practical purposes albuminuria is categorized into different classes—namely, normoalbuminuria (o30 mg albumin per day or per g creatinine), microalbuminuria (30–300 mg albumin per day or per g creatinine), and macroalbuminuria (4300 mg albumin/day or per g creatinine). The changes Kidney International (2014) 86, 40–49

between these albuminuria states represent a hallmark of the progression or regression of disease.9 Emerging evidence shows that individuals with high grades of albuminuria are at increased risk of accelerated loss of renal function.10 Whereas the association between the severity of albuminuria and renal disease progression was initially described in individuals with high albuminuria (41.0 g per day),11 more recent studies show that an increase in albuminuria, even within the range that is currently considered normal, indicates higher renal risk.10 This is a consistent finding that has been shown in different populations. In patients with type 2 diabetes followed up for at least 5 years, higher UACR at baseline was associated with a faster decline in renal function. Importantly, although within the normal range, a UACR of X10 mg/g in women or X5 mg/g in men was associated with a significantly greater rate of renal function decline.12 Similar data were found in patients with type 2 diabetes and microalbuminuria participating in the Irbesartan Microalbuminuria-2 (IRMA-2) trial. Subjects in the highest quintile of baseline albuminuria excretion (between 102 and 300 mg/min, which equals a UACR of B150 and 450 mg/g) had approximately 2.5-fold greater rate of renal function decline compared with subjects with urinary albumin excretion between 20 and 30 mg/min13 (which equals a UACR of B30 and 45 mg/g) (Figure 1a). The association between the increases in albuminuria and hard renal outcomes in type 2 diabetes was established in the ADVANCE trial.9 Although the majority of patients (69%) enrolled in this trial had albuminuria in the normal range, baseline albuminuria was an independent determinant of the progression to renal outcomes, and even subtle changes in albuminuria in the normal range were strongly associated with disease progression. 41

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Similar associations between albuminuria and renal function decline have been described in the non-diabetic hypertensive population. In 1998, Bigazzi et al.14 showed that subjects with essential hypertension and microalbuminuria had a faster rate of renal function decline (assessed by creatinine clearance) compared with subjects with normoalbuminuria (Figure 1b). These data were confirmed in a larger cohort of patients with essential hypertension, of whom the majority had normoalbuminuria (92%). Subjects who developed a renal event had higher baseline albumin-tocreatinine ratio (ACR) compared with subjects who did not develop a renal event (5.12 vs. 4.42 mg/g; Po0.001). Moreover, a regression analysis revealed that the ACR level at baseline predicted renal events independent of other renal risk markers.15 Finally, studies from the community cohorts Prevention of Renal and Vascular End-stage Disease (PREVEND) and the Nord-Trndelag Health (HUNT 2) provide further insight into the relationship between levels of albuminuria and renal disease in the general population.16–18 In the PREVEND cohort, higher UACR levels were associated with a faster rate of estimated glomerular filtration rate (eGFR) decline and an increased risk for ESRD (Figure 1c).16 As observed in individuals with diabetes or hypertension, the relation between albuminuria and renal disease progression persists even within the normoalbuminuric and microalbuminuric range. Similar association between subtle increases in albuminuria and progression to ESRD was found in the HUNT 2 study.18 Of note, in the HUNT 2 study the risk prediction of albuminuria alone performed significantly better than a clinical risk prediction score consisting of multiple risk factors including age, gender, physical activity, diabetes, systolic blood pressure, antihypertensive medication, and high-density lipoprotein cholesterol.18 This last aspect may be of great clinical relevance considering that albuminuria can be easily collected (and in big amounts) by the patients themselves. Because the progression from microalbuminuria to ESRD takes many years to manifest, few ESRD outcomes are observed in observational studies. Consequently, many studies were underpowered to investigate the association between microalbuminuria and ESRD. A collaborative metaanalysis was therefore performed to assess whether the severity of albuminuria associates with ESRD and whether albuminuria provides additional prognostic information beyond eGFR.19 In this meta-analysis involving 13 cohorts and 21,688 individuals, it was shown that albuminuria was independently associated with a higher risk for ESRD. In particular, compared with subjects with normoalbuminuria, those with microalbuminuria had a threefold higher risk for ESRD. The risk further increased with more severe albuminuria (Figure 2). Subsequent analyses from this collaborative initiative showed that the association between albuminuria and ESRD is similar in non-hypertensive versus hypertensive individuals and in non-diabetic versus diabetic individuals.20,21 These data indicate that, in the absence of

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comorbid conditions such as hypertension or diabetes, the association between albuminuria and ESRD persists. Hence, albuminuria is not a consequence of hypertension or diabetes but is a valid independent marker of progressive renal function loss. This notion is supported by another study comparing the rate of renal function decline in diabetic versus non-diabetic individuals.22 Subjects with diabetes had a higher risk of progressing to ESRD than did non-diabetic subjects. However, subjects with diabetes also had a fourfold higher UACR level (B2000 mg/g) compared with nondiabetic subjects (B500 mg/g). When the difference in UACR was taken into account, the difference in progression of renal function decline in diabetic and non-diabetic subjects disappeared, indicating that the higher rate of renal function decline in diabetic subjects is explained by the generally higher albuminuria level. Not only the albuminuria level itself but also changes in albuminuria (within the microalbuminuric range) over time predict renal or cardiovascular risk changes. The regression or progression of albuminuria frequently occurs in different populations. In patients with type 2 diabetes and microalbuminuria, it has been shown that those subjects in whom albuminuria declined by more than 50% over 2 years’ followup had a subsequent renal function decline of 1.8 ml/min per year. In contrast, in subjects without a 50% reduction in albuminuria long-term renal function decline was significantly larger, being 3.1 ml/min per year.23 These data imply that reduction in albuminuria is an integrated renal risk indicator. In summary, data from multiple studies in a broad range of patients show that subtle increases in albuminuria (even within the normo- or microalbuminuric range) are a determinant of renal outcome: higher exposure of albumin to renal tissue increases the chances of losing renal function Kidney International (2014) 86, 40–49

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over time, independent of the underlying renal disease or other comorbidities. It is important to note that the strong and consistent association between albuminuria and renal outcome does not mean that albuminuria is the sole factor associated with renal progression. Studies showing that subjects without microalbuminuria progress to ESRD demonstrate that other renal risk factors are involved as well.24 More important is the fact that, whenever albuminuria is increased for a certain period of time, it inevitably leads to progressive renal function decline. Thus, despite the fact that the susceptibility of progressive renal function decline may be dictated by multiple factors including environmental factors, concurrent diseases, or genetic variability, albuminuria predicts renal function loss in most circumstances,16,17,25–28 indicating that close monitoring of albuminuria and its change over time will help identify subjects at increased renal risk.

albuminuria to vascular dysfunction, supporting the concept that microalbuminuria is not only a marker of renal damage but also a more generalized marker of endothelial damage.39 A new technique was recently validated to measure the endothelial glycocalyx dimension in humans using imaging of the sublingual microcirculation by orthogonal polarization spectroscopy.40 Importantly, treatment with sulodexide—a commercially available compound, which leads to an increase in glycosaminoglycan synthesis—provided an increase in both the sublingual and retinal glycocalyx dimensions in patients with type 2 diabetes and reduced the transcapillary escape rate of albumin (a measure of general vascular leakage of albumin in the body and an indirect measure of albuminuria).41 Long-term studies are needed to prove whether restoration of glycocalyx size and function translates into better disease prognosis.

MICROALBUMINURIA IS A CAUSE AND A CONSEQUENCE OF RENAL DISEASE Cause of high urinary albumin excretion

Renal consequences of high urinary albumin excretion

Given its size and charge characteristics, it is believed that under physiological circumstances albumin is only minimally filtered in the glomeruli. The increased leakage of albumin should therefore be the result of glomerular damage.29,30 Glomerular (micro) albuminuria can be physiological— owing to an increase in hydrostatic pressure or an altered glomerular filtration coefficient, as in stress, exercise, and inflammation—or it can be pathological—for example, due to hypertension or renal disease. The integrity of the glomerulus depends on the function and interaction of at least three distinct layers—namely, the inner glomerular endothelial cell layer, the outer layer of glomerular epithelial cells or podocytes, and, between them, the glomerular basement membrane.29–31 Furthermore, mesangial cells and extracellular matrix surround the nephrons and help in maintaining the structure and function of the glomerular barrier.29–32 Damage to each individual component affects the excretion of albumin and may compromise the function of the other components and ultimately affect the whole nephron.31 Emerging recent data provided renewed interest in the importance of another component of the glomerular barrier—namely, the glycocalyx. The glycocalyx is a thin layer of proteoglycans with their associated glycosaminoglycans that covers the outer endothelial layer and its fenestrae in a gel-like diaphragm and excludes (charged) macromolecules from the ultrafiltrate. Thus, glycocalyx damage may affect the charge selectivity of the glomerular filtration barrier, leading to increased leakage of albumin in the ultrafiltrate. The glycocalyx layer is not restricted to the kidney but is present in all capillary beds. Indeed, alterations in the endothelial glycocalyx, for example, due to hyperglycemia,33 are implicated in the pathogenesis of atherosclerosis and have been associated with the onset of microalbuminuria in diabetes.34 Moreover, changes in urine albumin excretion have been associated with general albumin leakage throughout the body.35–37 Salmon et al.38 recently demonstrated that loss of endothelial glycocalyx links Kidney International (2014) 86, 40–49

Within the past few decades, the classical assumption of albuminuria as merely a reflection of disease has been challenged by consistent evidence that albumin is not an inert molecule but actually affects the function of several cell types in the kidney and may have a pathogenic role in renal disease.42–44 Several lines of evidence suggest a role for albuminuria and albumin-associated factors of the ultrafiltrate in chronic tubulointerstitial damage.45 Once filtrated by the glomerulus, albumin undergoes reuptake by the tubular cells, and it is degraded. However, in case of higher albumin concentrations this system may be overloaded, leading to increased albumin exposure in the tubular compartment, which triggers toxic effects and inflammatory responses.46,47 In vitro studies show that an overload of albumin exerts cytotoxic effects on proximal and distal tubular cells by activating a wide array of intracellular signaling pathways (e.g., extracellular signal-regulated kinase, nuclear factor-kB, protein kinase C),48–53 which induce the release of inflammatory (monocyte chemotactic protein-1, RANTES (regulated on activation normal T-cell expressed and secreted)),53–55 vasoactive (reactive oxygen species, endothelin),56–58 and fibrotic (tumor growth factor–b, collagens) substances,59–62 causing interstitial damage and ultimately leading to irreversible renal deterioration. Moreover, albumin overload may also cause cellular apoptosis,63,64 leading to decreased nephron functionality. Next to albumin itself, substances bound to albumin, such as free fatty acid, other proteins, or glycated albumin, can act as profibrotic and proinflammatory stimuli in the tubule and aggravate renal damage provoked by albuminuria.46,65–70 Importantly, treatment that reduces albuminuria also prevents inflammation and renal function deterioration.71 Intriguingly, most of the deleterious effects driven by albumin seem to be mediated by its tubular uptake59 and may explain renal disease progression in the presence of intact glomerular structure and permeability. Tubular reabsorption of albumin was demonstrated more than 40 years ago.46,47 Briefly, the proximal tubule brush border 43

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Figure 3 | Pathophysiological mechanisms of albumin-induced progressive renal dysfunction. Once albumin has passed the glomerular barrier, it undergoes reuptake by the tubular cells because of the cubilin–megalin complex. Albumin triggers a cascade of pathogenic mechanisms leading to inflammation, fibrosis, mesangial expansion, and hypertension, which ultimately cause progressive renal dysfunction. These mechanisms encompass the activation of intracellular signaling pathways (e.g., extracellular signal-regulated kinase (ERK), nuclear factorkB (NF-kB), protein kinase C (PKC)) and release of inflammatory (monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES)) vasoactive (reactive oxygen species (ROS), endothelin, and fibrotic (tumor growth factor-b (TGF-b), collagens)) substances, leading to irreversible renal damage.

reabsorbs albumin via a clathrin-mediated endocytic pathway,47,65 which utilizes the receptor megalin and its binding partner cubilin.72–75 Once internalized in endosomal vesicles, albumin dissociates from the cubilin–megalin complex. Megalin is then recycled to the apical membrane, whereas albumin is transported to the lysosomal compartment in which it is degraded.47 Excessive tubular reuptake of albumin has been shown to be detrimental for the kidney. In fact, tubular uptake of albumin triggers the activation of a wide array of cytotoxic signals that affect the interstitium, the fibroblast, and the nearby blood vessels, and may cause tubulointerstitial dysfunction, fibrosis, volume expansion, and hypertension, leading to a worse renal prognosis (Figure 3).44,45,76,77 This is supported by a study from Okada et al.78 showing that in type 2 diabetes patients with overt proteinuria the degree of tubular damage and tubulointerstitial inflammation was a strong determinant of renal outcome, whereas glomerular damage did not associate with renal prognosis. These experimental data of increased glomerular leakage followed by proximal reabsorption and damage suggest a couple of important things: first, albuminuria may increase because of diminished tubular albumin reabsorption, which will not damage the tubule or interstitium, and will thus not lead to increased renal function loss. Only when the filtered albumin is reabsorbed with it lead to renal damage. Indeed, in a recent experimental study it was shown that bardoxolone methyl, a known 44

suppressor of the detrimental nuclear factor-kB pathway, also inhibited tubular uptake of albumin. This was associated with increased albuminuria but did not provoke histological renal damage.79 Second, the degree of renal damage likely depends on the exposure of albumin in the tubular compartment over time rather than on a certain albumin concentration at a fixed time point. In other words, leakage of a large amount of albumin during a relatively short time frame could have a different prognosis compared with leakage of a small amount of albumin for a prolonged period of time. Indeed, in case of minimal change disease, massive amounts of albumin may pass the glomerulus without inducing directly visible damage. In most cases, the leakage of high amounts of albumin does not persist for a long period of time. Yet, in case the albuminuria does not remit in a relatively short period of time (spontaneously or through therapy), focal segmental glomerulosclerosis or membranous nephropathy can develop. Indeed, various studies have shown that the average albuminuria level over time is the strongest determinant of ESRD. Third, considering that albuminuria causes renal damage, the renoprotective effects of drugs that decrease albuminuria are explained by their ability to decrease the exposure to high albuminuria. They do not cause a direct improvement in structural renal function. Treatment discontinuation of antialbuminuric drugs will lead to a re-establishment of the albuminuria level to the pretreatment situation. This should happen as antialbuminuric Kidney International (2014) 86, 40–49

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drugs are not developed to cure high albuminuria but they just decrease the level. There is a clear analogy with blood pressure–lowering drugs. They are not developed to cure hypertension but are developed to decrease the exposure to high blood pressure and thereby improve renal/cardiovascular function. Discontinuation of blood pressure–lowering agents will lead to a rise in blood pressure to the pretreatment situation, just like discontinuation of antialbuminuric drugs (even in the normo- or microalbuminuria range after years of treatment) will lead to a return in albuminuria to the baseline value. To summarize, there is a growing body of evidence demonstrating that an excess of albumin delivered to the tubular compartment is deleterious for the kidney and severely affects renal function. These data underpin the validity of albuminuria not only as a risk indicator but also as an important causal factor in the initiation and progression of renal disease. MICROALBUMINURIA REDUCTION PREDICTS RENAL PROTECTION

An important criterion for valid surrogacy is that a druginduced change in the surrogate marker (albuminuria) predicts the same change in clinical outcomes (e.g., ESRD). Analyses from different clinical trials in different populations with different interventions have shown that drug-induced changes in albuminuria (within the microalbuminuria range) decrease the rate of renal function decline. Data from the IRMA-2 trial demonstrated that the reduction in albuminuria during angiotensin receptor blocker treatment was inversely associated with the rate of renal function decline: the higher

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the albuminuria reduction, the slower the rate of renal function decline.13 This association was independent of changes in blood pressure or other clinical characteristics. In another study, Gaede et al.80 showed that intensive treatment reduced albuminuria and slowed the progression of nephropathy compared with standard intervention. Interestingly, in that study the rate of GFR decline was significantly lower in patients who regressed from microalbuminuria to normoalbuminuria compared with those who remained microalbuminuric or progressed to macroalbuminuria. Moreover, long-term follow-up of this study showed that subjects in the intensive treatment arm experienced significantly fewer ESRD events compared with standard intervention.81 Similar results were obtained in non-diabetic patients with hypertension participating in the AASK trial: modifying proteinuria levels even in the very low range ameliorated the rate of GFR decline and attenuated the risk of progression to ESRD.25 The above-mentioned studies demonstrate that the degree of albuminuria control, mainly with A angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, is associated with the degree of long-term renoprotection. Importantly, this association has been observed with other drugs or dietary interventions as well. For example, intensive glucose control decreased albuminuria and delayed the progression of renal function loss in subjects with type 1 diabetes, of whom the majority had normo- or microalbuminuria.82 Interestingly, statistical adjustment for the difference in albuminuria between the intensive and conventional glucose therapy arms fully attenuated the treatment

Figure 4 | Albuminuria, blood pressure, and low-density lipoprotein (LDL) cholesterol reduction predict renal protection. Reduction in end-stage renal disease consequent to (a) albuminuria reduction, (b) blood pressure reduction, and (c) LDL cholesterol reduction. Pooled analysis is adapted from Lambers Heerspink et al.,83 the Treatment Trialists’ Collaboration,84 and Delahoy et al.,85 respectively. (a) ACEi, angiotensin-converting enzyme inhibitors; ADVANCE, Action in Diabetes and Vascular Disease, preterAx and diamicroN-MR; AIPRI, AngiotensinConverting Enzyme Inhibition in Progressive Renal Insufficiency; ARBs, angiotensin receptor blockers; DIAB-HYCAR, The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril Study; IDNT, Irbesartan Diabetic Nephropathy Trial; ONTARGET, Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; REIN, Ramipril Efficacy in Nephropathy; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan. (b) AASK, The African American Study of Kidney Disease and Hypertension; ACEi, angiotensin-converting enzyme inhibitors; ALLHAT, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Study; ARBs, angiotensin receptor blockers; CAMELOT, The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis study; CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; EUROPA, the EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary Artery disease; HDS, Hypertension in Diabetes Study Group; HOPE, Heart Outcomes Prevention Evaluation; IDNT, Irbesartan Diabetic Nephropathy Trial; LIFE, Losartan Intervention For Endpoint reduction in hypertension study; PART, Prevention of Atherosclerosis with Ramipril; PEACE, Prevention of Events with Angiotensin Converting Enzyme Inhibition; PROGRESS, The Perindopril Protection against Recurrent Stroke Study; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; SBP, systolic blood pressure; STOP2, the Swedish Trial in Old Patients with Hypertension-2 study; UKPDS, UK Prospective Diabetes Study Group; Val-HeFT, The Valsartan Heart Failure Trial. (c) AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of Lescol in Renal Transplants; CARE, Cholesterol And Recurrent Events; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASCOT-LLA, AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin Dependent Diabetes Mellitus; A-Z, A to Z Trial; CARDS, Collaborative Atorvastatin Diabetes Study; GISSI, Gruppo Italiano per 10 Studio della Sopravvivenza nell’lnfarto Miocardico; GREACE, GREek Atorvastatin and Coronary heart-disease Evaluation Study; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering; JUPITER, Justification for the Use of Statins in Prevention, An Intervention Trial Evaluating Rosuvastatin; LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease; LIPS, Lescol lntervention Prevention Study; MEGA, Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study); Post-CABG, post-coronary artery bypass graft; PROSPER, PROspective Study of Pravastatin in the Elderly at Risk; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study; 4D, German Diabetes and Dialysis Study; 4S, Scandinavian Simvastatin Survival Study.

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Diet in Renal Disease trial.11 In that trial, subjects with the largest reduction in proteinuria experienced the largest renoprotective benefit. Thus, for most drugs that reduce albuminuria, the change in albuminuria is associated with a

effect, suggesting that the reduction in albuminuria is a driving parameter for the renal protective effect conferred by intensive glucose control. Dietary protein restriction has also been shown to decrease proteinuria in the Modification of

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proportional effect on renal outcome: the greater the reduction in albuminuria, the greater the risk reduction. Although the association between changes in albuminuria and renal outcomes within trials lends support to valid surrogacy, it does not definitely prove the surrogacy concept. All of the aforementioned analyses were conducted post hoc and were no longer based on randomized comparisons. In addition, although these within-trial analyses were adjusted for a range of potential confounders, the influence of unmeasured confounders cannot be ignored. To avoid this type of bias, it is necessary to perform a combined analysis of multiple randomized controlled trials and link the treatment effect of a drug on albuminuria with the treatment effects on the clinical end point. The clear advantage of this so-called trial-level approach is that the estimated treatment effects on albuminuria and the hard end point are based on randomized comparison, thereby reducing the chance of bias. A joint analysis of multiple randomized clinical trials investigating the effects of renin–angiotensin system (RAAS) blockade on renal disease progression illustrates the association between the treatment effects on albuminuria and the treatment effects on hard renal end point: the larger the reduction of albuminuria in a trial, the larger the treatment effect on the hard renal end point (Figure 4a).83 The scatter plot for albuminuria closely resembles similar scatter plots of the accepted surrogate markers, blood pressure and cholesterol (Figures 4b and c).84,85 Collectively, these data indicate that the degree of albuminuria control, independent of the intervention that is used, determines the degree of renal protection. Not all studies unambiguously demonstrate that the change in albuminuria during therapy is associated with improved outcomes, and exceptions can always be found. Dual RAAS-blockade in the ONTARGET and ALTITUDE trial did not afford the expected cardiorenal protection despite the fact that dual RAAS-blockade decreased albuminuria.86,87 Possible explanations for these findings may be several. First, the ONTARGET study included only a small percentage of people with increased albuminuria levels. Of note, a post hoc analysis showed that, in patients with a larger reduction in albuminuria, treatment was associated with a significantly better cardiovascular and renal prognosis.88 Importantly, a similar analysis from the ALTITUDE trial showed that not only baseline albuminuria but also the 6-month change in albuminuria was an independent predictor of renal and cardiovascular outcomes: subjects with the largest reductions in albuminuria in the first 6 months showed a subsequent higher renal and cardiovascular risk reduction (HJ Lambers Heerspink et al. Lowering albuminuria reduces cardiorenal events: insights from ALTITUDE; American Society Nephrology Atlanta 2013). The second and most important point is that both ONTARGET and ALTITUDE suggest that the side effects of combined therapy (i.e., hyperkalemia or hypotension) offset the potential benefit of albuminuria lowering and ultimately result in adverse outcomes. Finally, it should be noted that the Kidney International (2014) 86, 40–49

achieved blood pressure in both the ONTARGET and ALTITUDE trials was lower with dual RAAS-blockade than with monotherapy. This has never been a reason to dismiss blood pressure as a valid surrogate marker, nor should it be a reason to negate the value of microalbuminuria as a useful surrogate. Despite piling evidence that albuminuria development and progression is associated with worse renal prognosis, regulatory agencies have still not accepted albuminuria as a valid surrogate end point. This is apparently justified by the limited evidence from intervention trials showing that a drug effect on renal outcomes can be predicted by its effect on albuminuria. Although large trials have been conducted with RAAS-blockade in patients with diabetic nephropathy, these data cannot be easily extrapolated to other drugs or diseases.89 Given the substantial risks to public health if a surrogate end point fails to provide accurate information about drug efficacy on clinical end points, additional prospective high-quality data are needed.89 To our knowledge, one trial that targets albuminuria directly is currently ongoing (NCT01858532) and results are awaited. CONCLUSION

The validity of microalbuminuria as a renal surrogate marker is supported by a strongly growing rationale. Numerous large clinical studies showed that albuminuria associates with renal outcome and that reduction of albuminuria, independently of the class of drug used, lowers the risk of renal events. Importantly, the association between a drug effect on albuminuria and hard renal outcome is similar to the association between drug effects on well-accepted surrogate end points such as blood pressure and cholesterol and hard clinical outcomes. Moreover, emerging experimental data demonstrate that albumin is not an inert molecule but causes and contributes to renal disease pathogenesis. In other words, reduction in albuminuria decreases the exposure to a proinflammatory and profibrotic molecule, thereby resulting in less structural worsening of the nephron, leading to a more preserved renal functionality. Thus, we amply demonstrated that microalbuminuria fulfills the criteria for valid surrogacy as described in the ‘statistical principles for clinical trials’ of the International Conference on Harmonization and should be accepted as a surrogate end point by regulatory agencies. Accepting microalbuminuria as a surrogate marker for renal outcomes would lead to less resource–consuming hard outcome trials, would accelerate the development of drugs for chronic renal impairment, and enable earlier access of these drugs to individual patients. DISCLOSURE

All the authors declared no competing interests. REFERENCES 1.

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