Albuminuria: a Great Risk Marker, but an Underestimated Target in Diabetes

SECTION II

Albuminuria: A Great Risk Marker, but an Underestimated Target in Diabetes

1 DICK DE ZEEUW, MD and cardiovascular disease progression in 2 ITAMAR RAZ, MD advanced diabetes, increased urinary albumin levels have their separate predictive power for risk of organ failure (3). iabetes is a growing disease with a the very early stages of the disease. More- An increased renal and cardiovascu- potentially devastating outcome. over, new antihypertensive therapies not lar risk profile is also observed even when D Diabetic patients run a great risk of only lower blood pressure, but also re- smaller amounts of albumin are present in developing multiple organ dysfunction duce albuminuria. We will address the the urine (microalbuminuria: 30–300 and ultimately organ failure. The current need of not only measuring the risk mg/day). Microalbuminuria heralds dia- approach of patients with diabetes is first marker, but also targeting therapies to betic nephropathy as well as cardiovascu- to assess their risk profile by measuring lower albuminuria. Finally, the individual lar risk (4,5). Although other risk factors risk factors such as glucose level, systemic response to such therapies appears to be (mainly increased blood pressure) already blood pressure, blood lipids, body highly variable, offering us opportunities play a major role in this stage, microalbu- weight, and smoking. Second, to reduce to optimize organ protection by individ- minuria also has important independent the risk, the patient is advised to make a ualizing therapies with the goal to over- value in estimating the cardiovascular and lifestyle change (lose weight and stop come therapy resistance. renal risk of a diabetic patient. smoking) and to take medication that reg- Clearly, diabetes constitutes a multi- Despite the clear power of using the ulates glucose and lowers blood pressure factorial disease in its organ damage (and level of albumin for marking renal and and cholesterol. This approach has in- maybe even in its cause). This forms a cardiovascular risk, the measurement if deed resulted in a slowing of progressive sound reason to look for multiple targets still markedly underused in worldwide organ dysfunction and has substantially (next to optimization of treating existing practice (6). One of the reasons for this prolonged life. targets). under use may be the fact that there is not However, the residual risk of diabetic yet a specific therapy that lowers albu- patients, despite “optimal” treatment of ALBUMINURIA AS A RISK minuria specifically. For other risk these risk factors, is still extremely high, MARKER — Large amounts of albu- factors, such as high glucose and hyper- and the number of patients is dramatically min in the urine (Ͼ300 mg/day) indicate tension, drugs are available to lower these growing. This has urged the medical pro- a late stage of diabetic renal disease and risk markers, with associated reduction of fession to improve risk profiling and de- indicate, next to loss of filtration rate, the risk. Currently, increased levels of albu- sign new therapeutic strategies to further degree of kidney damage. In addition, min are reduced by antihypertensive reduce existing risk. In addition, the however, the degree of increased albumin drugs that intervene in the renin- search for early disease markers was in- loss also heralds an increased chance of angiotensin-aldosterone system (RAAS) tensified with the goal to apply preventive losing kidney function. In fact, the more (7,8). Because such drugs are the recom- therapeutic measures in early stages of albumin is lost in the urine, the more mended therapy in diabetes, most doctors disease, instead of waiting until the dis- chance the individual has on reaching thus see no additive value in measuring ease had fully developed. end-stage renal disease (1). Intriguingly, urine albumin. The following paragraphs The next paragraphs will address the this predictive power of increased albu- will give reasons for measuring urine al- status of a “new” cardiovascular and renal min excretion does not only predict renal bumin in all individuals with diabetes. risk marker: increased levels of albumin progressive disease, but it also predicts an in the urine. This so-called albuminuria increased risk for cardiovascular disease ORGAN-PROTECTIVE not only marks risk in advanced stages of (2). Although classical risk factors such as PROPERTIES OF diabetic disease, but also indicates risk in hypertension play a major role in renal ALBUMINURIA LOWERING —As

●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● mentioned above, intervention in the RAAS using antihypertensive drugs like From the 1Department of Clinical Pharmacology, University Medical Center Groningen, University of Gro- 2 ACE inhibitors or angiotensin II receptor ningen, Groningen, the Netherlands; and the Diabetes Unit, Department of Medicine, Hadassah University blockers (ARBs) are proven to be associ- Hospital, Ein-Karem, Jerusalem, Israel. ϳ Address correspondence and reprint requests to D. de Zeeuw, Department of Clinical Pharmacology, ated with substantial reductions of 50% University Medical Center Groningen, Sector F, PO Box 169, 9700 AD Groningen, the Netherlands. E-mail: in albuminuria both in microalbuminuric [email protected]. and macroalbuminuric patients. Several D.d.Z. has been a paid consultant for Novartis Pharmaceuticals, Abbott Laboratories, Keryx Biopharma- studies have demonstrated that this low- ceuticals, Inc., and AstraZeneca Pharmaceuticals; I.R. has been a paid consultant for Pfizer, Johnson & Johnson, sanofi-aventis, Keryx Biopharmaceuticals, Inc., Andromeda, and Merck Sharp & Dohme. ering of albuminuria is associated with re- This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and duction of renal risk, independent of the Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted blood pressure–lowering effect of these educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli drugs (9,10). Recently, three important Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson. Abbreviations: ARB, angiotensin II receptor blocker; RAAS, renin-angiotensin-aldosterone system. large trials were published that specifi- DOI: 10.2337/dc08-s248 cally targeted renal risk in type 2 diabetic © 2008 by the American Diabetes Association. patients using ARBs. The results of these

S190 DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 de Zeeuw and Raz trials showed that ARBs are indeed effective in lowering blood pressure as well as albuminuria. In the long term, ARB treatment resulted in renal protection both in advanced diabetic nephropathy (11,12) and early diabetic renal disease (13). This renal protection goes beyond the blood pressure–lowering capacity of ARBs, since the blood pressure in the compara- tor arms of these trials (using conven- tional antihypertensive drugs) was the same as in the ARB arms. Intriguingly, albuminuria was only lowered in the ARB arms of these trials. Although these clinical trials cannot give an answer to the question whether this lowering of albuminuria is the “cause” of the renoprotective effect of ARBs, post hoc analysis of both the Irbesartan Diabetic Nephropa- thy Trial and the Reduction of Endpoints Figure 1—The individual degree of proteinuria lowering (after several weeks of therapy) is a in NIDDM with the Angiotensin II Antag- predictor for long-term (years) renal protection: the more proteinuria is lowered, the less the onist Losartan (RENAAL) trial clearly glomerular filtration rate (GFR) will decline during follow-up, both in diabetic (15) and non- diabetic renal (16) disease patients. showed that the more one reduces albuminuria, the more patients are protected against progressive renal disease (1,14). against cardiovascular and renal disease tients who had a drop in albuminuria in This appears not only to be applicable to progression. the first months of therapy showed a clear renal protection, but also to cardiovascu- The above findings with albuminuria renal protection during follow-up despite lar protection, since the level of albumin- constitute sound reason to measure albu- a rise in the blood pressure. In other uria reduction was also associated with minuria in each diabetic individual to words, monitoring therapy-induced the level of cardiovascular risk (2). monitor the effectiveness of RAAS inter- changes in albumin in individual patients Thus, albuminuria is not only a good vention therapy. However, the current is important independent of blood pres- risk marker, but the therapy-induced fall guideline tells us that antihypertensive sure changes, since it predicts the effec- of albuminuria is also predictive of renal therapy like RAAS intervention is targeted tiveness of renal protection. and cardiovascular protection. toward high blood pressure (and not to high albumin). In fact, one could argue FUTURE THERAPIES FOR INDIVIDUAL VARIABILITY that the variability in albuminuria reduc- (FURTHER) ALBUMINURIA IN THERAPY RESPONSE — Al- tion is likely paralleled by a similar vari- REDUCTION — Despite the fact that though RAAS intervention is clearly effec- ability in blood pressure–lowering we are able to reduce renal (and cardio- tive in lowering albuminuria, with an response. If true, than one would not vascular) risk in diabetic patients with average reduction around 50%, the indi- need to measure albuminuria, but just treatments that reduce high levels of risk vidual variability is high. Some patients measure and target for effective blood factors, recent trials have shown that the show a nearly 100% reduction in albu- pressure lowering. residual risk (even when there is optimal minuria, whereas others can show no Although albuminuria is usually ac- treatment applied) is extremely high. change or even a rise in albuminuria upon companied by increased blood pressure, An important reason for this high re- RAAS intervention. The important ques- recent new data from a post hoc analysis sidual renal and cardiovascular risk ob- tion is, whether this variability in re- of the RENAAL study give us a clear rea- served in diabetic patients is the fact that sponse is related to long-term renal (or son to measure and target not only blood the current therapies are not 100% effec- cardiovascular) outcome. Rossing et al. pressure but also albuminuria. Ei- tive. Many patients still suffer from insuf- (15, diabetes) and Apperloo et al. (16, jkelkamp et al. (17) found that the re- ficient glucose and blood pressure nondiabetes) have shown that individuals sponse to the ARB losartan was indeed regulation (particularly in type 2 diabe- who have a poor albuminuria-lowering highly variable both for blood pressure tes). Clearly, we need better medication as response in the first month of ACE inhi- lowering as well as albuminuria lowering: well as therapy compliance to battle this bition therapy are the individuals who roughly 60% showed a lowering for both residual risk. show progressive renal function loss dur- variables, whereas 40% showed no The residual risk can also for a large ing follow-up, whereas the individuals change or even a rise after the first months part be explained by the fact that the level who show an initial marked reduction in of therapy. However, an important new of albuminuria is not fully reduced to nor- albuminuria upon therapy are protected finding was that, in nearly 40% of the pa- mal by the current therapy strategies. And in the long run (Fig. 1). These data are tients, blood pressure response and albu- indeed the residual level of albuminuria is very similar to data of classical risk factors minuria response were nonconcordant: still a powerful predictor of the residual such as high blood pressure: the more an either blood pressure fell and albumin- renal and cardiovascular risk in this individual lowers blood pressure with uria rose, or albuminuria fell and blood population. therapy, the more that person is protected pressure rose. Most importantly, the pa- Which measures can we take to im-

DIABETES CARE, VOLUME 31, SUPPLEMENT 2, FEBRUARY 2008 S191 Albuminuria: marker or target of diabetes? prove the reduction in albuminuria, with uria (in addition to RAAS intervention). needs to be monitored and targeted in the goal to reduce this high residual renal New applications of existing drugs such each diabetic patient. and cardiovascular risk in the diabetic as statins and Paracalcitol (Abbott Labo- New therapies that further lower al- population? First, addition of a low- ratories, IL) (26) are currently under in- buminuria on top of RAAS intervention sodium diet and/or a diuretic to the RAAS vestigation for their additive effect on are currently under investigation and may intervention is extremely important for albuminuria lowering in addition to lead to further curtailing of the abundant both an optimal blood pressure as well an RAAS intervention. A drug that has been risk of patients with diabetes. optimal anti-albuminuric effect (18). Sec- proven to be additive to ACE inhibitors ond, dosing of the RAAS intervention with respect to albuminuria lowering is drug is important. Several studies have Sulodexide (Keryx Pharmaceuticals, NY). References shown that increasing doses of either ACE Gambaro et al. (27) showed that it was 1. de Zeeuw D, Remuzzi G, Parving HH, inhibitors or ARB results in a further de- very effective in lowering albuminuria. Keane WF, Zhang Z, Shahinfar S, Snapinn crease of albuminuria in many patients This drug is currently under study for its S, Cooper ME, Mitch WE, Brenner BM: (19,20). Important to note is that a further effect on renal protection both in mi- Proteinuria, a target for renoprotection in fall in albuminuria may even be seen at croalbuminuric as well as macroalbumin- patients with type 2 diabetic nephropa- doses far beyond the maximum recom- uric renal diabetic patients. thy: lessons from RENAAL. Kidney Int 65: mended dose, at which doses there is no 2309–2320, 2004 2. de Zeeuw D, Remuzzi G, Parving HH, additional blood pressure effect. Al- Keane WF, Zhang Z, Shahinfar S, Snapinn though it is clear that albuminuria can CONCLUSIONS — Next to the exist- S, Cooper ME, Mitch WE, Brenner BM: thus be further lowered, the question ing risk factors (mainly increased blood Albuminuria, a therapeutic target for car- whether this is associated with further re- pressure), albuminuria is a valuable tool diovascular protection in type 2 diabetic nal and cardiovascular protection is not in further decreasing the risk for progres- patients with nephropathy. Circulation yet answered. The only dose response sive organ function loss in patients with 110:921–927, 2004 study with RAAS intervention in diabetes diabetes, in particular with respect to the 3. Keane WF, Brenner BM, de Zeeuw D, is the Irbesartan MicroAlbuminuria in kidney and the cardiovascular system. Al- Grunfeld JP, Lash J, Lyle PA, McGill J, Type 2 Diabetic Subjects study. This buminuria assesses renal and cardiovas- Mitch WE, Remuzzi G, Shahinfar S, Snap- study indeed showed that 300 mg irbesar- cular risk independent of other risk inn SM, Toto R, Zhang Z, for the RENAAL Study Investigators: A risk score for pre- tan was significantly more efficient than markers both in advanced as well as in dicting end-stage renal disease in patients 150 mg as far as attenuating the transition early diabetic disease states. Despite the with type 2 diabetes and nephropathy: the from microalbuminuria to macroalbu- fact that albuminuria is as such men- RENAAL study. Clin J Am Soc Nephrol minuria (13). Further dosing studies on tioned in global guidelines for the diagno- 1:761–767, 2006 hard end points are awaited. sis and treatment of diabetes, albuminuria 4. Mogensen CE: Microalbuminuria as a Another way to try to enhance the al- is still markedly underused in the daily predictor of clinical diabetic nephropa- buminuria lowering is to switch the pa- practice of diabetes care. thy. Kidney Int 31:673–689, 1987 tient from ARBs to ACE inhibitors, or vice However, the use of albuminuria as a 5. Yuyun MF, Dinneen SF, Edwards OM, versa. However, nonresponders to ACE risk marker in diabetes is clearly needed. Wood E, Wareham NJ: Absolute level and inhibitors (as far as albuminuria lower- First, it helps in stratifying the patient’s rate of change of albuminuria over 1 year independently predict mortality and car- ing) remain nonresponders to ARBs (21). individual risk for renal and cardiovascu- diovascular events in patients with dia- The currently best option to enhance anti- lar disease and thus the need for “aggres- betic nephropathy. Diabet Med 20:277– albuminuric efficacy is to combine drugs sive” therapy using drugs that intervene in 282, 2003 that inhibit the RAAS. The current strate- the renin-angiotensin system. Second, 6. Snyder S, Pendergraph B: Detection and gies available to interfere in the RAAS are these antihypertensive drugs have a short- evaluation of chronic kidney disease. Am as follows: ACE inhibitors, ARBs, aldoste- term effect, not only lowering blood pres- Fam Physician 72:1723–1732, 2005 rone antagonists (22), and rennin inhibi- sure but also lowering albuminuria, 7. Gansevoort RT, Sluiter WJ, Hemmelder tors (23). All these drug classes have a whereas both renal and cardiovascular MH, de Zeeuw D, de Jong PE: Antipro- similar characteristic in lowering blood protection is seen in the long term. Inter- teinuric effect of blood-pressure-lowering pressure as well as albuminuria. The most estingly, the more albuminuria is lowered agents: a meta-analysis of comparative trials. Nephrol Dial Transplant 11:1963– tested combination is ACE inhibitors plus after initializing RAAS intervention ther- 1974, 1995 ARBs. This combination not only shows apy, the more the individual is protected 8. Vogt L, Navis G, de Zeeuw D: Renopro- an enhanced effect on albuminuria lower- in the long run. This is independent of the tection: a matter of blood pressure reduc- ing (24), but it also shows an enhanced blood pressure–lowering effect of these tion or agent-characteristics? J Am Soc effect on long-term renal outcome in non- drugs. Thus, albuminuria is not only a Nephrol 13 (Suppl. 3):S202–S207, 2002 diabetic renal disease patients (25). The marker of renal and cardiovascular risk, 9. Lewis EJ, Hunsicker LG, Bain RP, Rohde latter combination needs to be confirmed but also a marker of the protective treat- RD: The effect of angiotensin-converting- in other trials. With regard to albumin- ment effect of such drugs. The individual enzyme inhibition on diabetic nephropa- uria, combinations of ACE inhibitors and effect of RAAS intervention can be differ- thy: the Collaborative Study Group. aldosterone antagonists also have an ad- ent for blood pressure lowering and albu- N Engl J Med 329:1456–1462, 1993 10. The GISEN Group (Gruppo Italiano di ditive lowering effect; however, no hard minuria lowering. Because the long-term Studi Epidemiologici in Nefrologia): Ran- end point trials are published. outcome in these patients is indepen- domised placebo-controlled trial of effect Finally, currently ongoing or starting dently determined by the short-term ef- of ramipril on decline in glomerular filtra- studies are looking for new non–RAAS in- fect on albuminuria (independent from tion rate and risk of terminal renal failure tervention strategies that lower albumin- the blood pressure effect), albuminuria in proteinuric, non-diabetic nephropa-

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