Microalbuminuria: target for renoprotective therapy PRO Sara S. Roscioni, Hiddo J. Lambers Heerspink, Dick de Zeeuw  Kidney International  Volume 86, Issue 1, Pages 40-49 (July 2014) DOI: 10.1038/ki.2013.490 Copyright © 2014 International Society of Nephrology Terms and Conditions

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. Kidney International 2014 86, 40-49DOI: (10.1038/ki.2013.490) Copyright © 2014 International Society of Nephrology Terms and Conditions

Figure 2 Albuminuria predicts renal outcome. Adjusted hazard ratio (95% confidence interval) for end-stage renal disease (ESRD) by albuminuria category adjusted for age, sex, race, previous cardiovascular disease, smoking status, diabetes mellitus, systolic blood pressure, and serum total cholesterol concentration in four independent clinical studies in chronic kidney disease patients. Adapted from Astor et al.19 Kidney International 2014 86, 40-49DOI: (10.1038/ki.2013.490) Copyright © 2014 International Society of Nephrology Terms and Conditions

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 factor-κB (NF-κB), 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-β (TGF-β), collagens)) substances, leading to irreversible renal damage. Kidney International 2014 86, 40-49DOI: (10.1038/ki.2013.490) Copyright © 2014 International Society of Nephrology Terms and Conditions

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, Angiotensin-Converting 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. Kidney International 2014 86, 40-49DOI: (10.1038/ki.2013.490) Copyright © 2014 International Society of Nephrology Terms and Conditions