Diabetic Kidney Disease: A Report From an ADA Consensus Conference

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included (1) identification and monitoring, (2) cardiovascular disease and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage chronic kidney disease, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD. The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included (1) identification and monitoring, (2) cardiovascular disease and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage chronic kidney disease, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD. The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This increase in the number of people developing diabetes has had a major impact on the development of diabetic kidney disease (DKD).1de Boer I.H. Rue T.C. Hall Y.N. Heagerty P.J. Weiss N.S. Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States.JAMA. 2011; 305: 2532-2539Crossref PubMed Scopus (117) Google Scholar Although kidney disease attributable to diabetes is referred to as DKD, diabetes and various kidney diseases are common chronic conditions. Thus, people with diabetes may have other etiologies of chronic kidney disease (CKD) in addition to diabetes. Notably, DKD remains one of the most frequent complications of both types of diabetes, and diabetes is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have stabilized over the past few years,2Collins A.J. Foley R.N. Chavers B. et al.US Renal Data System 2013 annual data report.Am J Kidney Dis. 2014; 63: e219-e220Google Scholar differences remain among high-risk subgroups. Middle-aged African Americans, Native Americans, and Hispanics continue to have higher rates of ESRD. These disparities in health care may be linked, in part, to the increasing rates of obesity and type 2 diabetes in youth, which disproportionately occur in these populations and allow for the development of diabetes complications earlier in life. The overall costs of care for people with DKD are extraordinarily high, due in large part to the strong relationship of DKD with cardiovascular disease (CVD) and development of ESRD.3Collins A.J. Foley R.N. Chavers B. et al.US Renal Data System 2013 annual data report.Am J Kidney Dis. 2014; 63: e112-e116Google Scholar For example, overall Medicare expenditures for diabetes and CKD in the mostly older (≥ 65 years of age) Medicare population were approximately $25 billion in 2011. At the transition to ESRD, the per person per year costs were $20,000 for those covered by Medicare and $40,000 in the younger (< 65 years of age) group. Increased albuminuria and decreased glomerular filtration rate (GFR) are each independently and additively associated with an increase in all-cause and CVD mortality, and, in fact, most of the excess CVD of diabetes is accounted for by the population with DKD. Due to very high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association (ADA) in collaboration with the American Society of Nephrology (ASN) and the National Kidney Foundation (NKF). The objectives of convening the conference and publishing this consensus report were to address vital issues regarding patient care, highlighting current practices, gaps in knowledge, and new directions for improving outcomes in this high-risk population. The major sponsoring organization (ADA) and conference leadership (K.R.T. and M.E.M.) chose major topic areas meeting these objectives based on recent publications, public health trends, and input from stakeholders representing professional, academic, clinical, industry, and patient groups. This report contains summaries of the topic areas based on the conference proceedings and feedback from participants. Major topic areas in DKD included (1) identification and monitoring, (2) CVD and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system (RAAS) blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage CKD, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary with research recommendations is designed to guide advances in patient care and the generation of new knowledge that will meaningfully improve life for people with DKD. This consensus conference and corresponding report are not all-inclusive of important considerations. For example, the topics of geriatrics, pregnancy, and kidney disease progression in DKD were not specifically addressed. However, these topics were comprehensively covered in the NKF–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines for diabetes and CKD and the evidence reviews and recommendations made therein remain germane.4National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar Identifying and monitoring DKD relies upon assessments of kidney function, usually with an estimated GFR (eGFR) < 60 mL/min/1.73 m2, and kidney damage, usually by estimation of albuminuria > 30 mg/g creatinine. Widespread utilization of these simple laboratory measures has facilitated earlier recognition of DKD and has formed the basis for clinical staging. However, understanding the imprecision associated with these tests is critical to their appropriate utilization in clinical care. Routine reporting of eGFR with serum creatinine concentration has been widely implemented. However, many clinicians and patients remain unaware of the uncertainty associated with GFR estimating equations. P30, the performance measure for estimating equations, is the likelihood that the eGFR is within 30% of the measured GFR. The P30 for the most commonly used estimating equations is generally between 80% and 90%. Thus, the eGFR has, at best, a 90% chance of being within 30% of the measured GFR. In addition, the characteristics of the existing estimating equations make them significantly less precise at higher GFRs. This is of particular concern early in the course of DKD, which may be associated with an elevated GFR (also called hyperfiltration).5Magee G.M. Bilous R.W. Cardwell C.R. Hunter S.J. Kee F. Fogarty D.G. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.Diabetologia. 2009; 52: 691-697Crossref PubMed Scopus (77) Google Scholar Hyperfiltration is thought to be a manifestation of increased intraglomerular capillary pressure and has been implicated in the development and progression of experimental nephropathy in diabetic rodents. Reduction in intraglomerular capillary pressure and single nephron GFR by RAAS blockade in these animal models formed the basis for subsequent clinical trials.6Zatz R. Dunn B.R. Meyer T.W. Anderson S. Rennke H.G. Brenner B.M. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.J Clin Invest. 1986; 77: 1925-1930Crossref PubMed Google Scholar However, the link between glomerular hyperfiltration and subsequent albuminuria or eGFR loss in humans has not been consistently confirmed. A meta-analysis suggested that there was a 2.7-fold increased risk for the development of “microalbuminuria” (30-300 mg/24 h, or moderately increased albuminuria) in those with prior hyperfiltration, but this increased risk was lost when the level of glycemia was taken into account.5Magee G.M. Bilous R.W. Cardwell C.R. Hunter S.J. Kee F. Fogarty D.G. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.Diabetologia. 2009; 52: 691-697Crossref PubMed Scopus (77) Google Scholar Studies using RAAS-blocking agents generally show an acute reduction in eGFR, which is thought to be due to a reduction in glomerular hyperfiltration.7Evans M. Bain S.C. Hogan S. Bilous R.W. Collaborative Study Group ParticipantsIrbesartan delays progression of nephropathy as measured by estimated glomerular filtration rate: post hoc analysis of the Irbesartan Diabetic Nephropathy Trial.Nephrol Dial Transplant. 2012; 27: 2255-2263Crossref PubMed Scopus (10) Google Scholar One post hoc analysis of a RAAS antagonist has shown a significant inverse relationship between reduction of eGFR at 6 months and subsequent rate of loss of eGFR.8Holtkamp F.A. de Zeeuw D. Thomas M.C. et al.An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function.Kidney Int. 2011; 80: 282-287Crossref PubMed Scopus (40) Google Scholar In other words, the greater the initial reduction in eGFR, the lower the rate of later eGFR loss. This finding needs confirmation in prospective studies. Albuminuria is a marker for kidney/glomerular disease as well as for CVD risk and is often the first clinical indicator of the presence of DKD.9Bakris G.L. Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga.Diabetes Care. 2014; 37: 867-875Crossref PubMed Scopus (1) Google Scholar It is a clinically useful tool for predicting prognosis and for monitoring response to therapy. Despite the strength of albuminuria as a risk biomarker for DKD and CVD outcomes, there are considerable limitations (Box 1). Importantly, not all people with DKD and reduced eGFR have increased albuminuria. In the UK Prospective Diabetes Study (UKPDS), 51% of those who developed an estimated creatinine clearance of <60 mL/min/1.73 m2 ever tested positive for albuminuria.10Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy?.Diabet Med. 2008; 25: 25-29Crossref PubMed Scopus (63) Google Scholar Some, but not all, observational studies show that the rate of loss of GFR is slower in those type 2 diabetic patients with low or normal albuminuria.11Nosadini R. Velussi M. Brocco E. et al.Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate.Diabetes. 2000; 49: 476-484Crossref PubMed Google Scholar, 12MacIsaac R.J. Tsalamandris C. Panagiotopoulos S. Smith T.J. McNeil K.J. Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes.Diabetes Care. 2004; 27: 195-200Crossref PubMed Scopus (171) Google ScholarBox 1Albuminuria: Biomarker Use and Major LimitationsDiabetic Kidney DiseaseBiomarker Use•Higher albuminuria levels associate with faster eGFR decline•Discordance between lowering albuminuria by treatment and clinical eventsMajor Limitations•Not sensitive○Low eGFR present in half or more without increased albuminuriaCardiovascular DiseaseBiomarker Use•Independently predicts events and mortalityMajor Limitations•Nonstandardized measurement and reporting○Assays vary by ∼40%○Variably reported as concentration, ratio to creatinine, or timed excretion•Individual variability is large○Day-to-day variability ∼40%○Episodic increases with fever, urinary tract infection, exercise, congestive heart failure, hypertension, hyperglycemia, high-protein diet•Categorical nomenclature does not reflect continuous nature of association with DKD and CVD risks○Moderately increased albuminuria (“microalbuminuria”)○Severely increased albuminuria (“macroalbuminuria”) Diabetic Kidney DiseaseBiomarker Use•Higher albuminuria levels associate with faster eGFR decline•Discordance between lowering albuminuria by treatment and clinical eventsMajor Limitations•Not sensitive○Low eGFR present in half or more without increased albuminuriaCardiovascular DiseaseBiomarker Use•Independently predicts events and mortalityMajor Limitations•Nonstandardized measurement and reporting○Assays vary by ∼40%○Variably reported as concentration, ratio to creatinine, or timed excretion•Individual variability is large○Day-to-day variability ∼40%○Episodic increases with fever, urinary tract infection, exercise, congestive heart failure, hypertension, hyperglycemia, high-protein diet•Categorical nomenclature does not reflect continuous nature of association with DKD and CVD risks○Moderately increased albuminuria (“microalbuminuria”)○Severely increased albuminuria (“macroalbuminuria”) The absence of albuminuria in persons with a reduced eGFR and diabetes raises the possibility of nondiabetic CKD. The NKF-KDOQI Work Group for Diabetes and CKD concluded that the presence of retinopathy in patients with albuminuria > 300 mg/g creatinine was strongly suggestive of DKD, and its absence in those with reduced eGFR and albuminuria < 30-300 mg/g creatinine suggested nondiabetic CKD.4National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar These findings were confirmed in a recent meta-analysis.13He F. Xia X. Wu X.F. Yu X.Q. Huang F.X. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis.Diabetologia. 2013; 56: 457-466Crossref PubMed Scopus (6) Google Scholar Recommendation 1.4 from the NKF-KDOQI diabetes and CKD guidelines (Box 2) is particularly relevant for those with diabetes who have normal levels of albuminuria and an eGFR < 60 mL/min/1.73 m2.4National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google ScholarBox 2Other Cause(s) of CKD Should Be Considered in the Presence of Any of the Following Circumstances• Absence of diabetic retinopathy;• Low or rapidly decreasing GFR;• Rapidly increasing proteinuria or nephrotic syndrome;• Refractory hypertension;• Presence of active urinary sediment;• Signs or symptoms of other systemic disease; or• >30% reduction in GFR within 2-3 months after initiation of an ACE inhibitor or ARB. • Absence of diabetic retinopathy; • Low or rapidly decreasing GFR; • Rapidly increasing proteinuria or nephrotic syndrome; • Refractory hypertension; • Presence of active urinary sediment; • Signs or symptoms of other systemic disease; or • >30% reduction in GFR within 2-3 months after initiation of an ACE inhibitor or ARB. Measurement of albuminuria is not standardized and demonstrates significant imprecision. The most common assays were compared with a recently developed isotope-dilution mass spectrometry assay and varied by approximately 40% across albumin concentrations from 13 mg/L to 1,084 mg/L.14Bachmann L.M. Nilsson G. Bruns D.E. et al.State of the art for measurement of urine albumin: comparison of routine measurement procedures to isotope dilution tandem mass spectrometry.Clin Chem. 2014; 60: 471-480Crossref PubMed Scopus (2) Google Scholar Other barriers to the effective use of albuminuria in management of patients with diabetes include the nonstandardized reporting of results by clinical laboratories. Additionally, providers do not always understand how to interpret albuminuria results. Methods of assessment include the collection of urine specimens for albumin excretion rate over a specified time frame (typically 24 h) or the measurement of the urine albumin-creatinine ratio (ACR) in a spot collection, the latter being more commonly used because of patient convenience. Variation within individuals and studies may confound interpretation and risk assessment. There is considerable intraindividual daily variation in albuminuria. A coefficient of variation of 40% has traditionally been reported for those with type 1 diabetes and an ACR of 30-300 mg/g creatinine. Vagaries of study outcomes also cloud interpretation of albuminuria measurements. Examples include measurement of a single urine sample, collection at various times of the day, long periods between samplings, and measurement of only albumin concentration.10Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy?.Diabet Med. 2008; 25: 25-29Crossref PubMed Scopus (63) Google Scholar, 15Heart Outcomes Prevention Evaluation Study InvestigatorsEffects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.Lancet. 2000; 355: 253-259Abstract Full Text Full Text PDF PubMed Scopus (2640) Google Scholar, 16Patel A. MacMahon S. Chalmers J. et al.ADVANCE Collaborative GroupIntensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572Crossref PubMed Scopus (12) Google Scholar, 17Bilous R.W. Parving H.-H. Orchard T.J. et al.Renin angiotensin system blockade is effective in preventing microalbuminuria in hypertensive but not normotensive people with type 2 diabetes; further analysis of the DIRECT Programme. EASD, Stockholm, Sweden2010Google Scholar, 18Saydah S.H. Pavkov M.E. Zhang C. et al.Albuminuria prevalence in first morning void compared with previous random urine from adults in the National Health and Nutrition Examination Survey, 2009-2010.Clin Chem. 2013; 59: 675-683Crossref PubMed Scopus (7) Google Scholar Albuminuria may also be increased by episodic hyperglycemia, high blood pressure (BP), high-protein diet, exercise, fever, urinary tract infection, and congestive heart failure. To the contrary, sustained regression of moderately increased albuminuria from the 30-300 mg/g creatinine range to the normal range was 3 times more likely in patients who had a hemoglobin A1c (HbA1c) < 8.0%, systolic BP < 115 mm Hg, and serum lipids in target (total cholesterol < 198 mg/dL and triglycerides < 145 mg/dL) than those who did not meet these targets.19Perkins B.A. Ficociello L.H. Silva K.H. Finkelstein D.M. Warram J.H. Krolewski A.S. Regression of microalbuminuria in type 1 diabetes.N Engl J Med. 2003; 348: 2285-2293Crossref PubMed Scopus (366) Google Scholar Overall, standardizing urine collection by correlating the patient’s clinical situation (glycemia, BP, lipids, etc) with the number and timing of the samples is as important as the method of measurement and reporting of the albumin concentration. Recommendations from the ADA, NKF, and National Kidney Disease Education Program (NKDEP) support measuring albuminuria more than once and state that 2 of 3 samples should be elevated over a 3- to 6-month period for confirmation of a diagnosis of increased albuminuria.4National Kidney FoundationKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49: S12-S154PubMed Google Scholar, 20American Diabetes AssociationStandards of medical care in diabetes—2014.Diabetes Care. 2014; 37: S14-S80Crossref PubMed Scopus (139) Google Scholar, 21National Kidney Disease Education Program. Available from: http://nkdep.nih.gov/. Accessed 19 May 2014.Google Scholar, 22Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int. 2013; 3: S1-S150Crossref Scopus (39) Google Scholar Discordance between changes in albuminuria and kidney disease events has also been observed in a series of clinical trials. For example, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in people with long-duration type 2 diabetes, intensive glycemic control resulted in significantly fewer individuals developing albuminuria at moderately increased levels (> 30-300 mg/g creatinine) or severely increased levels (> 300 mg/g creatinine) but increased the risk of doubling of serum creatinine.23Ismail-Beigi F. Craven T. Banerji M.A. et al.ACCORD trial groupEffect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.Lancet. 2010; 376: 419-430Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar There was a reduction in both of these parameters in the intensive treatment arm of the UKPDS study in newly diagnosed patients, although the number of serum creatinine-doubling events was very few.10Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy?.Diabet Med. 2008; 25: 25-29Crossref PubMed Scopus (63) Google Scholar Thus, it is possible that the timing of the intervention in terms of diabetes duration may be critical. Some complications such as DKD onset and progression may be more amenable to prevention in short- rather than long-duration diabetes. On the other hand, patients with type 1 diabetes in the intensive arm of Diabetes Control and Complications Trial (DCCT)/ Epidemiology of Diabetes Interventions and Complications (EDIC) had reductions in both albuminuria and their risk for developing CKD (defined as a sustained eGFR < 60 mL/min/1.73 m2).24Rossing P. Prediction, progression and prevention of diabetic nephropathy. The Minkowski Lecture 2005.Diabetologia. 2006; 49: 11-19Crossref PubMed Scopus (38) Google Scholar The NKDEP Laboratory Working Group and the National Institute of Standards and Technology standardized the laboratory measurement of creatinine and are now collaborating with the International Federation of Clinical Chemistry and Laboratory Medicine to standardize the laboratory measurement and reporting of urine albumin. Reference methods and reference materials have been developed and are undergoing additional validation. However, even with standardization of serum creatinine and urine albumin measurements, residual imprecision of these biomarkers makes it likely that improved predictive tools will incorporate other biomarkers and patient characteristics. Until validated algorithms are available, clinicians are cautioned about predicting prognosis based on any single measurement of a particular biomarker, such as albuminuria. Serial monitoring of biomarkers is likely to reduce confounding “noise” and establish a temporal trend that may be more informative for prognosis. However, this approach has been challenged by the American College of Physicians, which recommended against monitoring albuminuria in patients with or without diabetes who are treated with RAAS antagonists (grade: weak recommendation, low-quality evidence).25Qaseem A. Hopkins Jr., R.H. Sweet D.E. Starkey M. Shekelle P. Clinical Guidelines Committee of the American College of PhysiciansScreening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians.Ann Intern Med. 2013; 159: 835-847Crossref PubMed Google Scholar It is clear that the relationship of albuminuria to ESRD and CVD risk is a continuum, starting from “normal” levels < 30 mg/g creatinine. In this regard, there has been a trend to no longer refer to categorical nomenclature of “microalbuminuria” (30-300 mg/g creatinine) and “macroalbuminuria” (>300 mg/g creatinine). Instead, reporting the urine albumin level as a continuous variable (eg, albumin excretion rate in mg/24 h or ACR in mg/g creatinine) may be preferred. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines have recently recommended a similar change for assessing CKD in general with albuminuria reported as normal to mildly increased (<30 mg/g creatinine), moderately increased (30-300 mg/g creatinine), or severely increased (>300 mg/g creatinine) and framed in the context of CKD stages 1 to 5 to determine risks.22Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int. 2013; 3: S1-S150Crossref Scopus (39) Google Scholar 1. What are the reporting cutoffs for the definition of normal albuminuria and what is the proper nomenclature? 2. Should urine albumin results be reported as a continuous variable (ie, eliminate “macro,” >300 mg/g creatinine, and “micro,” 30-300 mg/g creatinine, prefixes)? 3. Should there be sex-specific cutoffs that identify patients at increased risk of CVD as well as of progressive DKD? 4. Is there a practical strategy for screening patients that reduces intraindividual variability in ACR? 5. Can algorithms be developed to predict risk for progressive DKD, and which factors must be incorporated (eg, eGFR, albuminuria, rate of change in eGFR or albuminuria, BP, new biomarkers)? 6. What is the role of albuminuria monitoring in guiding therapy? 7. Is there a strategy to target aggressive management to those patients at greatest risk of progressive DKD (eg, patients on single-agent RAAS blockade and a rapidly declining eGFR of >5 mL/min/1.73 m2 per year)? 8. Can albuminuria be the primary end point in clinical trials to establish an evidence base for ongoing monitoring? Among patients with diabetes, those with kidney disease are consistently observed to have substantially elevated mortality rates.26Fox C.S. Matsushita K. Woodward M. et al.Chronic Kidney Disease Prognosis ConsortiumAssociations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.Lancet. 2012; 380: 1662-1673Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Much of this mortality is due to CVD, although noncardiovascular mortality is also increased. Albuminuria and eGFR are independently and additively associated with increased risks of CVD events, CVD mortality, and all-cause mortality.26Fox C.S. Matsushita K. Woodward M. et al.Chronic Kidney Disease Prognosis ConsortiumAssociations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.Lancet. 2012; 380: 1662-1673Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Both diabetes and CKD have been observed to have incidence rates of CVD events similar to patients with established coronary heart disease, leading to recommendations that patients with diabetes, CKD, or both should be treated for prevention of CVD as if they had already experienced such an event.27Tonelli M. Muntner P. Lloyd A. et al.Alberta Kidney Disease NetworkRisk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study.Lancet. 2012; 380: 807-814Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar In both type 1 and 2 diabetes, cohort studies suggest that increased risks of mortality and CVD are limited to patients who have evidence of DKD, and patients with normal levels of albuminuria