Diabetic Kidney Disease: A ReportFrom an ADA ConsensusConferenceDiabetes Care 2014;37:2864–2883 | DOI: 10.2337/dc14-1296

The incidence and prevalence of diabetes mellitus have grown significantlythroughout the world, due primarily to the increase in type 2 diabetes. This overallincrease in the number of people with diabetes has had a major impact ondevelopment of diabetic kidney disease (DKD), one of the most frequentcomplications of both types of diabetes. DKD is the leading cause of end-stage renaldisease (ESRD), accounting for approximately 50% of cases in the developed world.Although incidence rates for ESRD attributable toDKDhave recently stabilized, theserates 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 areextraordinarily high. In the Medicare population alone, DKD-related expendituresamong this mostly older group were nearly $25 billion in 2011. Due to the highhuman and societal costs, the Consensus Conference on Chronic Kidney Disease andDiabetes was convened by the American Diabetes Association in collaboration withthe American Society of Nephrology and the National Kidney Foundation to appraiseissues regarding patient management, highlighting current practices and newdirections. Major topic areas in DKD included 1) identification and monitoring, 2)cardiovascular disease and management of dyslipidemia, 3) hypertension and use ofrenin-angiotensin-aldosterone system blockade andmineralocorticoid receptor block-ade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition andgeneral care in advanced-stage chronic kidney disease, 6) children and adolescents,and 7)multidisciplinary approaches andmedical homemodels for health caredelivery.This current state summary and research recommendations are designed to guideadvances in care and the generation of new knowledge thatwillmeaningfully improvelife for people with DKD.

1University of Washington School of Medicine,Seattle, WA, and Providence Health Care,Spokane, WA2ComprehensiveHypertension Center, TheUniver-sity of Chicago Medicine, Chicago, IL (NationalKidney Foundation liaison)3Newcastle University, Newcastle upon Tyne, U.K.4American Diabetes Association, Alexandria, VA5Division of Nephrology, University of Washing-ton, Seattle, WA6SierraNevadaNephrologyConsultants, Reno,NV7Division of Metabolism, Endocrinology andNutrition, University of Washington School ofMedicine, Seattle, WA8School of Medicine, University of California,Irvine, Irvine, CA9National Institute of Diabetes and Digestive andKidney Diseases, National Institutes of Health,Bethesda, MD

10Department of Nephrology and Hypertension,Novick Center for Clinical and Translational Re-search, GlickmanUrological and Kidney Institute,Cleveland Clinic, Cleveland, OH11DepartmentofPharmacotherapy,CollegeofPhar-macy, Washington State University, Spokane, WA12Divisions of Nephrology and Pediatric Nephrol-ogy,Duke Clinical Research Institute, DukeUniver-sity School of Medicine, Durham, NC (AmericanSociety of Nephrology liaison)13Harry S. TrumanMemorial VeteransHospital, Co-lumbia, MO, and Department of Internal Medicine,Division of Nephrology and Hypertension, Univer-sity of Missouri School of Medicine, Columbia, MO14Division of Endocrinology, Metabolism andMolecular Medicine, Northwestern UniversityFeinberg School of Medicine, Chicago, IL

Corresponding author: Jane L. Chiang, jchiang@diabetes.org.

In collaboration with the American Society ofNephrology and the National Kidney Foundation

Organizational sponsors and participants: Amer-ican Diabetes Association, National Kidney Foun-dation, and American Society of Nephrology

This article is being published concurrently in Di-abetes Care and AJKD. The articles are identicalexcept for stylistic changes in keeping with eachjournal’s style. Either of these versions may beused in citing this article.

© 2014 by the American Diabetes Associationand the National Kidney Foundation. Readersmay use this article as long as the work is prop-erly cited, the use is educational and not forprofit, and the work is not altered.

Katherine R. Tuttle,1 George L. Bakris,2

Rudolf W. Bilous,3 Jane L. Chiang,4

Ian H. de Boer,5 Jordi Goldstein-Fuchs,6

Irl B. Hirsch,7 Kamyar Kalantar-Zadeh,8

Andrew S. Narva,9

Sankar D. Navaneethan,10

Joshua J. Neumiller,11 Uptal D. Patel,12

Robert E. Ratner,4 Adam T. Whaley-

Connell,13 and Mark E. Molitch14

2864 Diabetes Care Volume 37, October 2014

CONSENSU

SREP

ORT

The incidence and prevalence of diabe-tes mellitus have grown significantlythroughout the world, due primarily tothe increase in type 2 diabetes. This in-crease in the number of people devel-oping diabetes has had a major impacton the development of diabetic kidneydisease (DKD) (1). Although kidney dis-ease attributable to diabetes is referredto as DKD, diabetes and various kidneydiseases are common chronic condi-tions. Thus, people with diabetes mayhave other etiologies of chronic kidneydisease (CKD) in addition to diabetes.Notably, DKD remains one of the mostfrequent complications of both typesof diabetes, and diabetes is the leadingcause of end-stage renal disease (ESRD),accounting for approximately 50% ofcases in the developed world. Althoughincidence rates for ESRD attributable toDKD have stabilized over the past fewyears (2), differences remain amonghigh-risk subgroups. Middle-aged Afri-can Americans, Native Americans, andHispanics continue to have higher ratesof ESRD. These disparities in health caremay be linked, in part, to the increasingrates of obesity and type 2 diabetes inyouth, which disproportionately occurin these populations and allow for thedevelopment of diabetes complicationsearlier in life.The overall costs of care for people

with DKD are extraordinarily high, duein large part to the strong relationshipof DKD with cardiovascular disease(CVD) and development of ESRD (3).For example, overall Medicare expendi-tures for diabetes and CKD in the mostlyolder ($65 years of age) Medicare pop-ulation were approximately $25 billionin 2011. At the transition to ESRD, theper person per year costs were $20,000for those covered by Medicare and$40,000 in the younger (,65 years ofage) group. Increased albuminuria anddecreased glomerular filtration rate(GFR) are each independently and addi-tively associated with an increase in all-cause and CVD mortality, and, in fact,most of the excess CVD of diabetes isaccounted for by the population withDKD.Due to both very high human and so-

cietal costs, the Consensus Conferenceon Chronic Kidney Disease and Diabeteswas convened by the American DiabetesAssociation (ADA) in collaboration withthe American Society of Nephrology

(ASN) and the National Kidney Founda-tion (NKF). The objectives of conveningthe conference and publishing thisconsensus report were to addressvital issues regarding patient care,highlighting current practices, gapsin knowledge, and new directions forimproving outcomes in this high-riskpopulation.

The major sponsoring organization(ADA) and conference leadership (K.R.T.and M.E.M.) chose major topic areasmeeting these objectives based on re-cent publications, public health trends,and input from stakeholders represent-ing professional, academic, clinical, in-dustry, and patient groups. This reportcontains summaries of the topic areasbased on the conference proceedingsand feedback from participants. Majortopic areas in DKD included 1) identifica-tion andmonitoring, 2) CVD andmanage-ment of dyslipidemia, 3) hypertensionand use of renin-angiotensin-aldosteronesystem (RAAS) blockade and mineral-ocorticoid receptor (MR) blockade, 4)glycemia measurement, hypoglycemia,anddrug therapies,5) nutritionandgeneralcare in advanced-stageCKD,6) childrenandadolescents, and 7) multidisciplinary ap-proaches and medical home models forhealth care delivery.

This current state summary with re-search recommendations is designed toguide advances in patient care and thegeneration of new knowledge that willmeaningfully improve life for peoplewith DKD. This consensus conferenceand corresponding report are not all-inclusive of important considerations. Forexample, the topics of geriatrics, preg-nancy, and kidney disease progression inDKD were not specifically addressed.However, these topics were comprehen-sively covered in the National KidneyFoundation Kidney Disease OutcomesQuality Initiative (NKF KDOQI) guidelinesfor diabetes and CKD and the evidencereviews and recommendations madetherein remain germane (4).

IDENTIFICATION ANDMONITORING OF DKD

Laboratory Assessment of DKDIdentifying and monitoring DKD reliesupon assessments of kidney func-tion, usually with an estimated GFR(eGFR),60mL/min/1.73m2, and kidneydamage, usually by estimation of

albuminuria.30mg/g creatinine.Wide-spread utilization of these simple labora-tory measures has facilitated earlierrecognition of DKD and has formed thebasis for clinical staging. However, un-derstanding the imprecision associatedwith these tests is critical to their appro-priate utilization in clinical care.

Limitations of eGFRRoutine reporting of eGFR with serumcreatinine concentration has beenwidely implemented. However, manyclinicians and patients remain unawareof the uncertainty associated with GFRestimating equations. P30, the perfor-mance measure for estimating equa-tions, is the likelihood that the eGFR iswithin6 30% of the measured GFR. TheP30 for the most commonly used esti-mating equations is generally between80 and 90%. Thus, the eGFR has, atbest, a 90% chance of being within30% of the measured GFR. In addition,the characteristics of the existing esti-mating equations make them signifi-cantly less precise at higher GFRs.This is of particular concern early inthe course of DKD, which may be associ-ated with an elevated GFR (also calledhyperfiltration) (5).

Hyperfiltration is thought to be a man-ifestation of increased intraglomerularcapillary pressure and has been implicatedin the development and progression of ex-perimental nephropathy in diabetic ro-dents. Reduction in intraglomerularcapillary pressure and single nephronGFR by RAAS blockade in these animalmodels formed the basis for subsequentclinical trials (6). However, the link be-tween glomerular hyperfiltration andsubsequent albuminuria or eGFR loss inhumans has not been consistently con-firmed. A meta-analysis suggested thatthere was a 2.7-fold increased risk forthe development of “microalbuminuria”(30–300mg/24 h, moderately increased)in those with prior hyperfiltration, but thisincreased risk was lost when the level ofglycemiawas taken into account (5). Stud-ies using RAAS-blocking agents generallyshow an acute reduction in eGFR, which isthought to be due to a reduction in glo-merular hyperfiltration (7). One post hocanalysis of a RAAS antagonist has shown asignificant inverse relationship betweenreduction of eGFR at 6 months and sub-sequent rate of loss of eGFR (8). In otherwords, the greater the initial reduction in

care.diabetesjournals.org Tuttle and Associates 2865

eGFR, the lower the rate of later eGFRloss. This finding needs confirmation inprospective studies.

Limitations of AlbuminuriaAlbuminuria is a marker for kidney/glo-merular disease as well as for CVD riskand is often the first clinical indicator ofthe presence of DKD (9). It is a clinicallyuseful tool for predicting prognosis andfor monitoring response to therapy. De-spite the strength of albuminuria as arisk biomarker for DKD and CVD out-comes, there are considerable limita-tions (Table 1). Importantly, not allpeople with DKD and reduced eGFRhave increased albuminuria. In the UKProspective Diabetes Study (UKPDS),51% of those who developed an esti-mated creatinine clearance of ,60mL/min/1.73 m2 ever tested positivefor albuminuria (10). Some, but not all,observational studies show that the rateof loss of GFR is slower in those type 2diabetic patients with low or normal al-buminuria (11,12).The absence of albuminuria in per-

sons with a reduced eGFR and diabetesraises the possibility of nondiabetic CKD.The NKF KDOQI Work Group for Diabe-tes and CKD concluded that the pres-ence of retinopathy in patients withalbuminuria .300 mg/g creatininewas strongly suggestive of DKD, andits absence in those with reducedeGFR and albuminuria ,30–300 mg/gcreatinine suggested nondiabetic CKD (4).These findings were confirmed in a recentmeta-analysis (13). Recommendation

1.4 from the NKF KDOQI diabetes andCKD guidelines (Table 2) is particularlyrelevant for those with diabetes whohave normal levels of albuminuria andan eGFR ,60 mL/min/1.73 m2 (4).

Measurement of albuminuria is notstandardized and demonstrates signifi-cant imprecision. The most commonassays were compared with a recent-ly developed isotope dilution massspectrometry assay and varied by ap-proximately 40% across albumin con-centrations from 13 mg/L to 1,084 mg/L(14). Other barriers to the effective useof albuminuria in management of pa-tients with diabetes include the non-standardized reporting of results byclinical laboratories. Additionally, pro-viders do not always understand howto interpret albuminuria results. Meth-ods of assessment include the collectionof urine specimens for albumin excre-tion rate over a specified time frame(typically 24 h) or the measurement ofthe urine albumin/creatinine ratio (ACR)in a spot collection, the latter beingmore commonly used because of pa-tient convenience. Variation within indi-viduals and studies may confoundinterpretation and risk assessment.There is considerable intraindividualdaily variation in albuminuria. A coeffi-cient of variation of 40% has tradition-ally been reported for those with type 1diabetes and an ACR of 30–300 mg/gcreatinine. Vagaries of study outcomesalso cloud interpretation of albumin-uria measurements. Examples includemeasurement of a single urine sample,

collection at various times of the day,long periods between samplings, andmeasurement of only albumin concen-tration (10,15–18).

Albuminuria may also be increased byepisodic hyperglycemia, high bloodpressure (BP), high-protein diet, exer-cise, fever, urinary tract infection, andcongestive heart failure. To the con-trary, sustained regression of moder-ately increased albuminuria from the30–300 mg/g creatinine range to thenormal range was three times morelikely in patients who had a hemoglobinA1c (A1C),8.0%, systolic BP (SBP),115mmHg, and serum lipids in target (totalcholesterol ,198 mg/dL and triglycer-ides ,145 mg/dL) than those who didnot meet these targets (19). Overall,standardizing urine collection by corre-lating the patient’s clinical situation (gly-cemia, BP, lipids, etc.) with the numberand timing of the samples is as impor-tant as themethod ofmeasurement andreporting of the albumin concentration.Recommendations from the ADA, NKF,and National Kidney Disease EducationProgram (NKDEP) support measuringalbuminuria more than once and statethat two of three samples should be el-evated over a 3- to 6-month period forconfirmation of a diagnosis of increasedalbuminuria (4,20–22).

Discordance between changes in al-buminuria and kidney disease eventshas also been observed in a series ofclinical trials. For example, in theAction to Control Cardiovascular Risk inDiabetes (ACCORD) trial in people with

Table 1—Albuminuria: biomarker use and major limitations

Biomarker use Major limitations

DKD Not sensitiveHigher albuminuria levels associatewith faster eGFR decline c Low eGFR present in half or more without increased

albuminuriaDiscordance between lowering albuminuria by treatmentand clinical events

CVD Nonstandardized measurement and reportingIndependently predicts events and mortality c Assays vary by ;40%

c Variably reported as concentration, ratio to creatinine,or timed excretion

Individual variability is largec Day-to-day variability ;40%c Episodic increases with fever, urinary tract infection,exercise, congestive heart failure, hypertension,hyperglycemia, high-protein diet

Categorical nomenclature does not reflect continuousnature of association with DKD and CVD risks

cModerately increased albuminuria (“microalbuminuria”)c Severely increased albuminuria (“macroalbuminuria”)

2866 Consensus Report Diabetes Care Volume 37, October 2014

long-duration type 2 diabetes, intensiveglycemic control resulted in significantlyfewer individuals developing albumin-uria at moderately increased levels(.30–300 mg/g creatinine) or severelyincreased levels (.300 mg/g creatinine)but increased the risk of doubling of se-rum creatinine (23). There was a reduc-tion in both of these parameters in theintensive treatment arm of the UKPDSstudy in newly diagnosed patients, al-though the number of serum creatinine–doubling events was very few (10).Thus, it is possible that the timing of theintervention in terms of diabetes dura-tion may be critical. Some complicationssuch as DKD onset and progression maybemore amenable to prevention in short-rather than long-duration diabetes. Onthe other hand, patients with type 1 di-abetes in the intensive arm of DiabetesControl and Complications Trial (DCCT)/Epidemiology of Diabetes Interventionsand Complications (EDIC) had reductionsin both albuminuria and their risk for de-veloping CKD (defined as a sustainedeGFR,60 mL/min/1.73 m2) (24).The NKDEP Laboratory Working

Group and the National Institute ofStandards and Technology standardizedthe laboratory measurement of creati-nine and are now collaborating with theInternational Federation of ClinicalChemistry and Laboratory Medicine tostandardize the laboratory measure-ment and reporting of urine albumin.Reference methods and referencematerials have been developed andare undergoing additional validation.However, even with standardization ofserum creatinine and urine albuminmeasurements, residual imprecision ofthese biomarkers makes it likely thatimproved predictive tools will incorpo-rate other biomarkers and patient char-acteristics. Until validated algorithms are

available, clinicians are cautioned aboutpredicting prognosis based on any singlemeasurement of a particular biomarker,such as albuminuria. Serial monitoring ofbiomarkers is likely to reduce confound-ing “noise” and establish a temporaltrend that may be more informative forprognosis. However, this approach hasbeen challenged by the American Col-lege of Physicians, which recommendedagainst monitoring albuminuria in pa-tients with or without diabetes who aretreated with RAAS antagonists (Grade:weak recommendation, low-quality evi-dence) (25).

It is clear that the relationship of albu-minuria to ESRD and CVD risk is a contin-uum, starting from “normal” levels ,30mg/g creatinine. In this regard, there hasbeen a trend to no longer refer to cate-gorical nomenclature of “microalbumin-uria” (30–300 mg/g creatinine) and“macroalbuminuria” (.300 mg/g creat-inine). Instead, reporting the urine albu-min level as a continuous variable (e.g.,albumin excretion rate of XX mg/24 h orACR of XX mg/g creatinine) may be pre-ferred. The Kidney Disease: ImprovingGlobal Outcomes (KDIGO) guidelineshave recently recommended a similarchange for assessing CKD in generalwith albuminuria reported as normal tomildly increased (up to 30 mg/g creati-nine), moderately increased (30–300mg/g creatinine), or severely increased(.300 mg/g creatinine) and framed inthe context of CKD stages 1 to 5 to de-termine risks (22).

Future Clinical Research

1. What are the reporting cutoffs for thedefinition of normal albuminuria andwhat is the proper nomenclature?

2. Should urine albumin results be re-ported as a continuous variable (i.e.,eliminate “macro,” .300 mg/g

creatinine, and “micro,” 30–300mg/g creatinine, prefixes)?

3. Should there be sex-specific cutoffsthat identify patients at increasedrisk of CVD as well as of progres-sive DKD?

4. Is there a practical strategy forscreening patients that reduces in-traindividual variability in ACR?

5. Can algorithms be developed to pre-dict risk for progressive DKD, andwhich factors must be incorporated(e.g., eGFR, albuminuria, rate ofchange in eGFR or albuminuria, BP,new biomarkers)?

6. What is the role of albuminuria mon-itoring in guiding therapy?

7. Is there a strategy to target aggres-sive management on those patientsat greatest risk of progressive DKD(e.g., patients on single-agent RAASblockade and a rapidly decliningeGFR of .5 mL/min/year)?

8. Can albuminuria be the primary endpoint in clinical trials to establish anevidence base for ongoingmonitoring?

CVD AND MANAGEMENT OFDYSLIPIDEMIA

Cardiovascular Risks of DKDAmong patients with diabetes, thosewith kidney disease are consistently ob-served to have substantially elevatedmortality rates (26). Much of this mor-tality is due to CVD, although noncardio-vascular mortality is also increased.Albuminuria and eGFR are indepen-dently and additively associated withincreased risks of CVD events, CVD mor-tality, and all-cause mortality (26). Bothdiabetes and CKD have been observedto have incidence rates of CVD eventssimilar to patients with established cor-onary heart disease, leading to recom-mendations that patients with diabetes,CKD, or both should be treated for pre-vention of CVD as if they had alreadyexperienced such an event (27). Inboth type 1 and 2 diabetes, cohort stud-ies suggest that increased risks of mor-tality and CVD are limited to patientswho have evidence of DKD, and patientswith normal levels of albuminuria andeGFR have risks similar to the generalnondiabetic population (28–30). Theseobservations suggest that treatmentstrategies focused on mitigating thehigh CVD risk of patients with DKDshould be a high priority for improvingdiabetes outcomes.

Table 2—Other cause(s) of CKD should be considered in the presence of anyof the following circumstancesc Absence of diabetic retinopathy;

c Low or rapidly decreasing GFR;

c Rapidly increasing proteinuria or nephrotic syndrome;

c Refractory hypertension;

c Presence of active urinary sediment;

c Signs or symptoms of other systemic disease; or

c.30% reduction in GFR within 2–3 months after initiation of an ACE inhibitor or ARB.

Reproduced with permission from NKF (4).

care.diabetesjournals.org Tuttle and Associates 2867

While DKD may be in part a markerof systemic end-organ damage of di-abetes, abundant evidence suggeststhat DKD may contribute to the path-ogenesis of CVD. DKD may promoteCVD through a number of pathways,including atherosclerosis, myocardialhypertrophy, cardiac fibrosis, and me-dial artery calcification, leading tomyocardial infarction, stroke, conges-tive heart failure, sudden cardiac ar-rest, and peripheral vascular disease.The mechanisms through which DKDmay promote CVD include augmenta-tion of traditional cardiovascular riskfactors (e.g., hyperglycemia, hypogly-cemia, volume regulation and hyperten-sion, lipoprotein metabolism, systemicinflammation, oxidative stress, and endo-thelial dysfunction) and initiation ofmechanisms that are more specific to kid-ney disease (e.g., accumulation of smallmolecule toxins, anemia, and disorderedmineral metabolism). Moreover, thepresence of CKD may alter the risksand benefits of existing therapies target-ing CVD in diabetes, including bloodglucose control, BP control, lipid thera-pies, antiplatelet therapies, and coronaryrevascularization.

Dyslipidemia in DKDDKD is accompanied by abnormalitiesin lipid metabolism related to declinein kidney function that varies depend-ing on CKD stage. While LDL choles-terol is an established risk factor forCVD in the general population, itsprognostic value appears to be less inthose with CKD due to DKD or othercauses (31). The magnitude of reduc-tion in cholesterol levels in the CKDpopulation (including those who aredialysis-treated) with statin therapy issimilar to that in those with preservedkidney function (32). Clinical trials innondialysis-dependent CKD suggest thatCVD events and mortality are reducedwith statins and statins/ezetimibe com-pared with placebo (32). The beneficialeffects do not seem to be modified bythe presence or absence of diabetes.While the CVD benefits of statins arewell established, statins did not alterkidney disease progression in thosewith preexisting CKD (33). Thus, as rec-ommended by the recently releasedKDIGO guidelines, statins are recom-mended for all diabetic patients withnondialysis-dependent CKD (34). It

also recommends specific dosage forvarious statins in CKD population basedon the dose used in the clinical trials(34). While dose titration is not recom-mended, follow-up measurements could,at a minimum, help assess adherence tostatin therapy.

Clinical trials examining statins inthe dialysis population consistentlyshow no CVD or survival advantage,precluding recommendations for initi-ation of statins in dialysis patients.However, it is appropriate to considercontinuing statin therapy in those whoprogress to treatment by chronic dial-ysis. Among kidney transplant recipi-ents, an extension of the Assessmentof Lescol in Renal Transplantation(ALERT) trial showed CVD benefit sup-porting statin use in this population(35). A meta-analysis examining datafrom over 50 trials (elevated creatinekinase levels, abnormal liver functiontests, withdrawal from studies due toany adverse events) supports the safetyof statins in CKD (32). Doses of statinsused in clinical trials of CKD populationscan be reasonably applied in prac-tice. Despite the beneficial effects ofstatins, a significant proportion of theCKD population suffers from CVDevents, providing an opportunity forstudy of other strategies to reducerisk. While post hoc analyses of clinicaltrials using fibrates in the general pop-ulation showed benefits on CVD risk inthe CKD (eGFR 30–59 mL/min/1.73 m2)population, further studies are war-ranted before widespread use of theseagents in CKD is recommended (36).Another conundrum is that fibratesmay elevate serum creatinine by ef-fects independent of clearance by thekidneys, thus confounding eGFR esti-mates (37).

Future Clinical Research

1. How shouldwe tailor existing commontreatments for CVD risk reduction inthepresenceofDKD to increase safety,efficacy, or both?

2. Does follow-up measurement ofplasma lipids after the initiation of astatin further reduce CVD risk in DKDby enhancing adherence, facilitatingdose titration, or leading to the addi-tion of other lipid-lowering agents?

3. Are there novel kidney-specific ther-apies that can be used to mitigateexcess CVD risk in DKD?

HYPERTENSION AND USE OF RAASBLOCKADE AND MR BLOCKADE

HypertensionBased on the most recent Joint NationalCommittee (JNC) 8 and KDIGO guidelines,BP levels in diabetes are recommended tobe below 140/90 mmHg (38,39) in orderto reduce CVD mortality and slow CKDprogression. The support for these BPlevels is derived from a limited numberof randomized trials among patientswith diabetes with a focus on CVD eventoutcomes. However, there are no ran-domized controlled trials of BP levelsthat examine CKD events. The data thatsupport the BP level of ,140/90 mmHgto slow CKD progression come exclusivelyfrom three randomized trials of non-DKDthat include a participant mix of predom-inantly African Americans with hyperten-sive nephropathy, patients with IgAnephropathy, and patients with CKDwithout a specific diagnosis (40).

The relevance of this recommenda-tion has been called into question basedon data from 24-h BPmonitoring studiesthat identified masked hypertensionand failure of nocturnal dipping as con-founders for the relationships betweenBP levels and CKD progression (41).There is a need for future studies toinclude a nested cohort, or subset ofpatients within a larger clinical trial,with an ambulatory BP monitoring eval-uation. In this way, more completeinformation can be provided to inter-pret the effects of BP levels on clinicaloutcomes.

Another notable area that needsclose consideration is monitoring of di-astolic blood pressure (DBP) when treat-ing SBP in those with DKD. While thereare insufficient data to guide a lowerlimit for SBP in DKD, there is an adversesafety signal in clinical trials when DBP istreated to below 70 mmHg, and partic-ularly below 60 mmHg, especially inolder populations (42). Data from pa-tients with stage 3 or later CKD demon-strate that DBP,60mmHg is associatedwith higher incident rates of ESRD (43),while other studies in those withoutCKD found that ,65 mmHg and/or 70mmHg are associated with poor CVDoutcomes (44). Data from the ongoingSystolic Blood Pressure InterventionTrial (SPRINT) will likely provide furtherinformation on lowDBP in the context oftreating to a target SBP of 120 mmHg in

2868 Consensus Report Diabetes Care Volume 37, October 2014

CKD, although it should be noted thatthe trial does not include people withdiabetes (45).

RAAS BlockadeIt is clear from a body of clinical trial datathat interruption of the RAAS with ei-ther inhibition of the ACE or angiotensinreceptor blocker (ARB) contributes toreductions in kidney disease events inthose with stage 3 or later CKD whohave severely increased albuminuria(previously termed “macroalbumin-uria”), hypertension, and diabetes (46–48). Recently, there has been intensefocus on whether combinations of theseagents could further improve outcomesin DKD. To the contrary, data from stud-ies testing this hypothesis found serioussafety concerns, with two clinical trialsbeing stopped prematurely due to risksof hyperkalemia and/or acute kidneyinjury as well as for futility, althoughthe trials were underpowered for theirprimary outcomes (CKD and/or CVDevents) at the time of termination(49,50). A considerable number of per-sons with DKD remain on RAAS combi-nation therapy after many years of usein routine practice despite the clinicaltrial findings (49–51). If the use ofagents for dual RAAS blockade is contin-ued for those with DKD, caution andclose monitoring for the status of serumpotassium levels and kidney functionare advised (52).

MR BlockadeThe incorporation of MR blockade incombination with other RAAS inhibitorsremains an area of great interest thathas been explored in several short-term studies with a positive effect onalbuminuria reduction in DKD (53).There was an increase in hyperkalemicepisodes in those on dual therapy (49),and larger trials are needed, especiallyin light of the safety concerns with dualRAAS blockade employing other agents.Newer, nonsteroidal MR blockers are inphase 2 trials for CKD. In the meantime,there are clinical trial data in patientswith systolic heart failure, with andwithout diabetes, showing a benefit ofeplerenone on CVD outcomeswith a lowrate of hyperkalemia in the subset withstage 3 CKD (54).CVD clinical trials of various RAAS in-

hibitors and/or their combinations havetypically excluded patients with stages

3b and 4 CKD. As a result, efficacy andsafety cannot be reliably assessed in themore advanced CKD subsets. The adventof new potassium binding agents suchas patiromer (a polymer) and ZS-9 (aninorganic crystal) may allow furtherexploration of combined RAAS thera-pies that previously were limited by con-cerns about hyperkalemia. However,combination RAAS blockade therapiesare also associated with an increased in-cidence of acute kidney injury and pos-sibly other ischemic complications and,thus, cannot be recommended for CVDprotection in people with CKD at pres-ent (49,50,52,55).

Emerging Antihypertensive TherapiesPhase 2 studies combining a selectiveendothelin receptor antagonist withRAAS therapy in DKD suggest that thismay be a potential strategy for targetingfurther reductions in BP and albuminuria(56). However, the effect of this combina-tion on CKD events remains to be deter-mined and should be tested (57).

Device therapies for BP control haverecently been the subject of intenseinterest. Renal denervation for BP reduc-tion in patients with resistant hyperten-sion has been intensively investigated(58,59). The latest clinical trial showedno benefit for BP control, and therefore,this approach to clinical management isnot recommended in general or in CKD(59). Baroreflex activation therapy showspromise but is still experimental and un-der development (60).

Future Clinical Research

1. Are combination therapies for thecontrol of BP safe and effective forreduction of kidney disease events inDKD?

2. Are MR blockade agents in the DKDpopulation safe and effective forreducing kidney disease or CVDevents?

3. Does combined RAAS inhibition withendothelin receptor antagonists re-duce kidney disease events in DKD?

GLYCEMIA MEASUREMENT,HYPOGLYCEMIA, AND DRUGTHERAPIES

Glycemia MeasurementA1C has limitations in the general popu-lation and is even less precise in the set-ting of DKD (61). In the typical 120-daylife cycle of a red blood cell, the A1C re-flects time-averaged exposure to glucose.

Accelerated red blood cell turnover is amajor cause of imprecision of A1C. Eryth-rocyte survival times become shorter aseGFR falls, resulting in lower A1C. Glyca-tion rate can also be influenced bytemperature, acid–base balance, and he-moglobin concentration (62). Onset ofanemia associated with advancing DKDis linked to deficiencies of iron, folate, anderythropoietin, each of which can influenceA1C levels. Therapy with erythrocyte-stimulating agents lowers A1C further,perhaps due to rapid changes in hemoglo-bin concentrations (63,64).

Patients with eGFR levels ,60mL/min/1.73 m2 are more prone to hy-poglycemia. The reasons behind this as-sociation are multifactorial but includethe prolonged action of hypoglycemicagents (particularly sulfonylureas andinsulin), alcohol intake, chronic malnu-trition, acute caloric deprivation, andthe deficiency of gluconeogenic precur-sors as kidney function declines. In theACCORD study, compared with patientswith normal kidney function, those withbaseline serum creatinine of 1.3–1.5mg/dL had a 66% increased risk of se-vere hypoglycemia (defined as hypo-glycemia requiring the assistanceof another person) (65). There is aU-shaped relationship between A1Cand mortality (Fig. 1), suggesting thathypoglycemia may be a reason forhigher mortality in those with A1C levels,6.5% (66–68). However, there areother potential etiologies for highermortality in this population with im-paired kidney function. While A1C levelsbetween 7–8% appear to be associatedwith the highest survival rates in retro-spective analyses of DKD patients,the imprecision of A1C measurementsmakes specific targets for people withDKD difficult to define. However, mea-surement of A1C should still be per-formed, as the trending of the levelscan assist in therapy decisions. Impor-tantly, an A1C that is low or trendinglower due to measurement imprecisionand/or a reduction in kidney functionmay be taken as an indication of im-proved glycemic control when it is not.Rather, it may be an ominous sign ofprogressive DKD.

Serum fructosamine has been pro-posed as an alternate glycemic bio-marker particularly in settings whereA1C is less reliable. While fructosaminegenerally reflects the previous 2 to 3

care.diabetesjournals.org Tuttle and Associates 2869

weeks of glycemia, it also reflects totalserum proteins that undergo glycation.Since the most abundant serum proteinis albumin, hypoalbuminemia will resultin low fructosamine levels. This is a ma-jor limitation in DKD patients. Similarly,serum levels of 1,5-anhydroglucitol, asugar alcohol from the diet, are lost inthe urinewith glucose and are dependenton the kidney’s tubular threshold forglucose reclamation. Since this processis maximal at a blood glucose level ofapproximately 180 mg/dL, it will belost in the urine in many diabetic pa-tients. In particular, this test is not rec-ommended for CKD stage 4 or 5 (69).Another emerging marker for glycemiais glycated albumin (GA), a ketoamineformed via nonenzymatic glycation ofalbumin reflecting average glycemiaover 2 to 3 weeks. Unlike A1C and other

glycemic biomarkers, GA is less affectedby low eGFR, anemia, or other con-founding conditions (70). Outcomestudies are limited, but initial data sug-gest GA is associated with mortality andhospitalization (71). However, GA is notclinically available in the U.S. Notably,there are no clinical outcome studiesassessing GA levels with microvascularor macrovascular complications in dia-betes, and the relationship betweenGA and A1C is not linear. Therefore, GAlevels cannot be extrapolated to cor-responding A1C levels to assess risks ofcomplications. Data are scant for contin-uous glucose monitoring (CGM) in peo-ple with either type 1 or 2 diabetes andlow eGFR. However, given the high riskof hypoglycemia in this population,CGM is a potential tool for glycemicmonitoring.

Given the limitations of the most fre-quently used glycemic biomarker, A1C,and the high risk of hypoglycemia, specificdecisions on therapy should be based onself-monitoring of blood glucose (SMBG).Specific glycemic targets must considerovertreatment as well as undertreatmentof blood glucose. Both preprandial andpostprandial glycemic targets need tobe individualized based on a patient’sknowledge and drug regimen, especiallyif it includes insulin. Blood glucose testingsupplies need to be available in adequatequantities to allow sufficient monitoringto achieve therapeutic goals.

Drug Therapies

Hypoglycemia

Risk of hypoglycemia is increased in peo-ple with DKD when the eGFR is ,60mL/min/1.73 m2. This is partly due todecreased clearance of hypoglycemicagents and decreased gluconeogenesisby the kidney (72,73). Accordingly, doseadjustments are required for many hy-poglycemic agents when used in peoplewith DKD (Table 3). Insulin clearance de-creases in parallel with a decline in eGFR(73–75). As is true with insulin use ingeneral, frequent SMBG and appropri-ate patient-specific dose titration arecritically important to achieve individualtreatment goals and avoid hypoglyce-mia (73–75). Once patients are initiatedon chronic dialysis treatment, exoge-nous insulin requirements often declinedue to reduced insulin resistance on theone hand and emergence of malnutritionon the other (76). It should also bepointed out that older patients withDKD tend to progress to ESRD less com-monly than younger patients (77), largelydue to the competing risk of death fromCVD (78). Older individuals also are atgreater risk for hypoglycemia and for ad-verse consequences from hypoglycemia(79,80). Thus, greater care to avoid hypo-glycemia is needed in the older patientwith CKD and less stringent A1C targetsof treatment are recommended (81).

Metformin

Metformin use is contraindicated, percurrent U.S. Food and Drug Administra-tion (FDA) prescribing information, inmen with a serum creatinine $1.5mg/dL and in women with a serum cre-atinine$1.4 mg/dL. Metformin shouldalso be used cautiously in patients withconditions that interfere with the me-tabolism and excretion of lactic acid,

Figure 1—Risk of mortality in patients with diabetes and ESRD. A: Risk of mortality by initial A1C,adjusted for age, sex, race, BMI, years of dialysis, albumin, creatinine, 10 comorbid conditions,insulin use, hemoglobin, HDL cholesterol, country, and study phase. B: Risk of mortality by meanA1C, adjusted for age, sex, race, BMI, years of dialysis, albumin, creatinine, 10 comorbid con-ditions, insulin use, hemoglobin, HDL cholesterol, country, and study phase. Reproduced withpermission from ADA (68).

2870 Consensus Report Diabetes Care Volume 37, October 2014

such as heart failure and liver disease,and during acute illness and/or instancesof tissue hypoxia (82,83). Althoughlactic acidosis occurs in people withdiabetes regardless of metformin use,the role of metformin per se in lacticacidosis is controversial at best. How-ever, metformin may predispose to lac-tic acidosis in the event of seriousintercurrent illness (84). Despite theseconcerns and published case reports(85), current data indicate the overall

risk of metformin-associated lactic aci-dosis is low (86,87). It has been sug-gested that eGFR may be a moreappropriate measure to assess contin-ued metformin use considering thatthe serum creatinine level can trans-late into widely varying eGFR levels de-pending on race, age, and muscle mass(73). In turn, a recent reviewproposedmet-formin use should be reevaluated at aneGFR,45 mL/min/1.73 m2 with a reduc-tion in maximum dose to 1,000 mg/day

and discontinued when ,30 mL/min/1.73 m2 (Table 4) (83). However, metfor-min should be discontinued in situationsthat are associated with a high risk ofacute kidney injury, such as sepsis, hypo-tension, acute myocardial infarction, anduse of radiographic contrast or othernephrotoxic agents.

Sulfonylureas and Glinides

Sulfonylurea use in CKD requires carefulattention to dosing to avoid hypoglycemia

Table 3—Recommended dose adjustments for noninsulin antihyperglycemic agents in DKD

Medication In patients with impaired GFR In dialysis patients

BiguanidesMetformin U.S. prescribing information states “do not use if serum

creatinine $1.5 mg/dL in men, $1.4 mg/dL in women”Contraindicated

British National Formulary and the Japanese Society ofNephrology recommend cessation if eGFR,30 mL/min/1.73 m2

Second-generation sulfonylureasGlipizide No dose adjustment required No dose adjustment requiredGlimepiride Initiate conservatively at 1 mg daily Initiate conservatively at 1 mg dailyGlyburide Avoid use Avoid use

MeglitinidesRepaglinide Initiate conservatively at 0.5 mg with meals if eGFR

,30 mL/min/1.73 m2No clear guidelines exist

Nateglinide Initiate conservatively at 60 mg with meals if eGFR,30 mL/min/1.73 m2

No clear guidelines exist

TZDsPioglitazone No dose adjustment required 15–30 mg daily has been used (190)

a-Glucosidase inhibitorsAcarbose Avoid if eGFR ,30 mL/min/1.73 m2 Avoid useMiglitol Avoid if eGFR ,25 mL/min/1.73 m2 Avoid use

GLP-1 receptor agonistsExenatide Not recommended with eGFR ,30 mL/min/1.73 m2 Avoid useLiraglutide Not recommended with eGFR ,60 mL/min/1.73 m2 Manufacturer does not recommend

use (currently under study)Albiglutide No dose adjustment required No clear guidelines existdlimited clinical

experience in severe impairment ofkidney function

DPP-4 inhibitors

Sitagliptin 100 mg daily if eGFR .50 mL/min/1.73 m2 25 mg daily

50 mg daily if eGFR 30–50 mL/min/1.73 m2

25 mg daily if eGFR ,30 mL/min/1.73 m2

Saxagliptin 5 mg daily if eGFR .50 mL/min/1.73 m2 2.5 mg daily

2.5 mg daily if eGFR #50 mL/min/1.73 m2

Linagliptin No dose adjustment required No dose adjustment required

Alogliptin 25 mg daily if eGFR .60 mL/min/1.73 m26.25 mg daily

12.5 mg daily if eGFR 30–60 mL/min/1.73 m2

6.25 mg daily if eGFR ,30 mL/min/1.73 m2

AmylinomimeticsPramlintide No dose adjustment required with eGFR

.30 mL/min/1.73 m2Avoid use

Not recommended with eGFR ,30 mL/min/1.73 m2

SGLT2 inhibitorsCanagliflozin No dose adjustment required if eGFR$60 mL/min/1.73 m2 Avoid use

100 mg daily if eGFR 45–59 mL/min/1.73 m2

Avoid use and discontinue in patients with eGFR,45 mL/min/1.73 m2

Dapagliflozin Avoid use if eGFR ,60 mL/min/1.73 m2 Avoid use

care.diabetesjournals.org Tuttle and Associates 2871

(73). Glyburide is extensively metabolizedin the liver into several activemetabolitesthat are excreted by the kidney and is notrecommended for use in CKD (73,88). Gli-mepiride is associated with less hypogly-cemia when compared with glyburide(89). Glipizide is metabolized by the liverinto several inactive metabolites, and itsclearance and elimination half-life are notaffected by a reduction in eGFR (90), thusdose adjustments in patients with CKDare not necessary (91). Considering theinherent risk of hypoglycemia with sulfo-nylurea use, however, cautious use iswarranted even with glipizide. Similarto the sulfonylureas, the main concernwith repaglinide and nateglinide use inCKD is a potentially increased risk of hy-poglycemia. Conservative initial doses ofthese agents are recommended sincelower doses are typically needed in thispopulation (73,92,93).

Thiazolidinediones

The thiazolidinediones (TZDs) are nearlycompletely metabolized by the liver(94–96). Despite the lack of a need fordosage adjustments in patients withCKD, TZD use is generally avoided inCKD due to side effects such as refrac-tory fluid retention, hypertension, andincreased fracture risk (73,97).

a-Glucosidase Inhibitors

The a-glucosidase inhibitors, acarboseand miglitol, are minimally absorbedfrom the gastrointestinal tract, yetplasma levels can increase in CKD (76).Therefore, caution is advised for use ofthese agents in diabetic patients withlow eGFR (,30 mL/min/1.73 m2) (73).

Incretins

The prescribing information for exena-tide recommends discontinuation withan eGFR,30 mL/min/1.73 m2. The kid-neys are not a major pathway of elimi-nation for liraglutide; however, its use is

not recommended with an eGFR ,60mL/min/1.73 m2 due to a current lackof data in this population. GLP-1 recep-tor agonist use has been associated withpostmarketing reports of decreased kid-ney function (98), yet such toxicity hasnot been observed in clinical trials orpopulation-based observational studiesto date (99–102). The majority of casereports of decreased kidney functionwith exenatide have involved at leastone contributory factor such as conges-tive heart failure, pancreatitis, infection,and/or the use of concomitant medica-tions such as diuretics, RAAS inhibitors,and nonsteroidal anti-inflammatorydrugs (98).

The dipeptidyl peptidase-4 (DPP-4)inhibitors have potential advantages inpeople with CKD as they are associatedwith a low risk of hypoglycemia and areweight-neutral (103,104). All of the cur-rently available DPP-4 inhibitors can beused in CKD, but sitagliptin, saxagliptin,and alogliptin require downward dosetitration based on eGFR (105–108). Lina-gliptin, in contrast, does not requiredose adjustment based on kidney func-tion (109,110). A meta-analysis hasshown that DPP-4 inhibitors appear tobe especially effective in Asian people(111).

Sodium-Glucose Cotransporter 2 Inhibitors

There are currently two sodium-glucosecotransporter 2 (SGLT2) inhibitors avail-able in the U.S.dcanagliflozin and dapa-gliflozin. SGLT2 inhibitors improveglycemia by increasing disposal of glucosevia the urine (112). Dapagliflozin is notrecommended for use with an eGFR,60mL/min/1.73m2 as glycemic efficacyis negligible (113). Canagliflozin is recom-mended to be used at a reduced dose of100 mg/day with an eGFR of 45–59mL/min/1.73m2 and is not recommendedwith an eGFR ,45 mL/min/1.73 m2.

SGLT2 inhibitors have been associatedwith an initial slight decrease in eGFR inclinical trials (114). This decrease in eGFRmay be a hemodynamic effect to de-crease glomerular hyperfiltration be-cause eGFR trends back toward baselinewith continued treatment (114,115).However, longer-term follow-up in largergroups of patients with diabetes and CKDis needed to confirm safety for kidneydisease and other outcomes.

Future Clinical Research

1. What is the relationship between es-timated average glucose and A1C andGA for individuals with advanced-stage CKD?

2. Can CGM improve our understandingof the frequency and impact of hypo-glycemia in DKD?

3. What are ideal targets for glycemiabased on biomarkers and direct glu-cose monitoring in DKD?

4. In a comparative effectiveness study,what is the effect of using differentinsulin and noninsulin regimens inpatients with diabetes and CKD onglycemic control and hypoglycemicevents?

NUTRITION AND GENERAL CARE INADVANCED-STAGE CKD

Nutritional TherapyFor the goals of reducing DKD onset andprogression, approaches to nutritionaltherapy are a subject of much debate.Extensive discussion of dietary manage-ment in diabetes and obesity is beyondthe scope of this review. Instead, thefocus is on extremes of macronutrientintake that have been associated withadverse outcomes, followed by assess-ment of concepts for healthful eatingthat is supported by clinical evidencerelevant to DKD. It is well recognizedthat very low2protein diets can leadto protein malnutrition (116). Con-versely, excessive protein intake is asso-ciatedwith increased albuminuria, morerapid kidney function loss, and CVDmor-tality (117–121). Likewise high-fat diets,defined as more than 30% of total calo-ries, exacerbate hyperlipidemia and,therefore, can be inferred to increaseCVD risk. An increasing body of evidencesuggests that dietary pattern intakerather than a sole focus on individualnutrients may offer a more practicalapproach to dietary management ofchronic diseases (122–124).

Table 4—Recommended dose adjustments for metformin based on eGFR

eGFR (mL/min/1.73 m2) Proposed action

$60 No contraindication to metforminMonitor kidney function annually

,60 and $45 Continue useIncrease monitoring of renal function (every 3–6 months)

,45 and $30 Prescribe metformin with cautionUse lower dose (e.g., 50%, or half-maximal dose)Closely monitor renal function (every 3 months)Do not start new patients on metformin

,30 Stop metformin

Adapted with permission from ADA (83).

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Dietary Protein and DKD

Both quantity and quality of protein andamino acids have been identified to beimportant for maintenance of adequatenutritional status in CKD, whether re-lated to diabetes or other causes (125).Identification of optimal dietary proteinintake is further complicated in DKD bythe fact that kidney disease confersunique metabolic abnormalities thatcan include alterations in mineral me-tabolism, metabolic acidosis, anemia, vi-tamin D deficiency, loss of lean musclemass, and susceptibility to malnutrition.The relationship of dietary protein toDKD prevention and progression hasbeen widely debated for many years.Nutritional studies are inherently diffi-cult to conduct and are subject to nu-merous limitations such as variablecomposition and adherence for studydiets, multiple nutrients changed, dif-ferent outcome measurements for kid-ney disease, small sample sizes, andshort duration of studies.Dietary protein reduction has pro-

duced variable findings across clinicaltrials(126–133).Theeffectsofalow-protein(daily intake of 0.6 g protein/kg idealbody weight), low-phosphorus (500–1,000 mg/day) diet were comparedwith those of a control diet containing$1.0 g protein/kg ideal body weight perday and$1,000 mg phosphorus per dayin 35 patients with type 1 diabetesand DKD. Study participants on the low-protein, low-phosphorus diet had aslower rate of decline in iothalamate GFRover the course of the study. Anotherstudy (134) evaluated a reduced-proteinversus a usual-protein diet in 82 patientswith type1diabetes andprogressiveDKDover 4 years. Actual protein intake duringthe follow-upperiodwas0.89g/kg/day inthe reduced-protein group and 1.02 g/kg/day in the usual-protein group. ESRDor death occurred in 10% of patients onthe reduced-protein diet versus 27% ofpatients on the usual-protein diet (P 50.042). The relative risk of death orESRD after baseline adjustment for CVDand diabetes risk factors was 0.23 for pa-tients on the reduced-protein diet (P 50.01).Ameta-analysisofnutritionstudiesevaluated 13 randomized controlled clin-ical trials and reportedanoverall effectofreduced-protein intake to slow GFR de-cline that was greater in diabetic thannondiabetic participants with evidenceof a greater effect over time. To the

contrary, similarbenefits ofa low-proteindiet were not observed in 69 patientswith either type 1 (n5 32) or type 2 (n537) diabetes and moderately to se-verely increased albuminuria on a low-protein (0.6 g/kg/day) diet or a “free”(nonstandardized) protein diet for 12months (116). Other studies and meta-analyses have also reported negativeresults (127,135). However, there aremany limitations of the previous studies,including combining type 1 and type 2 di-abetic patients with varying stages ofCKD, inconsistent concurrent manage-ment strategies (e.g., RAAS blockers),small sample sizes resulting in lack of sta-tistical power, varying durations of in-tervention, lack of identification anduniformity of protein sources (e.g., plantversus animal) and other dietary compo-nents (fats, carbohydrates, phosphorus,and sodium), and incomplete assessmentof dietary adherence.

Despite ongoing controversy, NKFKDOQI (4), KDIGO (22), and the ADA(20) provide clinical guidelines for die-tary management of diabetes and CKD(4,20,22,136). The NKF KDOQI ClinicalPractice Guidelines and Clinical PracticeRecommendationsforDiabetesandChronicKidney Disease recommend a targetprotein intake of 0.8 g/kg body weightper day (the recommended daily allow-ance) for nondialysis-dependent DKD(Grade B evidence) (4). KDIGO 2012 Clin-ical Practice Guideline for the Evaluationand Management of Chronic KidneyDisease also suggests a dietary proteinintake of 0.8 g/kg/body weight per dayin adults with diabetes and GFR ,30mL/min/1.73 m2 with appropriate nutri-tional education (Grade 2c evidence)(22). The ADA recommends “usual” (nothigh) dietary protein intake (Grade Aevidence) (136). Both NKF KDOQI andKDIGO guidelines recommend avoidanceofhigh levels of protein intake, definedasmore than 20%of kcal fromprotein (4) or.1.3 g/kg/day of protein for individualswith CKD (22). Table 5 summarizes theserecommendations along with those forother macronutrients for DKD.

Carbohydrates and Fats

Whole-grain carbohydrates and fiberand fresh fruits and vegetables are rec-ommended as part of a healthy diet forindividuals with DKD (125,136). Thenumber of portions and specific foodselections from these food groups often

need to be limited in advanced stagesof CKD due to the potassium and phos-phorus loads imposed by these foods(125). Carbohydrates are an importantcomponent of lower-protein calories.Whether a change in carbohydratefood selections will result in improve-ment in DKD outcomes is not known.

There is a growing body of literaturesuggesting beneficial effects of omega-3fatty acids on albuminuria in DKD(137,138). However, definitive conclu-sions to support dietary recommenda-tions are not yet available. The generalrecommendation for DKD is to includeomega-3 and omega-9 fatty acids as partof total dietary fat intake while decreas-ing intake of saturated fats and foodsources of trans fatty acids (4).

Sodium

Dietary sodium reduction in individualswith CKD has been shown to reduce BPirrespective of diabetes status. The rec-ommended range of dietary sodium in-take for individuals with kidney diseaseis 1,500–3,000 mg/day (Table 6). Toaccomplish this lower level of sodiumintake, nutrition recommendations in-clude increasing dietary intake of freshcooked foods and reducing intake of fastfoods and highly processed food prod-ucts (125,136).

Examining Dietary Patterns of Intake

Recent approaches to managing DKDapply dietary patterns that incorporatethe above principles within whole diets.Both the Mediterranean (122) and Die-tary Approaches to Stop Hypertension(DASH) diets (123) comprise an en-hanced intake of whole-grain (complex,unrefined) carbohydrates, fruits, vege-tables, and plant proteins, includingnuts, seeds, and beans. Although fish isincluded in these diets, intake of otheranimal proteins and whole-fat dairyproducts is decreased compared withthe Western diet (124). The Mediterra-nean diet also incorporates olive oil andred wine. Focusing on dietary patternsin conjunction with principles of healthylifestyle management is a progressiveapproach to dietary management ofDKD. Whether a healthy diet patternwill affect albuminuria, DKD progres-sion, CVD outcomes, or weight manage-ment is unclear. However, the currentWestern dietary pattern, enriched in an-imal protein, fat (total and saturated),sodium, sugar, and calories, is strongly

care.diabetesjournals.org Tuttle and Associates 2873

associated with many chronic diseasesand exacerbation of risk factors (i.e.,hypertension, obesity, CVD) (124). Pat-terns of eating that have been associ-ated with improvement in BP, weight,other risk factors, and overall diseaseprevention can be incorporated into adiet for individuals with DKD (Table 6).It is important that individuals achieveand maintain adequate nutritional in-takes of nutrients as well as a healthyBMI to enhance risk reduction and pro-mote overall health.

General Care in Advanced-Stage CKDGiven the inherently progressive natureof CKD, people with DKD, if they survivethrough other complications of diabeticmacro- andmicrovascular disease, oftenexperience the advanced stages of CKDwith their eGFR reaching values ,30mL/min/1.73 m2 (139). Kidney replace-ment therapy will be needed for thesepeople to survive the ravages of uremiawith a progressive worsening of kidney

function. This section will briefly reviewcertain, but not all, aspects of advancedDKD. How the choice of modality oftreatmentdhemodialysis, peritonealdialysis, and transplantationdis madeis beyond the scope of this discussion.

Type 2 diabetes is the leading cause ofESRD in the U.S. and many countriesglobally. Approximately half of the en-tire 450,000 dialysis patients in the U.S.have ESRD secondary to type 2 diabetes(140). These patients have a high prev-alence of comorbid conditions, a highrate of hospitalization, a low health-related quality of life, as well as an exces-sively high mortality rate (15–20% peryear), mostly because of CVD events(140). Observational studies in dialysis pa-tients, including those with type 2diabetes, have indicated the lack of asignificant association between tradi-tional CVD risk factors and mortality.The existence of a paradoxical or re-verse association in which obesity,

hypercholesterolemia, and hyperten-sion appear to confer survival advan-tages has been described (141,142).The time discrepancy between the com-peting risk factors, i.e., overnutrition(long-term risks) versus undernutrition(short-term risks), may explain the over-whelming role of protein-energy wast-ing, inflammation, and cachexia incausing this so-called reverse epidemi-ology (143–146). Other comorbidities ofadvanced stages of CKD, such as second-ary hyperparathyroidism, appear tohave similar associations in diabeticand nondiabetic patients for complica-tions, health care costs, and survival(147).

Glycemia and Mortality Risk in Dialysis

Patients

The role of improved glycemic control inameliorating the exceedingly highmortal-ity risk of dialysis treatment and diabetesis unclear. The treatment of hyperglyce-mia in dialysis patients is challenging,

Table 5—Macronutrient recommendations in DKD

OrganizationLower ranges of

dietary protein intakeHigher ranges of

dietary protein intake Carbohydrate Fatty acids Sodium

KDIGO 2012 ClinicalPractice Guidelinefor the Evaluationand Management ofChronic KidneyDisease (22)

0.8 g protein/kg/dayin adults withdiabetes and GFR,30mL/min/1.73m2

with appropriateeducation

Avoid protein intake.1.3 g/kg/day inadults with CKD atrisk for progression;specific commentfor DKD notprovided

Specificrecommendationnot provided

Specificrecommendationnot provided

Lower salt intake to,2 g of sodium perday (5 g of sodiumchloride), unlesscontraindicated

KDOQI 2007 ClinicalPractice Guidelinesand Clinical PracticeRecommendationsfor Diabetes andChronic KidneyDisease (4)

Recommended dietaryallowance of 0.8 g/kg body weight perday for people withDKD and CKD stages1–4

Avoid high-proteindiets defined as$20% of total dailycalories

Specificrecommendationnot provided

Increase intake ofomega-3 andomega-9 fatty acids

Reduction of intake2.3 g/day asrecommended bythe DASH diet

ADA Standards ofMedical Care inDiabetesd2014 (20)and NutritionTherapyRecommendationsfor the Managementof Adults WithDiabetes (136)

Maintain usual level ofdietary proteinintake (136);approximated byreported studiessurveying dietintake in peoplewith diabetes to beapproximately16–18% of totalcalories (20)

Specific comment notprovided

Specificrecommendationfor DKD notprovided. Fordiabetes, includecarbohydrates fromvegetables, fruits,whole grains,legumes, and dairyproducts overintake fromcarbohydratescontaining addedsugar, fat, andsodium. Avoidbeverages,products with high-fructose corn syrup,and sucrose

Total fat:individualized

Specificrecommendationfor DKD notprovided

Omega-3: samerecommendationas for generalpublic. Cholesterol,saturated, transfats: same as forgeneral public

For individuals withdiabetes, reducesodium to ,2,300mg/day asrecommended forthe general publicMono- and

polyunsaturatedfats: integrated tocomment regardingpotential benefitsof a Mediterraneandiet pattern

2874 Consensus Report Diabetes Care Volume 37, October 2014

given changes in glucose homeostasis,the questionable accuracy of glycemiccontrol metrics, and the altered pharma-cological properties of glucose-loweringdrugs by kidney dysfunction, the uremicmilieu, and the dialysis procedure, as pre-viously discussed. Up to one-third of di-alysis patients with type 2 diabetesexperience falling glucose levels withA1C levels ,6%. The causes and clinicalimplications of this observation have notbeen determined, although undernutri-tion and limited substrate availabilityare likely operative (139,148–150).

Conventional methods of glycemic con-trol assessment are confounded by thelaboratory abnormalities and comor-bidities associated with kidney failure.Similar to more recent approaches inthe general population, there is concernthat intensive glycemic control regi-mens aimed at glucose normalizationmay be harmful in diabetic dialysis pa-tients. There is uncertainty surroundingthe optimal glycemic target in this popu-lation, although recent epidemiologicdata suggest that A1C ranges from 6–8% to 7–9% are associated with better

survival rates (151). This associationexists in both hemodialysis (152,153)and peritoneal dialysis patients withdiabetes (154). Pretransplant glycemiccontrol is also associated withposttransplant outcomes in kidneytransplant recipients with diabetes(155).

New-Onset Diabetes After Transplantation

A clinically important and unique condi-tion is the development of new-onsetdiabetes after transplantation (NODAT)(156). NODAT is defined as persistence

Table 6—Approaches to incorporating diet patterns for diet management of DKD for type 1 and type 2 diabetes*

Nutrient Concept How? What? Quantity

Protein Explore/sampleplant proteins

Incorporate vegan proteinsources into meal plan, de-emphasize intake of fattyanimal protein sources suchas marbled red meats,poultry products with skin,shellfish

Dried beans and peas Amount to maintain optimalglycemic control, astolerated; maintain orobtain optimal nutritionalstatus

Dairy products: emphasizenonfat and low-fat versionsin diet, sample nondairymilk products

LegumesNuts and seedsSoyQuinoaNonfat yogurts, milks, lower-fat cheese selections

Include almond, rice, soy milk

Carbohydrates:complex

Explore/sample Include high-fiber, whole-grain products,de-emphasize refined whiteflour2based products

Whole/mixed-grain breads,pastas, cereals; wild, brownrice types

Within carbohydratecounting/diabetesmanagement plan, astolerated

Fruits andvegetables

High-fiber fruits/vegetables Include as part of meals snacksand different formats suchas smoothies

Fresh fruits and vegetables ofchoice, fresh cookedvegetables ideal, precookedchoices available withoutseasonings

6–8 servings per day asappropriate for meal planand carbohydrate counting

Fat Omega-9 and omega-3 fattyacids as a component offat source

Enrich diet with olive oil, fishoil, and vegetarian sourcesof omega-3 fatty acids, de-emphasize saturated fatsources and genericvegetable oils that areenriched in omega-6 fattyacids

Include olive oil/canola oil2based margarines and fats,choose omega-3–enrichedwhole-grain breads andcereals when available

Within meal plan for caloriesand palatability

Sodium Maximize approaches tolower sodium and saltintake

Reduce free salt use Use sodium-free fresh anddried herbs, spices, andherbal blends, whenavailable

1,500–3,000 mg daily;transition toward lowerrange of intake

Use fresh cooked foods,purchase unseasonedoptions of foods, putsauces/flavorings on side

Weightmanagement

If overweight, work on weightreduction

Decrease calories, increasecalorie utilization througha regular exercise program,avoid excessively high-protein diets (i.e., .20%kcal from protein)

Balanced proportions ofprotein, carbohydrate, andfat within individualizedapproach to maintaineuglycemia

Based on individuallydetermined ideal/healthybody weight, gradualweight loss toward goal toallow for altered eatingpattern, ongoingmodifications in diet asweight goal approachedand glycemia managementis modified

*Inclusion of vegan protein sources, complex carbohydrates, and increased intake of fruits and vegetables may increase serum levels ofpotassium and phosphorus in later stages of eGFR (i.e., GFR ,30 mL/min/m2). Serum levels of these minerals will need to be monitored inthose individuals.

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of hyperglycemia (meeting criteria fordiabetes) beyond initial hospitalization

in transplanted patients without preex-

isting diabetes and occurs in 15–25% of

patients who undergo organ transplan-

tation (156,157). Immunosuppressive

regimens including steroid and calci-

neurin inhibitors, in particular tacroli-

mus, have been implicated in thedevelopment of NODAT (156). Calci-neurin inhibitors may lead to pancreaticcell apoptosis with resultant decline ininsulin secretion, or they may also in-terfere with the calcineurin/nuclearfactor of activated T-cell pathway,leading to distortion of the skeletalmuscle glucose uptake (157). Post-transplant increases in appetite andweight gain may also play a role inthe development of NODAT. NODATindependently increases the risk ofcardiovascular events and infectionsand shortens kidney allograft longev-ity and patient survival (158). Judi-cious glycemic control and otherpreventative and management strate-gies have been suggested, includingresting the pancreatic b-cells by insu-lin administration during the periodimmediately after transplant and in-tensive lifestyle modification uponkidney transplantation to lower the in-cidence of NODAT (158).

Future Clinical Research

1. What are the effects of a Mediterra-nean diet and/or a DASH diet pattern

versus a conventional “diabetes

diet” on eGFR, albuminuria, and nu-

tritional status in individuals with

DKD?2. What is the comparative effect of an-

imal and plant protein sources oneGFR, albuminuria, and lipid profilesin DKD?

3. What is the impact of fatty acid sourcessuch as omega-3 versus omega-9 fatson eGFR, albuminuria, and CVD riskfactors in DKD?

4. What changes risks of adverse out-comes in ESRD patients with diabe-tes versus patients with earlier-stageCKD and diabetes?

5. Why do many dialysis patients expe-rience spontaneous resolution of hy-perglycemia?

6. How can NODAT be prevented andmanaged without shortening allo-graft or patient longevity?

CHILDREN AND ADOLESCENTS

Risks of Hypertension and DKDHistorically, it was assumed that diabe-tes complications primarily affectedadults with long-standing and/or poorlycontrolled disease and spared childrenwith recent-onset disease. A paucity ofclinical research in the pediatric popu-lation perpetuated this assumption.However, recent studies contradictthose tenets and paint a remarkably dif-ferent picture. The multicenter Treat-ment Options for Type 2 Diabetes inAdolescents and Youth (TODAY) studyprospectively evaluated the incidence,prevalence, and risk factors for develop-ing hypertension and increased albu-minuria in youth with early type 2diabetes (ages 10–17 years, ,2 yearsdiabetes duration, n 5 699). In the rel-atively short follow-up period (averagefollow-up 3.9 years), 33.8% had hyper-tension (11.6% at baseline) and 16.6%had moderately increased albuminuria(30–300 mg/24 h) (6.3% at baseline)(159). Hypertension in youth with type2 diabetes required multiple medica-tions and was refractory to treatment.In less than 4 years, the prevalence ofmoderately to severely increased albu-minuria tripled, with disease progres-sion rates in the youth (2.6% annualrate) similar to that seen in the UKPDSpopulation.

Cross-sectional studies in type 1 diabe-tes corroborate the TODAY findings. Themulticenter Adolescent Type 1 DiabetesCardio-Renal Intervention Trial (AdDIT)(n5 3,353, age 10–16 years) used ACR toassign risk: those in the highest tertilewere treatedwith ACE inhibitors and sta-tins, while those in the middle and lowertertiles were observed. Vascular mea-surements, kidney disease markers, andcardiovascular markers demonstratedthat youth in the highest tertile hadmore rapid decline in kidney and cardio-vascular function despite treatment;however, those in the lower-risk groupsalso showed evidence of endothelialdysfunction, suggesting that ACR is acontinuous risk factor for kidney andcardiovascular dysfunction (160).Another study in youth with type 1diabetes (age.11 years, mean 14 years;mean A1C 8.3%; .2-year duration,mean 6.3 years) found that 16.1%already had moderately increased

albuminuria, 30.3% had dyslipidemia,and 12.3% had hypertension (161).

Treatment of Hypertension and DKDThe KDIGO recommendations for chil-dren with CKD do not specifically ad-dress youth with DKD. However, sincethere are few data for treating youthwith DKD, following the general KDIGOrecommendations may be appropriatefor this population. For youth, KDIGOrecommends treating BP levels thatare consistently above the 90th percen-tile to achieve systolic and diastolicreadings #50th percentile for age, sex,and height, unless achieving these tar-gets is limited by signs or symptoms ofhypotension. An ARB or ACE inhibitormay be used in youth with CKD whenBP-lowering agents are indicated, re-gardless of the proteinuria levels (22).Meticulous glycemic control, lifestylemodification, and smoking cessationare also means of preventing and treat-ing albuminuria (20). The FDA-approvedtherapeutic options for treating youthwith type 1 and type 2 diabetes are cur-rently limited to metformin (age $10years) and insulin. In youth with evi-dence of CKD, the options are evenmore limited, since metformin may becontraindicated.

The horizon for future therapies re-mains bleak due to drug developmentand regulatory challenges: the absolutenumber of youth with diabetes remainsrelatively small compared with the adultpopulation (;190,000 youth comparedwith 26 million adults) (162,163); studyrecruitment is difficult, especially in ra-cial and ethnic minorities predomi-nantly affected by type 2 diabetes;there are potential drug safety con-cerns; and regulatory hurdles are seem-ingly insurmountable. After adjustingfor completeness of ascertainment, re-cent reports on the increasing incidenceof type 1 (representing a 21.1% increasefrom 2001–2009; 95% CI 15.6–27.0) andtype 2 (representing a 30.5% increasefrom 2001–2009; 95% CI 17.3–45.1) di-abetes in youth indicate that future clin-ical research is not only needed butmandatory for this highly vulnerablepopulation (164).

Future Clinical Research

1. In youth, is there a difference be-tween type 1 and type 2 diabetes inthe development of DKD?

2876 Consensus Report Diabetes Care Volume 37, October 2014

2. Which laboratory measures are mostappropriate to assess kidney func-tion in youth with diabetes?

3. What are the best therapeutic op-tions for treating DKD in youth?

4. What is the trajectory for youth withdiabetes who subsequently developDKD?

MULTIDISCIPLINARY APPROACHESAND MEDICAL HOME MODELS FORHEALTH CARE DELIVERY

Multidisciplinary Approaches forComprehensive CareOptimal care for patients with DKD iscomplex and best managed using com-prehensive multifactorial risk-reductionstrategies (160,161). There is a growingconsensus that patient outcomes aremost improved with simultaneous con-trol of BP, glucose, and lipids; use of anti-platelet agent therapy when indicated;and lifestyle modifications that includesmoking cessation, a healthy diet, exer-cise, and weight reduction among thosewho are overweight or obese (4,20).Smoking is associated with progressivekidney disease (167,168) and is stronglyassociated with CVD events, supportingthe inclusion of smoking cessation amongrisk-reduction strategies. Dietary ap-proaches may facilitate control of BPand management of DKD (4,20,123).Physical activity is associated with a delayin the decline of kidney function (169)and improves other risk factors in pa-tients with CKD (170). A high BMI is astrong, potentially modifiable, risk factorfor both CKD and ESRD (171). However,caution is also warranted considering ob-servations about so-called reverse epide-miology, associating higher weight withinthe overweight/obese range with highersurvival in ESRD, as previously discussed.In earlier stages of CKD, weight loss isassociated with reduced albuminuriaand a slowing decline in kidney function(172). While addressing single risk factorsor even a few together may be effective,targeting multiple risk factors concomi-tantly can result in dramatic reductionsin microvascular and macrovascular com-plications (165,166,173–175). Althoughnew therapies hold promise for improv-ing outcomes among patients with DKD,simultaneous control of multiple conven-tional risk factors effectively reduces thehigh risks of ESRD, CVD events, and death(4,20).

Yet control of multiple risk factors of-ten remains suboptimal (4,176) leading topoor outcomes. Nearly 95% of the com-plex tasks for self-management fall uponpatients themselves (177), yet mostpatients encounter considerable difficultyin following recommended treatmentsand behaviors. Long-term nonadherencerates to physician recommendationsrange between 33–75% (178). Manypatients also lack assistance with theirself-management, a problem exacer-bated by physicians who vary widelyin their provision of recommendationsdespite the challenges that patientsface. Emotional well-being is a criticalcomponent for optimal care and self-management; however, depression is of-ten under-recognized despite affectingabout one in four people with either di-abetes (179) or CKD (180).

To overcome all of these challenges, alarge number of programs have emergedto facilitate improved self-management,including disease management, case man-agement, group clinics, or other organiza-tional and practice changes (177,181).Several multifactorial interventions havebeen evaluated in dozens of studieswith a variety of study designs, inter-ventions, and intended targets (e.g.,health system, providers, and patients)(177,181,182). Many have been effectivein improving intermediate outcomes, in-cluding testing for complications and con-trol of BP and metabolic abnormalities.Multiple risk factor intervention is essen-tial to reducing risks of death and kidneydisease progression (Table 7).

Despite the promise of simulta-neously targeting multiple risk factors,translating approaches from researchsettings to routine clinical practice ischallenging and broad implementationhas been limited. Optimal managementrequires team-based approaches withmultidisciplinary expertise and involve-ment from internists, diabetologists,nephrologists, nutritionists, behavioral-ists, nurses, educators, and pharmacistsat various times during the clinicalcourse. Such comprehensive care is of-ten limited and challenging to imple-ment in routine clinical practice.Although people routinely work to-gether in health care, several barriersprevent explicit efforts to develop inter-professional, multidisciplinary team-based care (185). Establishing cohesiveand high-functioning patients and

teams requires dedicated effort and re-sources. If the potential benefits to teammembers are not outweighed by the in-vestments in the effort required, thenother incentives may be necessary.When considering various specialties,colocalization to minimize patient bar-riers to access may be difficult or infea-sible. Finally, common barriers includeother logistical barriers, lack of experi-ence or expertise, deficient infrastructure,cultural silos, resistance to change, and in-adequate or absent reimbursement (185).

Medical Home Models for Health CareDeliveryAlthough numerous challenges impedetranslation of multidisciplinary ap-proaches to clinical practice, newefficientintervention paradigms are emergingthat may better provide the comprehen-sive, multidisciplinary care teams thatsupport the patient self-managementnecessary to manage the complex clinicalentity of DKD. Team-based approachesinclude those delivered through inte-grated delivery systems, patient-centeredmedical homes (PCMH), and accountablecare organizations. Such multidisci-plinary approaches are able to deliverhigh-quality care by identifying high-riskindividuals using registries, increasing pa-tient engagement and self-management,managing complex patients with coordi-nated multispecialty input, and optimiz-ing management with decision supportat the point of care. Until recently, suchintegrated approaches have evolved pri-marily within integrated delivery systemsbecause of an alignment of incentivesthat support the additional investmentsnecessary to provide team-based com-prehensive care (186–188). However, re-cent evolution of financing mechanismsfor chronic disease care has increasedthe focus toward greater population-based accountability through capitatedpayment models.

Several demonstration projects ofPCMHs for diabetes have been highlyeffective at improving outcomes whilealso being more efficient (189). In a de-tailed review of eight PCMH initiatives(Table 8) (189), prepost comparisonssupport the ability of PCMHs toimprove the quality of care across anumber of dimensions. Althougheach demonstration project variedaccording to how PCMHs were estab-lished, all included reimbursement

care.diabetesjournals.org Tuttle and Associates 2877

enhancement and most utilized casemanagement. Payment mechanisms in-cluded fee-for-service with per member,per month fees as well as bonus pay-ments for achieving predefined perfor-mance metrics with or without sharedsavings. Practice coaches, learning collab-oratives, or registry-based populationmanagement software facilitated prac-tice changes. The National Committeefor Quality Assurance certification formedical homes certifies practices acrossthe dimensions that fulfill medical homecriteria. In addition to managing the var-ious barriers that often arise, good lead-ership and dedication to transformationare critical to the fruitful teamwork re-quired to be successful. Online resourcesand specific strategies to implementpractice change are available throughthe National Diabetes EducationProgram (www.betterdiabetescare.nih.gov).The passage of the Affordable Care

Act has provided support for a varietyof innovative delivery systems in an ef-fort to “bend the cost curve” of medicalcare. As accountable care organizationscontinue to develop, their impact onpopulation management for com-plex patients with DKD will becomeclearer. Ongoing payment reform will be

critical to stimulate broader dissemi-nation and implementation of multiplerisk factor and multidisciplinary ap-proaches and to ensure long-termsustainability.

Future Clinical Research

1. What are the resources required toprovide necessary care for peoplewith DKD?

2. What incentives improve medicalcare and patient adherence in DKD?

3. What is the most efficient deliverysystem for complex cases of diabetessuch as those with DKD?

4. When should patients with DKD bereferred to other members of thetreatment team?

5. What is the best way to utilize multi-disciplinary health care providers(certified diabetes educators, phar-macists, nurse practitioners, physi-cian assistants) for care of peoplewith DKD?

6. What is the best way to continue op-timal diabetes care in the context oftreating ESRD by dialysis or kidneytransplant?

7. How can other important clinicaloutcomes be optimized in ESRD pa-tients (e.g., amputations, retinopa-thy, CVD)?

CONCLUSIONSDKD has emerged as amajor aftermath oftheworldwide diabetes pandemic. There-fore, diabetes prevention must remain atthe cornerstone of reducing DKD. Identi-fication of DKD depends upon screeningfor increased albuminuria and low eGFR.Both measurements have considerableimprecision, highlighting the need forbetter identification methods, especiallyfor people at high risk of DKD complica-tions. Prevention of CVD, amajor cause ofdeath in DKD, centers uponmanagementof LDL cholesterol and BP. More needs tobe learned about risk factors unique tothe DKD population to improve risk strat-ification as well as treatment strategies.Along with efficacy, heightened aware-ness surrounding safety of new therapeu-tic approaches is essential. Safety mustalso be carefully evaluated when ap-proved drugs are used in combinationor for new indications. For example, therecently halted clinical trials of dual RAASblockade in DKD underscored this pointby revealing increased risks of hyperkale-mia and acute kidney injury.

Glycemic control is at the core of gooddiabetes care. However, effects of inten-sive glycemic control vary with severity ofDKD. Those with low eGFR are at high riskfor hypoglycemia, an immediate and

Table 7—Recommendations for multiple risk factor management in DKD (20,39,183,184)

Risk factor General recommendations for diabetes Modifications for DKD

Hyperlipidemia Goal LDL ,100 mg/dL or 30–40% reduction from baseline No specific goal for LDL cholesterol, consider measuringlipids to assess adherence to medication regimenTreatment consists of dietary modifications

Treatment consists of dietary modificationsStatins are recommended in patients with overt CVD andthose over the age of 40 years with another risk factorfor CVD

Statin or statin-ezetimibe combination is recommended inpatients with nondialysis-dependent CKD

For high-CVD-risk patients, ,70 mg/dL is an option Reduced doses of statins are recommended for eGFR ,60mL/min/1.73 m2

Initiation of statin therapy has not been shown to bebeneficial in patients undergoing chronic dialysistreatment

Statins may reduce CVD risk in kidney transplant recipients

Hypertension Goal BP is ,140/80 mmHg Goal BP is ,140/90 mmHgTreatment consists of lifestyle modifications and oralmedications that generally should include RAAS blockers

Goal BP is,130/80mmHg if urine ACR.30mg/g creatinineGoals for treatment are based primarily on studies of

patients with nondiabetic CKDTreatment consists of lifestyle modifications and oral

medications that usually include RAAS blockersUse of more than one RAAS blocker should generally be

avoided

Hyperglycemia Goal is A1C ,7% A1C,8% when GFR,60 mL/min/1.73 m2 due to increasedrisks of hypoglycemiaA goal of,6.5%may be appropriate in early-onset diabetes

in younger patients Imprecision of A1C with CKD strengthens reliance of SMBGin making treatment decisionsTreatment consists of lifestyle modification, oral

medications, and injectable medications, includinginsulin

Doses of insulin and other injectable and oral medicationsused to lower blood glucose often need to be reduced foreGFR ,60 mL/min/1.73 m2

2878 Consensus Report Diabetes Care Volume 37, October 2014

serious adverse event. The number oforal agents that can be used to treat hy-perglycemia in patients with DKD is quitelimited due to decreased drug clearanceand side effects. Insulin doses commonlyrequire reduction, particularly due to therisk of hypoglycemia. Diabetes manage-ment is further complicated by challengeswith glycemic monitoring due to a bias tothe low of A1C related to heightened redblood cell turnover. As such, SMBG is crit-ical to achieve glycemic goals and miti-gate risk of hypoglycemia. In olderadults with long-standing diabetes andCKD, greater care to avoid hypoglycemiais needed and less stringent A1C targetsare recommended (81).Nutritional recommendations are

modified for advanced DKD (stages 4–5CKD) to reduce risk of hyperkalemia, hy-perphosphatemia, bone mineral metabo-lism disorders, hypertension, and kidneydisease progression.With the adjustmentof various macro- and micronutrients, di-etary recommendations become extraor-dinarily complex. Therefore, currentstrategies emphasize whole diets(e.g., Mediterranean-style or DASH) withmodification for kidney disease. Rela-tionships between conventional risk fac-tors for CKD and CVD (e.g., body weight,BP, lipids) are reversed or “U-shaped”with advanced DKD, suggesting thatgoals for the general population cannotbe simply extrapolated to this group.Care of patients with DKD is extraor-

dinarily challenging due to multiple com-orbidities, disparities, and complexities ofhealth care delivery systems. Disparities

in DKD appear to be linked to increasingrates of type 2 diabetes in youth, whichdisproportionately occurs in racial andethnic minorities and allows for the de-velopment of diabetes complications ear-lier in life. These special populations,particularly high-risk youth,merit focusedattention. Medical home models and in-tegration of multiple risk factor manage-ment, keeping the patient-at-center, areof great potential for high-risk groups. Im-portantly, team care including health careprofessionals from various disciplines andeffective communication are require-ments for successful attainment of inte-grated, whole-person care. Noveltherapies for DKD are urgently neededto improve clinically relevant outcomes,yet they must be accompanied by bettermethods for health care delivery and im-plementation in order to succeed. Thekey issues and accompanying researchrecommendations for DKD highlightedby this conference will help lead theway forward, filling gaps in knowledgethat advance care and meaningfully im-prove life for people with DKD.

Acknowledgments. ADA thanks K.R.T. andM.E.M. for serving as co-chairs for the Consen-sus Conference on Chronic Kidney Disease andDiabetes, held 20222 March 2014. ADA alsothanks ASN (Tod Ibrahim, Phillip Kokemueller,U.D.P.) and NKF (Emily Howell, Kerry Willis,G.L.B.) for participating in the conference ascollaborators. The authors thank ADA staffmembers Erika Gebel Berg, PhD, for significanteditorial contributions and Sonya Pendleton foradministrative support.

Duality of Interest. All authors have com-pleted the Unified Competing Interest form atwww.icmje.org/conflicts-of-interest (availableupon request from J.L.C.) and declare the fol-lowing conflicts of interest. K.R.T. has receivedpersonal fees from Eli Lilly and Co. G.L.B. hasreceived grants from Takeda and consultancyfees for his institution from AbbVie, Takeda,Medtronic, Relypsa, Daiichi Sankyo, Janssen,Novartis, and Bayer. R.W.B. has received per-sonal fees fromRoche Pharma, AbbVie,Mitsubishi,and Boehringer Ingelheim. I.H.d.B. has receivedgrants from AbbVie. I.B.H. has received grantsfrom Sanofi and Halozyme and personal feesfrom Abbott and Roche. K.K.-Z. has receivedhonoraria from Abbott, AbbVie, Amgen,Fresnius, DaVita, Keryx, Otsuka, and Shire. S.D.N.received grants from the National Institutes ofHealth/NIDDK and Genzyme. J.J.N. has receivedgrants from AstraZeneca, Johnson & Johnson,Merck, and Novo Nordisk. U.D.P. has receivedpersonal fees from Amgen and grants fromAmgen, Daiichi Sankyo, Eli Lilly and Co., LuitpoldPharmaceuticals, Angion Biomedica Corp., CSLLimited, Ablative Solutions Inc., Kia Pharmaceuti-cals, Reata Pharmaceuticals, Keryx, and GileadSciences. M.E.M. has received grants fromSanofi, Bayer, Eli Lilly and Co., Novo Nordisk,and Novartis and consultant fees from AbbVie,Merck, Janssen, AstraZeneca, and Bristol-MyersSquibb. No other potential conflicts of interestrelevant to this article were reported.

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Table 8—PCMH demonstration projects in diabetes (189)

PCMH demonstration projects Outcomes

Community Care of NorthCarolinad1998

Estimated annual savings of $161 million fordiabetes care

Geisingerd2006 2.5-fold improvement in meeting nine qualityindicators

Pennsylvania Chronic CareInitiatived2008 Self-management goals increased from 20 to 70%

Group Health Cooperatived2007 11% reduction in hospitalizationsBy 21 months, return on investment of $1.50 foreach $1 spent

Health Partnersd2002 24% reduction in hospitalizations

Southeastern PennsylvaniaChronic Care Initiatived200722011

5% more A1C testing but more abnormal results11% greater monitoring for diabetic nephropathy

Pioneer accountable careorganizations

25 of 32 had reduced risk-adjusted readmission ratescompared with benchmark plans

68% of people with diabetes reached BP targetscompared with 55% in benchmark plans

57% with diabetes reached LDL cholesterol targetscompared with 48% in benchmark plans

care.diabetesjournals.org Tuttle and Associates 2879

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