Nephropathy in DiabetesAMERICAN DIABETES ASSOCIATION

D iabetes has become the most com-mon single cause of end-stage renaldisease (ESRD) in the U.S. and Eu-rope; this is due to the facts that 1) dia-betes, particularly type 2, is increasing inprevalence; 2) diabetes patients now livelonger; and 3) patients with diabetic ESRDare now being accepted for treatment inESRD programs where formerly they hadbeen excluded. In the U.S., diabetic ne-phropathy accounts for about 40% of newcases of ESRD, and in 1997, the cost fortreatment of diabetic patients with ESRDwas in excess of $15.6 billion. About 2030% of patients with type 1 or type 2 di-abetes develop evidence of nephropathy,but in type 2 diabetes, a considerablysmaller fraction of these progress toESRD. However, because of the muchgreater prevalence of type 2 diabetes, suchpatients constitute over half of those dia-betic patients currently starting on dialy-sis. There is considerable racial/ethnicvariability in this regard, with NativeAmericans, Hispanics (especially Mexi-can-Americans), and African-Americanshaving much higher risks of developingESRD than non-Hispanic whites withtype 2 diabetes. Recent studies have nowdemonstrated that the onset and course ofdiabetic nephropathy can be amelioratedto a very significant degree by several in-terventions, but these interventions havetheir greatest impact if instituted at apoint very early in the course of the de-velopment of this complication. This po-sition statement is based on recent reviewarticles that discuss published researchand issues that remain unresolved andprovides recommendations regarding the

detection, prevention, and treatment ofearly nephropathy.

NATURAL HISTORY OFDIABETIC NEPHROPATHY The earliest clinical evidence of nephrop-athy is the appearance of low but abnor-mal levels ( 30 mg/day or 20g/min) ofalbumin in the urine, referred to as mi-croalbuminuria, and patients with mi-croalbuminuria are referred to as havingincipient nephropathy. Without specificinterventions, 80% of subjects withtype 1 diabetes who develop sustainedmicroalbuminuria have their urinary al-bumin excretion increase at a rate of1020% per year to the stage of overtnephropathy or clinical albuminuria(300 mg/24 h or 200 g/min) over aperiod of 1015 years, with hypertensionalso developing along the way. Once overtnephropathy occurs, without specific in-terventions, the glomerular filtration rate(GFR) gradually falls over a period of sev-eral years at a rate that is highly variablefrom individual to individual (220 ml min1 year1). ESRD develops in 50%of type 1 diabetic individuals with overtnephropathy within 10 years and in75% by 20 years.

A higher proportion of individualswith type 2 diabetes are found to havemicroalbuminuria and overt nephropa-thy shortly after the diagnosis of their di-abetes, because diabetes is actuallypresent for many years before the diagno-sis is made and also because the presenceof albuminuria may be less specific for thepresence of diabetic nephropathy, asshown by biopsy studies. Without spe-cific interventions, 2040% of type 2 di-

abetic patients with microalbuminuriaprogress to overt nephropathy, but by 20years after onset of overt nephropathy,only 20% will have progressed toESRD. Once the GFR begins to fall, therates of fall in GFR are again highly vari-able from one individual to another, butoverall, they may not be substantially dif-ferent between patients with type 1 andpatients with type 2 diabetes. However,the greater risk of dying from associatedcoronary artery disease in the older pop-ulation with type 2 diabetes may preventmany with earlier stages of nephropathyfrom progressing to ESRD. As therapiesand interventions for coronary artery dis-ease continue to improve, however, morepatients with type 2 diabetes may be ex-pected to survive long enough to developrenal failure.

In addition to its being the earliestmanifestation of nephropathy, albumin-uria is a marker of greatly increased car-diovascular morbidity and mortality forpatients with either type 1 or type 2 dia-betes. Thus, the finding of microalbumin-uria is an indication for screening forpossible vascular disease and aggressiveintervention to reduce all cardiovascularrisk factors (e.g., lowering of LDL choles-terol, antihypertensive therapy, cessationof smoking, institution of exercise, etc.).In addition, there is some preliminary ev-idence to suggest that lowering of choles-terol may also reduce the level ofproteinuria.

SCREENING FORALBUMINURIA A test for thepresence of microalbumin should be per-formed at diagnosis in patients with type 2diabetes. Microalbuminuria rarely occurswith short duration of type 1 diabetes;therefore, screening in individuals with type1 diabetes should begin after 5 years diseaseduration. Some evidence suggests that theprepubertal duration of diabetes may be im-portant in the development of microvascu-lar complications; therefore, clinicaljudgement should be exercised when indi-vidualizing these recommendations. Be-

The recommendations in this paper are based on the evidence reviewed in the following publications:Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Rev 3:510564, 1995; and Pre-vention of diabetic renal disease with special reference to microalbuminuria. Lancet 346:10801084, 1995.

The initial draft of this paper was prepared by Mark E. Molitch, MD (chair); Ralph A. DeFronzo, MD; MarionJ. Franz, MS, RD, CDE; William F. Keane, MD; Carl Erik Mogensen, MD; Hans-Henrik Parving, MD; and MichaelW. Steffes, MD, PhD. The paper was peer-reviewed, modified, and approved by the Professional Practice Com-mittee and the Executive Committee, November 1996. Most recent review/revision, October 2001.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DCCB, dihy-dropyridine calcium channel blocker; ESRD, end-stage renal disease: GFR, glomerular filtration rate;UKPDS, United Kingdom Prospective Diabetes Study.

2004 by the American Diabetes Association.

P O S I T I O N S T A T E M E N T

DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004 S79

cause of the difficulty in precise dating ofthe onset of type 2 diabetes, such screeningshould begin at the time of diagnosis. Afterthe initial screening and in the absence ofpreviously demonstrated microalbumin-uria, a test for the presence of microalbuminshould be performed annually.

Screening for microalbuminuria canbe performed by three methods: 1) mea-surement of the albumin-to-creatinine ra-tio in a random spot collection; 2) 24-hcollection with creatinine, allowing the si-multaneous measurement of creatinineclearance; and 3) timed (e.g., 4-h or over-night) collection. The first method is oftenfound to be the easiest to carry out in anoffice setting, generally provides accurateinformation, and is therefore preferred;first-void or other morning collections arebest because of the known diurnal varia-tion in albumin excretion, but if this tim-ing cannot be used, uniformity of timingfor different collections in the same indi-vidual should be employed. Specific as-says are needed to detect microalbumi-nuria because standard hospital labora-tory assays for urinary protein are not suf-ficiently sensitive to measure such levels.Microalbuminuria is said to be present ifurinary albumin excretion is 30 mg/24h (equivalent to 20 g/min on a timedspecimen or 30 mg/g creatinine on a ran-dom sample) (Table 1). Short-term hy-perglycemia, exercise, urinary tractinfections, marked hypertension, heartfailure, and acute febrile illness can causetransient elevations in urinary albuminexcretion. If assays for microalbuminuriaare not readily available, screening withreagent tablets or dipsticks for microalbu-min may be carried out, since they showacceptable sensitivity (95%) and specific-ity (93%) when carried out by trainedpersonnel. Because reagent strips only in-dicate concentration and do not correctfor creatinine as the spot urine albumin-

to-creatinine ratio does, they are subjectto possible errors from alterations in urineconcentration. All positive tests by re-agent strips or tablets should be con-firmed by more specific methods. There isalso marked day-to-day variability in al-bumin excretion, so at least two of threecollections done in a 3- to 6-month periodshould show elevated levels before desig-nating a patient as having microalbumin-uria. An algorithm for microalbuminuriascreening is given in Fig. 1.

The role of annual microalbuminuriaassessment is less clear after diagnosis ofmicroalbuminuria and institution of an-giotensin-converting enzyme (ACE) in-hibitor or angiotensin receptor blocker(ARB) therapy and blood pressure con-trol. Many experts recommend continuedsurveillance to assess both response totherapy and progression of disease. In ad-dition to assessment of urinary albuminexcretion, assessment of glomerular func-tion is important in patients with diabetickidney disease.

EFFECT OF GLYCEMICCONTROL The Diabetes Controland Complications Trial (DCCT) and theUnited Kingdom Prospective DiabetesStudy (UKPDS) have definitively shownthat intensive diabetes therapy can signif-icantly reduce the risk of the developmentof microalbuminuria and overt nephrop-athy in people with diabetes. The glyce-mic control recommendations for allpatients with diabetes in the American Di-abetes Associations Standards of Medi-cal Care for Patients with DiabetesMellitus should be followed in this re-gard.

HYPERTENSION CONTROL In patients with type 1 diabetes, hyper-

tension is usually caused by underlyingdiabetic nephropathy and typically be-comes manifest about the time that pa-tients develop microalbuminuria. Inpatients with type 2 diabetes, hyperten-sion is present at the time of diagnosis ofdiabetes in about one-third of patients.The common coexistence of glucose in-tolerance, hypertension, elevated LDLcholesterol and triglycerides, and a reduc-tion in HDL cholesterol, obesity, and sus-ceptibility to cardiovascular diseasesuggests that they may relate to commonunderlying mechanisms, such as insulinresistance; and this complex is often re-ferred to as syndrome X and/or the meta-bolic syndrome. Hypertension in type 2diabetic patients may also be related tounderlying diabetic nephropathy, be dueto coexisting essential hypertension, orbe due to a myriad of other secondarycauses, such as renal vascular disease. Iso-lated systolic hypertension has been at-tributed to the loss of elastic complianceof atherosclerotic large vessels. In general,the hypertension in patients with bothtypes of diabetes is associated with an ex-panded plasma volume, increased pe-ripheral vascular resistance, and lowrenin activity.

Both systolic and diastolic hyperten-sion markedly accelerate the progressionof diabetic nephropathy, and aggressiveantihypertensive management is able togreatly decrease the rate of fall of GFR.Appropriate antihypertensive interven-tion can significantly increase the medianlife expectancy in patients with type 1 di-abetes, with a reduction in mortality from94 to 45% and a reduction in the need fordialysis and transplantation from 73 to31% 16 years after the development ofovert nephropathy.

In accordance with the Standards ofMedical Care in Diabetes Mellitus, theposition statement on HypertensionManagement in Adults With Diabetes,and other recommendations, the primarygoal of therapy for nonpregnant diabeticpatients 18 years of age is to decreaseblood pressure to and maintain it at130mmHg systolic and80 mmHg diastolic.For patients with isolated systolic hyper-tension with a systolic pressure of 180mmHg, the initial goal of treatment is togradually lower the systolic blood pres-sure in stages. If initial goals are met andwell tolerated, further lowering may beindicated.

A major aspect of initial treatment

Table 1Definitions of abnormalities in albumin excretion

CategorySpot collection

(g/mg creatinine)24-h collection

(mg/24 h)Timed collection

(g/min)

Normal 30 30 20Microalbuminuria 30299 30299 20199Clinical albuminuria 300 300 200

Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-monthperiod should be abnormal before considering a patient to have crossed one of these diagnostic thresholds.Exercise within 24 h, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension,pyuria, and hematuria may elevate urinary albumin excretion over baseline values.

Position Statement

S80 DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004

should consist of lifestyle modifications,such as weight loss, reduction of salt andalcohol intake, and exercise, as outlinedin the Standards of Medical Care for Pa-tients with Diabetes Mellitus and the po-sition statement on Treatment ofHypertension in Adults with Diabetes. Inpatients with underlying nephropathy,treatment with ACE inhibitors or ARBs isalso indicated as part of initial therapy(see below). If after 46 weeks sufficientblood pressure reduction has not oc-curred, additional pharmacological ther-apy is indicated. (See the AmericanDiabetes Association position statementTreatment of Hypertension in Adultswith Diabetes for a complete discussionon this subject.) In general, these medica-tions may be added in stepwise fashionand their individual use may depend onother factors such as fluid overload andvascular disease.

USE OFANTIHYPERTENSIVEAGENTS The positive response toantihypertensive treatment coupled withthe concept that often there is a progres-

sive deterioration of renal function re-gardless of the underlying etiology gaverise to the idea that hemodynamic factorsmay be critical in furthering the fall inGFR. In this hypothesis, damage to glo-meruli causes changes in the microcircu-lation that result in hyperfiltrationoccurring in the remaining glomeruliwith increased intraglomerular pressureand increased sensitivity to angiotensin II;the single-nephron hyperfiltration withintraglomerular hypertension is itselfdamaging. Many studies have shown thatin hypertensive patients with type 1 dia-betes, ACE inhibitors can reduce the levelof albuminuria and the rate of progressionof renal disease to a greater degree thanother antihypertensive agents that lowerblood pressure by an equal amount.Other studies have shown that there isbenefit in reducing the progression of mi-croalbuminuria in normotensive patientswith type 1 diabetes and normotensiveand hypertensive patients with type 2 di-abetes.

Use of ACE inhibitors or ARBs mayexacerbate hyperkalemia in patients withadvanced renal insufficiency and/or hy-poreninemic hypoaldosteronism. In older

patients with bilateral renal artery steno-sis and in patients with advanced renaldisease even without renal artery stenosis,ACE inhibitors may cause a rapid declinein renal function. Whether this occurswith ARBs is unknown. Cough may alsooccur with ACE inhibitors. ACE inhibi-tors are contraindicated in pregnancy andtherefore should be used with caution inwomen of childbearing potential. There isno data on ARB use in pregnancy, butthey are classified as class C/D.

Because of the high proportion ofpatients who progress from microalbu-minuria to overt nephropathy and subse-quently to ESRD, use of ACE inhibitors orARBs is recommended for all patientswith microalbuminuria or advancedstages of neuropathy. The effect of ACEinhibitors appears to be a class effect, sochoice of agent may depend on cost andcompliance issues.

The recent UKPDS compared antihy-pertensive treatment with an ACE inhibitorto that with a -blocker. Both drugs wereequally effective in lowering blood pressureand there were no significant differencesin the incidence of microalbuminuria orproteinuria. However, because of the lowprevalence of nephropathy in the popula-tion studied, it is unclear whether therewere sufficient events to observe a protec-tive effect of either drug on the progres-sion of nephropathy. Some studies havedemonstrated that the non-dihydropyri-dine calcium channel blocker (NDCCB)classes of calcium-channel blockers canreduce the level of albuminuria, but nostudies to date have demonstrated a re-duction in the rate of fall of GFR with theiruse.

PROTEIN RESTRICTION Animalstudies have shown that restriction of di-etary protein intake also reduces hyperfil-tration and intraglomerular pressure andretards the progression of several modelsof renal disease, including diabetic glo-merulopathy: Several small studies in hu-mans with diabetic nephropathy haveshown that a prescribed protein-restricted diet of 0.6 g kg1 day1 (sub-jects actually only achieved a restriction of0.8 g kg1 day1) retards the rate of fallof GFR modestly. However, the ModifiedDiet in Renal Disease Study, in which only3% of the patients had type 2 diabetes andnone had type 1 diabetes, failed to show aclear benefit of protein restriction.

Figure 1Screening for microalbuminuria.

Diabetic Nephropathy

DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004 S81

At this point in time, the general con-sensus is to prescribe a protein intake ofapproximately the adult RecommendedDietary Allowance (RDA) of 0.8 g kg1 day1 (10% of daily calories) in the pa-tient with overt nephropathy. However, ithas been suggested that once the GFR be-gins to fall, further restriction to 0.6 g kg1 day1 may prove useful in slowingthe decline of GFR in selected patients.On the other hand, nutrition deficiencymay occur in some individuals and maybe associated with muscle weakness. Pro-tein-restricted meal plans should be de-signed by a registered dietitian familiarwith all components of the dietary man-agement of diabetes.

OTHER ASPECTSOF TREATMENT Other standardmodalities for the treatment of progres-sive renal disease and its complications(e.g., osteodystrophy) must also be usedwhen indicated, such as sodium andphosphate restriction and use of phos-phate binders. When the GFR begins todecline substantially, referral to a physi-cian experienced in the care of such pa-tients is indicated. Radiocontrast mediaare particularly nephrotoxic in patientswith diabetic nephropathy, and azotemicpatients should be carefully hydrated be-fore receiving any procedures requiringcontrast that cannot be avoided.

General recommendations To reduce the risk and/or slow the pro-

gression of nephropathy, optimize glu-cose control. (A)

To reduce the risk and/or slow the pro-gression of nephropathy, optimizeblood pressure control. (A)

Screening Perform an annual test for the presence

of microalbuminia in 1) type 1 diabeticpatients who have had diabetes 5years and 2) all type 2 diabetic patientsstarting at diagnosis. (E)

Treatment In the treatment of albuminuria/

nephropathy both ACE inhibitors andARBs can be used: In hypertensive type 1 diabetic pa-

tients with any degree of albumin-uria, ACE inhibitors have beenshown to delay the progression of ne-

phropathy. (A) In hypertensive type 2 diabetic pa-

tients with microalbuminuria, ACEinhibitors and ARBs have been shownto delay the progression to macro-albuminuria. (A)

In patients with type 2 diabetes, hy-pertension, macroalbuminuria, andrenal insufficiency (serum creatinine1.5 mg/dl), ARBs have been shownto delay the progression of nephrop-athy. (A)

If one class is not tolerated, the othershould be substituted. (E)

With regards to slowing the progres-sion of nephropathy, the use of DCCBsas initial therapy is not more effectivethan placebo. Their use in nephropathyshould be restricted to additional ther-apy to further lower blood pressure inpatients already treated with ACE in-hibitors or ARBs. (B)

In the setting of the albuminuria or ne-phropathy, in patients unable to toler-ate ACE inhibitors and/or ARBs,consider the use of non-DCCBs,-blockers, or diuretics for the manage-ment of blood pressure. (E)

With the onset of overt nephropathy,initiate protein restriction to 0.8 g kg1 body wt day1 (10% of dailycalories), the current adult RDA forprotein. Further restriction may be use-ful in slowing the decline of GFR in se-lected patients. (B)

If ACE inhibitors or ARBs are used,monitor serum potassium levels for thedevelopment of hyperkalemia. (B)

Consider referral to a physician experi-enced in the care of diabetic renal dis-ease when either the GFR has fallen to60 ml min1 1.73 m2 or difficul-ties have occurred in the managementof hypertension or hyperkalemia. (B)

SUMMARY Annual screening formicroalbuminuria will allow the identifi-cation of patients with nephropathy at apoint very early in its course. Improvingglycemic control, aggressive antihyper-tensive treatment, and the use of ACE in-hibitors or ARBs will slow the rate ofprogression of nephropathy. In addition,protein restriction and other treatment

modalities such as phosphate loweringmay have benefits in selected patients.

BibliographyAmerican Diabetes Association. Diabetes 2001

Vital Statistics. Alexandria, VA, ADA, 2001American Diabetes Association: Standards of

medical care in diabetes (Position State-ment). Diabetes Care 27: (Suppl. 1):S15S35, 2004

American Diabetes Association: Hypertensionmanagement in adults with diabetes (Posi-tion Statement). Diabetes Care 27 (Suppl.1):S65S67, 2004

Bakris GL, Williams M, Dworkin L, Elliott WJ,Epstein M, Toto R, Tuttle K, Douglas J,Hsueh W, Sowers J: Preserving renal func-tion in adults with hypertension and diabe-tes: a consensus approach. Am J Kid Dis 36:646661, 2000

Brenner BM, Cooper ME, de Zeeuw D, KeaneWF, Mitch WE, Parving HH, Remuzzi G,Snapinn SM, Zhang Z, Shahinfar S: Effectsof losartan on renal and cardiovascular out-comes in patients with type 2 diabetes andnephropathy. N Engl J Med 345:861869, 2001

DeFronzo RA: Diabetic nephropathy: etiologicand therapeutic considerations. DiabetesRev 3:510564, 1995

Diabetes Control and Complications Trial Re-search Group: The effect of intensive treat-ment of diabetes on the development andprogression of long-term complications ininsulin-dependent diabetes mellitus. N EnglJ Med 329:977986, 1993

Lewis EJ, Hunsicker LG, Clarke WR, Berl T,Pohl MA, Lewis JB, Ritz E, Atkins RC, RohdeBS, Raz I: Renoprotective effect of the angio-tensin-receptor antagonist irbesartan in pa-tients with nephropathy due to type 2diabetes. N Eng J Med 345:851860, 2001

Lewis EJ, Hunsicker LG, Bain RP, and RohdeRD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropa-thy. The Collaborative Study Group. N EnglJ Med 329:14561462, 1993

Mogensen CE, Keane WF, Bennett PH, JerumsG, Parving H-H, Passa P, Steffes MW, StrikerGE, Viberti GC: Prevention of diabetic renaldisease with special reference to microalbu-minuria. Lancet 346:10801084, 1995

Mogensen CE, Neldam S, Tikkanen I, Oren S,Viskoper R, Watts RW, Cooper ME: Ran-domised controlled trial of dual blockade ofrenin-angiotensin system in patients withhypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesar-tan and Lisinopril Microalbuminuria (CALM)Study. BMJ 14401444, 2000

Parving HH, Lehnert H, Brochner-MortensenJ, Gomis R, Andersen S, Arner P: The effectof irbesartan on the development of diabetic

Position Statement

S82 DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004

nephropathy in patients with type 2 diabe-tes. N Engl J Med 345:870878, 2001

UK Prospective Diabetes Study Group: Effi-cacy of atenolol and captopril in reducingthe risk of macrovascular complications intype 2 diabetes (UKPDS 39). BMJ 317:713

720, 1998UK Prospective Diabetes Study Group: In-

tensive blood glucose control with sul-phonylureas or insulin compared withconventional treatment and risk of com-plications in patients with type 2 diabetes

(UKPDS 33). Lancet 352:837 853, 1998UK Prospective Diabetes Study Group: Tight

blood pressure control and risk of macro-vascular and microvascular complicationsin type 2 diabetes (UKPDS 38). BMJ 317:703713, 1998

Diabetic Nephropathy

DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004 S83