POSITION STATEMENT

Nephropathy in

AMERICAN DIABETES ASSOCIATION

iabetes has become the most com- detection, prevention, and treatment of abetic patients with mon single cause of end-stage renal early nephropathy. progress to overt nephropathy, but by 20 D disease (ESRD) in the U.S. and Eu- years after onset of overt nephropathy, ϳ rope; this is due to the facts that 1) dia- NATURAL HISTORY OF only 20% will have progressed to betes, particularly type 2, is increasing in DIABETIC NEPHROPATHY — ESRD. Once the GFR begins to fall, the prevalence; 2) diabetes patients now live The earliest clinical evidence of nephrop- rates of fall in GFR are again highly vari- longer; and 3) patients with diabetic ESRD athy is the appearance of low but abnor- able from one individual to another, but are now being accepted for treatment in mal levels (Ն 30 mg/day or 20 ␮g/min) of overall, they may not be substantially dif- ESRD programs where formerly they had albumin in the urine, referred to as mi- ferent between patients with type 1 and been excluded. In the U.S., diabetic ne- croalbuminuria, and patients with mi- patients with . However, phropathy accounts for about 40% of new croalbuminuria are referred to as having the greater risk of dying from associated cases of ESRD, and in 1997, the cost for incipient nephropathy. Without specific coronary artery disease in the older pop- treatment of diabetic patients with ESRD interventions, ϳ80% of subjects with ulation with type 2 diabetes may prevent many with earlier stages of nephropathy was in excess of $15.6 billion. About 20– who develop sustained from progressing to ESRD. As therapies 30% of patients with type 1 or type 2 di- microalbuminuria have their urinary al- and interventions for coronary artery dis- abetes develop evidence of nephropathy, bumin excretion increase at a rate of ϳ10–20% per year to the stage of overt ease continue to improve, however, more but in type 2 diabetes, a considerably patients with type 2 diabetes may be ex- smaller fraction of these progress to nephropathy or clinical Ն Ն ␮ pected to survive long enough to develop ESRD. However, because of the much ( 300 mg/24 h or 200 g/min) over a period of 10–15 years, with renal failure. greater prevalence of type 2 diabetes, such In addition to its being the earliest patients constitute over half of those dia- also developing along the way. Once overt nephropathy occurs, without specific in- manifestation of nephropathy, albumin- betic patients currently starting on dialy- uria is a marker of greatly increased car- sis. There is considerable racial/ethnic terventions, the glomerular filtration rate (GFR) gradually falls over a period of sev- diovascular morbidity and mortality for variability in this regard, with Native patients with either type 1 or type 2 dia- Americans, Hispanics (especially Mexi- eral years at a rate that is highly variable from individual to individual (2–20 ml betes. Thus, the finding of microalbumin- can-Americans), and African-Americans Ϫ Ϫ min 1 year 1). ESRD develops in 50% uria is an indication for screening for having much higher risks of developing of type 1 diabetic individuals with overt possible vascular disease and aggressive ESRD than non-Hispanic whites with nephropathy within 10 years and in intervention to reduce all cardiovascular type 2 diabetes. Recent studies have now Ͼ75% by 20 years. risk factors (e.g., lowering of LDL choles- demonstrated that the onset and course of A higher proportion of individuals terol, antihypertensive therapy, cessation diabetic nephropathy can be ameliorated with type 2 diabetes are found to have of smoking, institution of exercise, etc.). to a very significant degree by several in- microalbuminuria and overt nephropa- In addition, there is some preliminary ev- terventions, but these interventions have thy shortly after the diagnosis of their di- idence to suggest that lowering of choles- their greatest impact if instituted at a abetes, because diabetes is actually terol may also reduce the level of point very early in the course of the de- present for many years before the diagno- . velopment of this . This po- sis is made and also because the presence sition statement is based on recent review of albuminuria may be less specific for the SCREENING FOR articles that discuss published research presence of diabetic nephropathy, as ALBUMINURIA — A test for the and issues that remain unresolved and shown by biopsy studies. Without spe- presence of microalbumin should be per- provides recommendations regarding the cific interventions, 20–40% of type 2 di- formed at diagnosis in patients with type 2 ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● diabetes. Microalbuminuria rarely occurs The recommendations in this paper are based on the evidence reviewed in the following publications: with short duration of type 1 diabetes; Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Rev 3:510–564, 1995; and Pre- therefore, screening in individuals with type vention of diabetic renal disease with special reference to microalbuminuria. Lancet 346:1080–1084, 1995. The initial draft of this paper was prepared by Mark E. Molitch, MD (chair); Ralph A. DeFronzo, MD; Marion 1 diabetes should begin after 5 years’ disease J. Franz, MS, RD, CDE; William F. Keane, MD; Carl Erik Mogensen, MD; Hans-Henrik Parving, MD; and Michael duration. Some evidence suggests that the W. Steffes, MD, PhD. The paper was peer-reviewed, modified, and approved by the Professional Practice Com- prepubertal duration of diabetes may be im- mittee and the Executive Committee, November 1996. Most recent review/revision, October 2001. portant in the development of microvascu- Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DCCB, dihy- dropyridine calcium channel blocker; ESRD, end-stage renal disease: GFR, glomerular filtration rate; lar complications; therefore, clinical UKPDS, United Kingdom Prospective Diabetes Study. judgement should be exercised when indi- © 2004 by the American Diabetes Association. vidualizing these recommendations. Be-

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

Table 1—Definitions of abnormalities in albumin excretion tension is usually caused by underlying diabetic nephropathy and typically be- Spot collection 24-h collection Timed collection comes manifest about the time that pa- Category (␮g/mg ) (mg/24 h) (␮g/min) tients develop microalbuminuria. In patients with type 2 diabetes, hyperten- Normal Ͻ30 Ͻ30 Ͻ20 sion is present at the time of diagnosis of Microalbuminuria 30–299 30–299 20–199 diabetes in about one-third of patients. Clinical albuminuria Ն300 Ն300 Ն200 The common coexistence of glucose in- Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month tolerance, hypertension, elevated LDL period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. cholesterol and triglycerides, and a reduc- Exercise within 24 h, infection, fever, congestive heart failure, marked , marked hypertension, tion in HDL cholesterol, obesity, and sus- pyuria, and hematuria may elevate urinary albumin excretion over baseline values. ceptibility to suggests that they may relate to common underlying mechanisms, such as cause of the difficulty in precise dating of to-creatinine ratio does, they are subject resistance; and this complex is often re- the onset of type 2 diabetes, such screening to possible errors from alterations in urine ferred to as syndrome X and/or the meta- should begin at the time of diagnosis. After concentration. All positive tests by re- bolic syndrome. Hypertension in type 2 the initial screening and in the absence of agent strips or tablets should be con- diabetic patients may also be related to previously demonstrated microalbumin- firmed by more specific methods. There is underlying diabetic nephropathy, be due uria, a test for the presence of microalbumin also marked day-to-day variability in al- to coexisting “essential” hypertension, or should be performed annually. bumin excretion, so at least two of three be due to a myriad of other secondary Screening for microalbuminuria can collections done in a 3- to 6-month period causes, such as renal vascular disease. Iso- be performed by three methods: 1) mea- should show elevated levels before desig- lated systolic hypertension has been at- surement of the albumin-to-creatinine ra- nating a patient as having microalbumin- tributed to the loss of elastic compliance tio in a random spot collection; 2) 24-h uria. An algorithm for microalbuminuria of atherosclerotic large vessels. In general, collection with creatinine, allowing the si- screening is given in Fig. 1. the hypertension in patients with both multaneous measurement of creatinine The role of annual microalbuminuria types of diabetes is associated with an ex- clearance; and 3) timed (e.g., 4-h or over- assessment is less clear after diagnosis of panded plasma volume, increased pe- night) collection. The first method is often microalbuminuria and institution of an- ripheral vascular resistance, and low found to be the easiest to carry out in an giotensin-converting enzyme (ACE) in- renin activity. office setting, generally provides accurate hibitor or angiotensin receptor blocker Both systolic and diastolic hyperten- information, and is therefore preferred; (ARB) therapy and con- sion markedly accelerate the progression first-void or other morning collections are trol. Many experts recommend continued of diabetic nephropathy, and aggressive best because of the known diurnal varia- surveillance to assess both response to antihypertensive management is able to tion in albumin excretion, but if this tim- therapy and progression of disease. In ad- greatly decrease the rate of fall of GFR. ing cannot be used, uniformity of timing dition to assessment of urinary albumin Appropriate antihypertensive interven- for different collections in the same indi- excretion, assessment of glomerular func- tion can significantly increase the median vidual should be employed. Specific as- tion is important in patients with diabetic life expectancy in patients with type 1 di- says are needed to detect microalbumi- disease. abetes, with a reduction in mortality from nuria because standard hospital labora- 94 to 45% and a reduction in the need for tory assays for urinary protein are not suf- dialysis and transplantation from 73 to ficiently sensitive to measure such levels. EFFECT OF GLYCEMIC 31% 16 years after the development of Microalbuminuria is said to be present if CONTROL — The Diabetes Control overt nephropathy. urinary albumin excretion is Ն30 mg/24 and Complications Trial (DCCT) and the In accordance with the “Standards of h (equivalent to 20 ␮g/min on a timed United Kingdom Prospective Diabetes Medical Care in Diabetes Mellitus,” the specimen or 30 mg/g creatinine on a ran- Study (UKPDS) have definitively shown position statement on “Hypertension dom sample) (Table 1). Short-term hy- that intensive diabetes therapy can signif- Management in Adults With Diabetes,” perglycemia, exercise, urinary tract icantly reduce the risk of the development and other recommendations, the primary infections, marked hypertension, heart of microalbuminuria and overt nephrop- goal of therapy for nonpregnant diabetic failure, and acute febrile illness can cause athy in people with diabetes. The glyce- patients Ն18 years of age is to decrease transient elevations in urinary albumin mic control recommendations for all blood pressure to and maintain it at Ͻ130 excretion. If assays for microalbuminuria patients with diabetes in the American Di- mmHg systolic and Ͻ80 mmHg diastolic. are not readily available, screening with abetes Association’s “Standards of Medi- For patients with isolated systolic hyper- reagent tablets or dipsticks for microalbu- cal Care for Patients with Diabetes tension with a systolic pressure of Ն180 min may be carried out, since they show Mellitus” should be followed in this re- mmHg, the initial goal of treatment is to acceptable sensitivity (95%) and specific- gard. gradually lower the systolic blood pres- ity (93%) when carried out by trained sure in stages. If initial goals are met and personnel. Because reagent strips only in- well tolerated, further lowering may be dicate concentration and do not correct HYPERTENSION CONTROL — indicated. for creatinine as the spot urine albumin- In patients with type 1 diabetes, hyper- A major aspect of initial treatment

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

patients with bilateral renal artery steno- sis and in patients with advanced renal disease even without renal artery stenosis, ACE inhibitors may cause a rapid decline in renal function. Whether this occurs with ARBs is unknown. Cough may also occur with ACE inhibitors. ACE inhibi- tors are contraindicated in pregnancy and therefore should be used with caution in women of childbearing potential. There is no data on ARB use in pregnancy, but they are classified as class C/D. Because of the high proportion of patients who progress from microalbu- minuria to overt nephropathy and subse- quently to ESRD, use of ACE inhibitors or ARBs is recommended for all patients with microalbuminuria or advanced stages of neuropathy. The effect of ACE inhibitors appears to be a class effect, so choice of agent may depend on cost and compliance issues. The recent UKPDS compared antihy- pertensive treatment with an ACE inhibitor to that with a ␤-blocker. Both drugs were equally effective in lowering blood pressure and there were no significant differences in the incidence of microalbuminuria or Figure 1—Screening for microalbuminuria. proteinuria. However, because of the low prevalence of nephropathy in the popula- tion studied, it is unclear whether there should consist of lifestyle modifications, sive deterioration of renal function re- were sufficient events to observe a protec- such as weight loss, reduction of salt and gardless of the underlying etiology gave tive effect of either drug on the progres- alcohol intake, and exercise, as outlined rise to the idea that hemodynamic factors sion of nephropathy. Some studies have in the “Standards of Medical Care for Pa- may be critical in furthering the fall in demonstrated that the non-dihydropyri- tients with Diabetes Mellitus” and the po- GFR. In this hypothesis, damage to glo- dine calcium channel blocker (NDCCB) sition statement on “Treatment of meruli causes changes in the microcircu- classes of calcium-channel blockers can Hypertension in Adults with Diabetes.” In lation that result in hyperfiltration reduce the level of albuminuria, but no patients with underlying nephropathy, occurring in the remaining glomeruli studies to date have demonstrated a re- treatment with ACE inhibitors or ARBs is with increased intraglomerular pressure duction in the rate of fall of GFR with their also indicated as part of initial therapy and increased sensitivity to angiotensin II; use. (see below). If after 4–6 weeks sufficient the single- hyperfiltration with blood pressure reduction has not oc- intraglomerular hypertension is itself curred, additional pharmacological ther- damaging. Many studies have shown that PROTEIN RESTRICTION — Animal apy is indicated. (See the American in hypertensive patients with type 1 dia- studies have shown that restriction of di- Diabetes Association position statement betes, ACE inhibitors can reduce the level etary protein intake also reduces hyperfil- “Treatment of Hypertension in Adults of albuminuria and the rate of progression tration and intraglomerular pressure and with Diabetes” for a complete discussion of renal disease to a greater degree than retards the progression of several models on this subject.) In general, these medica- other antihypertensive agents that lower of renal disease, including diabetic glo- tions may be added in stepwise fashion blood pressure by an equal amount. merulopathy: Several small studies in hu- and their individual use may depend on Other studies have shown that there is mans with diabetic nephropathy have other factors such as fluid overload and benefit in reducing the progression of mi- shown that a prescribed protein- Ϫ Ϫ vascular disease. croalbuminuria in normotensive patients restricted diet of 0.6 g kg 1 day 1 (sub- with type 1 diabetes and normotensive jects actually only achieved a restriction of Ϫ Ϫ and hypertensive patients with type 2 di- 0.8 g kg 1 day 1) retards the rate of fall USE OF abetes. of GFR modestly. However, the Modified ANTIHYPERTENSIVE Use of ACE inhibitors or ARBs may Diet in Renal Disease Study, in which only AGENTS — The positive response to exacerbate hyperkalemia in patients with 3% of the patients had type 2 diabetes and antihypertensive treatment coupled with advanced renal insufficiency and/or hy- none had type 1 diabetes, failed to show a the concept that often there is a progres- poreninemic . In older clear benefit of protein restriction.

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

At this point in time, the general con- phropathy. (A) modalities such as phosphate lowering sensus is to prescribe a protein intake of • In hypertensive type 2 diabetic pa- may have benefits in selected patients. approximately the adult Recommended tients with microalbuminuria, ACE Ϫ Dietary Allowance (RDA) of 0.8 g kg 1 inhibitors and ARBs have been shown Ϫ day 1 (ϳ10% of daily calories) in the pa- to delay the progression to macro- tient with overt nephropathy. However, it albuminuria. (A) Bibliography American Diabetes Association. Diabetes 2001 has been suggested that once the GFR be- • In patients with type 2 diabetes, hy- Vital Statistics. Alexandria, VA, ADA, 2001 gins to fall, further restriction to 0.6 g pertension, macroalbuminuria, and Ϫ Ϫ American Diabetes Association: Standards of kg 1 day 1 may prove useful in slowing renal insufficiency (serum creatinine Ͼ medical care in diabetes (Position State- the decline of GFR in selected patients. 1.5 mg/dl), ARBs have been shown ment). Diabetes Care 27: (Suppl. 1):S15– On the other hand, nutrition deficiency to delay the progression of nephrop- S35, 2004 may occur in some individuals and may athy. (A) American Diabetes Association: Hypertension be associated with muscle weakness. Pro- management in adults with diabetes (Posi- tein-restricted meal plans should be de- ● If one class is not tolerated, the other tion Statement). Diabetes Care 27 (Suppl. signed by a registered dietitian familiar should be substituted. (E) 1):S65–S67, 2004 with all components of the dietary man- Bakris GL, Williams M, Dworkin L, Elliott WJ, agement of diabetes. ● With regards to slowing the progres- Epstein M, Toto R, Tuttle K, Douglas J, sion of nephropathy, the use of DCCBs Hsueh W, Sowers J: Preserving renal func- OTHER ASPECTS as initial therapy is not more effective tion in adults with hypertension and diabe- OF TREATMENT — Other standard than placebo. Their use in nephropathy tes: a consensus approach. Am J Kid Dis 36: modalities for the treatment of progres- should be restricted to additional ther- 646–661, 2000 Brenner BM, Cooper ME, de Zeeuw D, Keane sive renal disease and its complications apy to further lower blood pressure in (e.g., osteodystrophy) must also be used WF, Mitch WE, Parving HH, Remuzzi G, patients already treated with ACE in- Snapinn SM, Zhang Z, Shahinfar S: Effects when indicated, such as sodium and hibitors or ARBs. (B) phosphate restriction and use of phos- of on renal and cardiovascular out- comes in patients with type 2 diabetes and phate binders. When the GFR begins to ● In the setting of the albuminuria or ne- nephropathy. N Engl J Med 345:861–869, 2001 decline substantially, referral to a physi- phropathy, in patients unable to toler- cian experienced in the care of such pa- DeFronzo RA: Diabetic nephropathy: etiologic ate ACE inhibitors and/or ARBs, and therapeutic considerations. Diabetes tients is indicated. Radiocontrast media consider the use of non-DCCBs, Rev 3:510–564, 1995 are particularly nephrotoxic in patients ␤-blockers, or diuretics for the manage- Diabetes Control and Complications Trial Re- with diabetic nephropathy, and azotemic ment of blood pressure. (E) search Group: The effect of intensive treat- patients should be carefully hydrated be- ment of diabetes on the development and fore receiving any procedures requiring ● With the onset of overt nephropathy, progression of long-term complications in contrast that cannot be avoided. initiate protein restriction to Յ0.8 g insulin-dependent diabetes mellitus. N Engl Ϫ Ϫ kg 1 body wt day 1 (ϳ10% of daily J Med 329:977–986, 1993 General recommendations calories), the current adult RDA for Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde ● protein. Further restriction may be use- To reduce the risk and/or slow the pro- BS, Raz I: Renoprotective effect of the angio- gression of nephropathy, optimize glu- ful in slowing the decline of GFR in se- tensin-receptor antagonist in pa- cose control. (A) lected patients. (B) tients with nephropathy due to type 2 diabetes. N Eng J Med 345:851–860, 2001 ● ● To reduce the risk and/or slow the pro- If ACE inhibitors or ARBs are used, Lewis EJ, Hunsicker LG, Bain RP, and Rohde gression of nephropathy, optimize monitor serum potassium levels for the RD. The effect of angiotensin-converting- blood pressure control. (A) development of hyperkalemia. (B) enzyme inhibition on diabetic nephropa- thy. The Collaborative Study Group. N Engl ● Consider referral to a physician experi- J Med 329:1456–1462, 1993 Screening Mogensen CE, Keane WF, Bennett PH, Jerums ● enced in the care of diabetic renal dis- Perform an annual test for the presence ease when either the GFR has fallen to G, Parving H-H, Passa P, Steffes MW, Striker of microalbuminia in 1) type 1 diabetic Ͻ Ϫ1 Ϫ2 GE, Viberti GC: Prevention of diabetic renal Ͼ 60 ml min 1.73 m or difficul- patients who have had diabetes 5 ties have occurred in the management disease with special reference to microalbu- years and 2) all type 2 diabetic patients of hypertension or hyperkalemia. (B) minuria. Lancet 346:1080–1084, 1995 starting at diagnosis. (E) Mogensen CE, Neldam S, Tikkanen I, Oren S, SUMMARY — Annual screening for Viskoper R, Watts RW, Cooper ME: Ran- domised controlled trial of dual blockade of Treatment microalbuminuria will allow the identifi- ● renin-angiotensin system in patients with In the treatment of albuminuria/ cation of patients with nephropathy at a hypertension, microalbuminuria, and non- nephropathy both ACE inhibitors and point very early in its course. Improving insulin dependent diabetes: the Candesar- ARBs can be used: glycemic control, aggressive antihyper- tan and Microalbuminuria (CALM) • In hypertensive type 1 diabetic pa- tensive treatment, and the use of ACE in- Study. BMJ 1440–1444, 2000 tients with any degree of albumin- hibitors or ARBs will slow the rate of Parving HH, Lehnert H, Brochner-Mortensen uria, ACE inhibitors have been progression of nephropathy. In addition, J, Gomis R, Andersen S, Arner P: The effect shown to delay the progression of ne- protein restriction and other treatment of irbesartan on the development of diabetic

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

nephropathy in patients with type 2 diabe- 720, 1998 (UKPDS 33). Lancet 352:837– 853, 1998 tes. N Engl J Med 345:870–878, 2001 UK Prospective Diabetes Study Group: In- UK Prospective Diabetes Study Group: Tight UK Prospective Diabetes Study Group: Effi- tensive blood glucose control with sul- blood pressure control and risk of macro- cacy of atenolol and in reducing phonylureas or insulin compared with vascular and microvascular complications the risk of macrovascular complications in conventional treatment and risk of com- in type 2 diabetes (UKPDS 38). BMJ 317: type 2 diabetes (UKPDS 39). BMJ 317:713– plications in patients with type 2 diabetes 703–713, 1998

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