POSITION STATEMENT

Diabetic Nephropathy

AMERICAN ASSOCIATION

iabetes has become the most com- NATURAL HISTORY OF GFR begins to fall, the rates of fall in GFR mon single cause of end-stage renal DIABETIC NEPHROPATHY — are again highly variable from one indi- D disease (ESRD) in the U.S. and Eu- The earliest clinical evidence of nephrop- vidual to another, but overall, they may rope; this is due to the facts that 1) dia- athy is the appearance of low but abnor- not be substantially different between pa- betes, particularly type 2, is increasing in mal levels (Ն 30 mg/day or 20 ␮g/min) of tients with type 1 and patients with type 2 prevalence; 2) diabetes patients now live albumin in the urine, referred to as mi- diabetes. However, the greater risk of dy- longer; and 3) patients with diabetic ESRD croalbuminuria, and patients with mi- ing from associated coronary artery dis- are now being accepted for treatment in croalbuminuria are referred to as having ease in the older population with type 2 ESRD programs where formerly they had incipient nephropathy. Without specific diabetes may prevent many with earlier been excluded. In the U.S., diabetic ne- interventions, ϳ80% of subjects with stages of nephropathy from progressing phropathy accounts for about 40% of new who develop sustained to ESRD. As therapies and interventions cases of ESRD, and in 1997, the cost for have their urinary al- for coronary artery disease continue to treatment of diabetic patients with ESRD bumin excretion increase at a rate of improve, however, more patients with was in excess of $15.6 billion. About 20– ϳ10–20% per year to the stage of overt may be expected to sur- 30% of patients with type 1 or type 2 di- nephropathy or clinical vive long enough to develop renal failure. abetes develop evidence of nephropathy, (Ն300 mg/24 h or Ն200 ␮g/min) over a In addition to its being the earliest but in type 2 diabetes, a considerably period of 10–15 years, with manifestation of nephropathy, albumin- smaller fraction of these progress to also developing along the way. Once overt uria is a marker of greatly increased car- ESRD. However, because of the much nephropathy occurs, without specific in- diovascular morbidity and mortality for greater prevalence of type 2 diabetes, such terventions, the glomerular filtration rate patients with either type 1 or type 2 dia- patients constitute over half of those dia- (GFR) gradually falls over a period of sev- betes. Thus, the finding of microalbumin- betic patients currently starting on dialy- eral years at a rate that is highly variable uria is an indication for screening for sis. There is considerable racial/ethnic from individual to individual (2–20 ml possible vascular disease and aggressive Ϫ Ϫ variability in this regard, with Native min 1 year 1). ESRD develops in 50% intervention to reduce all cardiovascular Americans, Hispanics (especially Mexi- of type 1 diabetic individuals with overt risk factors (e.g., lowering of LDL choles- can-Americans), and African-Americans nephropathy within 10 years and in terol, antihypertensive therapy, cessation having much higher risks of developing Ͼ75% by 20 years. of smoking, institution of exercise, etc.). ESRD than non-Hispanic whites with A higher proportion of individuals In addition, there is some preliminary ev- type 2 diabetes. Recent studies have now with type 2 diabetes are found to have idence to suggest that lowering of choles- demonstrated that the onset and course of microalbuminuria and overt nephropa- terol may also reduce the level of diabetic nephropathy can be ameliorated thy shortly after the diagnosis of their di- . to a very significant degree by several in- abetes, because diabetes is actually terventions, but these interventions have present for many years before the diagno- their greatest impact if instituted at a sis is made and also because the presence SCREENING FOR point very early in the course of the de- of albuminuria may be less specific for the ALBUMINURIA — A routine urinal- velopment of this . This po- presence of diabetic nephropathy, as ysis should be performed at diagnosis in sition statement is based on recent review shown by biopsy studies. Without spe- patients with type 2 diabetes. If the urinal- articles that discuss published research cific interventions, 20–40% of type 2 pa- ysis is positive for protein, a quantitative and issues that remain unresolved and tients with microalbuminuria progress to measure is frequently helpful in the devel- provides recommendations regarding the overt nephropathy, but by 20 years after opment of a treatment plan. If the urinal- detection, prevention, and treatment of onset of overt nephropathy, only ϳ20% ysis is negative for protein, a test for the early nephropathy. will have progressed to ESRD. Once the presence of microalbumin is necessary. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Microalbuminuria rarely occurs with short duration of type 1 diabetes; there- The recommendations in this paper are based on the evidence reviewed in the following publications: fore, screening in individuals with type 1 Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Rev 3:510–564, 1995; and Pre- vention of diabetic renal disease with special reference to microalbuminuria. Lancet 346:1080–1084, 1995. diabetes should begin after 5 years’ dis- The initial draft of this paper was prepared by Mark E. Molitch, MD (chair); Ralph A. DeFronzo, MD; Marion ease duration. Some evidence suggests J. Franz, MS, RD, CDE; William F. Keane, MD; Carl Erik Mogensen, MD; Hans-Henrik Parving, MD; and Michael that the prepubertal duration of diabetes W. Steffes, MD, PhD. The paper was peer-reviewed, modified, and approved by the Professional Practice Com- may be important in the development of mittee and the Executive Committee, November 1996. Most recent review/revision, October 2001. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DCCB, dihy- microvascular complications; therefore, dropyridine calcium channel blocker; ESRD, end-stage renal disease: GFR, glomerular filtration rate; clinical judgement should be exercised UKPDS, United Kingdom Prospective Diabetes Study. when individualizing these recommenda-

DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 S85 Position Statement

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

S86 DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 Position Statement

with increased intra-glomerular pressure and increased sensitivity to angiotensin II; the single- hyperfiltration with intraglomerular hypertension is itself damaging. Many studies have shown that in hypertensive patients with type 1 dia- betes, ACE inhibitors can reduce the level of albuminuria and can reduce the rate of progression of renal disease to a greater degree than other antihypertensive agents that lower blood pressure by an equal amount. Other studies have shown that there is benefit in reducing the progres- sion of microalbuminuria in normoten- sive patients with type 1 diabetes and normotensive and hypertensive patients with type 2 diabetes. Use of ACE inhibitors or ARBs may exacerbate hyperkalemia in patients with advanced renal insufficiency and/or hy- poreninemic . In older 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- Figure 1—Screening for microalbuminuria. quently to ESRD, use of ACE inhibitors or In type 1 diabetes, screening for microalbuminuria should begin after 5 years’ disease duration. ARBs is recommended for all patientsء with microalbuminuria or advanced stages of neuropathy. The effect of ACE inhibitors appears to be a class effect, so A major aspect of initial treatment tions may be added in stepwise fashion choice of agent may depend on cost and should consist of lifestyle modifications, and their individual use may depend on compliance issues. such as weight loss, reduction of salt and other factors such as fluid overload and The recent UKPDS compared antihy- alcohol intake, and exercise, as outlined vascular disease. pertensive treatment with an ACE inhibitor in the “Standards of Medical Care for Pa- to that with a ␤-blocker. Both drugs were tients with Diabetes Mellitus” and the po- equally effective in lowering blood pressure sition statement on “Treatment of USE OF and there were no significant differences Hypertension in Adults with Diabetes.” In ANTIHYPERTENSIVE in the incidence of microalbuminuria or patients with underlying nephropathy, AGENTS — The positive response to proteinuria. However, because of the low treatment with ACE inhibitors or ARBs is antihypertensive treatment coupled with prevalence of nephropathy in the popula- also indicated as part of initial therapy the concept that often there is a progres- tion studied, it is unclear whether there (see below). If after 4–6 weeks sufficient sive deterioration of renal function re- were sufficient events to observe a protec- blood pressure reduction has not oc- gardless of the underlying etiology gave tive effect of either drug on the progres- curred, additional pharmacological ther- rise to the idea that hemodynamic factors sion of nephropathy. Some studies have apy is indicated. (See the American may be critical in furthering the fall in demonstrated that the non-dihydropyri- Diabetes Association position statement GFR. In this hypothesis, damage to glo- dine calcium channel blocker (NDCCB) “Treatment of Hypertension in Adults meruli causes changes in the microcircu- classes of calcium-channel blockers can with Diabetes” for a complete discussion lation that result in hyperfiltration reduce the level of albuminuria, but no on this subject.) In general, these medica- occurring in the remaining glomeruli studies to date have demonstrated a re-

DIABETES CARE, VOLUME 25, SUPPLEMENT 1, JANUARY 2002 S87 Position Statement duction in the rate of fall of GFR with their ● To reduce the risk and/or slow the pro- ● Consider the use of non-DCCBs in pa- use. gression of nephropathy, optimize tients unable to tolerate ACE inhibitors blood pressure control. or ARBs. PROTEIN RESTRICTION — Animal studies have shown that restriction of di- Screening SUMMARY — Annual screening for etary protein intake also reduces hyperfil- Expert consesus microalbuminuria will allow the identifi- tration and intraglomerular pressure and ● Perform an annual test for the presence cation of patients with nephropathy at a retards the progression of several models of microalbuminia in 1) type 1 diabetic point very early in its course. Improving of renal disease, including diabetic glo- patients who have had diabetes Ͼ5 glycemic control, aggressive antihyper- merulopathy: Several small studies in hu- years and 2) all type 2 diabetic patients tensive treatment, and the use of ACE in- mans with diabetic nephropathy have starting at diagnosis. hibitors or ARBs will slow the rate of shown that a prescribed protein- progression of nephropathy. In addition, Ϫ1 Ϫ1 restricted diet of 0.6 g kg day (sub- protein restriction and other treatment jects actually only achieved a restriction of Treatment modalities such as phosphate lowering Ϫ1 Ϫ1 0.8 g kg day ) retards the rate of fall A-Level evidence may have benefits in selected patients. of GFR modestly. However, the Modified ● In the treatment of albuminuria/ Diet in Renal Disease Study, in which only nephropathy both ACE inhibitors and 3% of the patients had type 2 diabetes and ARBs can be used: Bibliography none had type 1 diabetes, failed to show a • In hypertensive and nonhypertensive American Diabetes Association. Diabetes 2001 clear benefit of protein restriction. type 1 diabetic patients with mi- Vital Statistics. Alexandria, VA, ADA, 2001 At this point in time, the general con- croalbuminuria or clinical albumin- American Diabetes Association: Standards of sensus is to prescribe a protein intake of uria, ACE inhibitors are the initial medical care for patients with diabetes mel- approximately the adult Recommended agents of choice; litus (Position Statement). Diabetes Care 25: Ϫ Dietary Allowance (RDA) of 0.8 g kg 1 • In hypertensive type 2 diabetic pa- (Suppl. 1):S33–S49, 2002 Ϫ day 1 (ϳ 10% of daily calories) in the tients wiht microalbuminuria or clin- American Diabetes Association: Treatment of ical albuminuria, ARBS are the initial hypertension in adults with diabetes (Posi- patient with overt nephropathy. How- tion Statement). Diabetes Care 25 (Suppl. ever, it has been suggested that once the agents of choice. 1):S71–S73, 2002 GFR begins to fall, further restriction to Bakris GL, Williams M, Dworkin L, Elliott WJ, Ϫ1 Ϫ1 0.6 g kg day may prove useful in ● If one class is not tolerated, the other Epstein M, Toto R, Tuttle K, Douglas J, slowing the decline of GFR in selected pa- should be substituted. Hsueh W, Sowers J: Preserving renal func- tients. On the other hand, nutrition defi- tion in adults with hypertension and diabe- ciency may occur in some individuals and tes: a consensus approach. Am J Kid Dis 36: may be associated with muscle weakness. B-Level evidence 646–661, 2000 ● Protein-restricted meal plans should be With the onset of overt nephropathy, Brenner BM, Cooper ME, de Zeeuw D, Keane initiate protein restriction to Յ0.8 g WF, Mitch WE, Parving HH, Remuzzi G, designed by a registered dietitian familiar Ϫ Ϫ kg 1 body wt day 1 (ϳ10% of daily Snapinn SM, Zhang Z, Shahinfar S: Effects with all components of the dietary man- of on renal and cardiovascular out- agement of diabetes. calories), the current adult recom- mended daily allowance for protein. comes in patients with type 2 diabetes and nephropathy. N Engl J med 345:861–869, 2001 OTHER ASPECTS Further restriction may be useful in DeFronzo RA: Diabetic nephropathy: etiologic OF TREATMENT — Other standard slowing the decline of GFR in selected and therapeutic considerations. Diabetes modalities for the treatment of progres- patients. Rev 3:510–564, 1995 sive renal disease and its complications Diabetes Control and Complications Trial Re- (e.g., osteodystrophy) must also be used ● Combination of ACE inhibitors and search Group: The effect of intensive treat- ment of diabetes on the development and when indicated, such as sodium and ARBs will decrease albuminuria more phosphate restriction and use of phos- progression of long-term complications in than use of either agent alone. insulin-dependent diabetes mellitus. N Engl phate binders. When the GFR begins to J Med 329:977–986, 1993 decline substantially, referral to a physi- Lewis EJ, Hunsicker LG, Clarke WR, Berl T, cian experienced in the care of such pa- Expert consensus ● If ACE inhibitors or ARBs are used, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde tients is indicated. Radiocontrast media BS, Raz I: Renoprotective effect of the angio- monitor serum potassium levels for the are particularly nephrotoxic in patients tensin-receptor antagonist in pa- with diabetic nephropathy, and azotemic development of hyperkalemia. tients with nephropathy due to type 2 patients should be carefully hydrated be- diabetes. N Eng J Med 345:851–860, 2001 fore receiving any procedures requiring ● Consider referral to a physician experi- Lewis EJ, Hunsicker LG, Bain RP, and Rohde contrast that cannot be avoided. enced in the care of diabetic renal dis- RD. The effect of angiotensin-converting- ease when the GFR has fallen to either enzyme inhibition on diabetic nephropa- Ϫ Ϫ thy. The Collaborative Study Group. N Engl General recommendations Ͻ70 ml min 1 173 m 2, serum cre- Ͼ J Med 329:1456–1462, 1993 A-Level evidence atinine has increased to 2.0 mg/dl Mogensen CE, Keane WF, Bennett PH, Jerums ● To reduce the risk and/or slow the pro- (Ͼ180 ␮mol/l), or difficulties occur in G, Parving H-H, Passa P, Steffes MW, Striker gression of nephropathy, optimize glu- the management of hypertension or hy- GE, Viberti GC: Prevention of diabetic renal cose control. perkalemia. disease with special reference to microalbu-

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minuria. Lancet 346:1080–1084, 1995 J, Gomis R, Andersen S, Arner P: The effect tensive blood glucose control with sul- Mogensen CE, Neldam S, Tikkanen I, Oren S, of irbesartan on the development of diabetic phonylureas or insulin compared with Viskoper R, Watts RW, Cooper ME: Ran- nephropathy in patients with type 2 diabe- conventional treatment and risk of com- domised controlled trial of dual blockade tes. N Engl J Med 345:870–878, 2001 plications in patients with type 2 diabetes ofrenin-angiotensin system in patients with UK Prospective Diabetes Study Group: Effi- (UKPDS 33). Lancet 352:837– 853, 1998 hypertension, microalbuminuria, and non- cacy of atenolol and in reducing UK Prospective Diabetes Study Group: Tight insulin dependent diabetes: the candesartan the risk of macrovascular complications in blood pressure control and risk of macro- and microalbuminuria (CALM) type 2 diabetes (UKPDS 39). BMJ 317:713– vascular and microvascular complications study. BMJ 1440–1444, 2000 720, 1998 in type 2 diabetes (UKPDS 38). BMJ 317: Parving HH, Lehnert H, Brochner-Mortensen UK Prospective Diabetes Study Group: In- 703–713, 1998

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