CLINICA L PR AC TICE
Clinical Practice
This Journal feature begins with a case vignette highlighting
a common clinical problem. Evidence supporting various
strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the authors’
clinical recommendations.
N EPHROPATHY IN P ATIENTS
WITH T YPE 2 D IABETES
GIUSEPPE REMUZZI, M.D., ARRIGO SCHIEPPATI, M.D.,
AND PIERO RUGGENENTI, M.D.
A 60-year-old man was found to have type 2 di-
abetes mellitus two months ago. He has a serum
creatinine level of 1.5 mg per deciliter (133 µmol
per liter); a dipstick test shows proteinuria (++).
His systolic blood pressure is 150 mm Hg, and his
diastolic pressure is 90 mm Hg. He smokes half
a pack of cigarettes daily. What can be done to
reduce his risk of progressive renal disease?
THE CLINICAL PROBLEM
Nephropathy associated with type 2 diabetes is
the most frequent cause of end-stage renal disease in
the United States, Europe, and Japan. In the United
States, the incidence of diabetic nephropathy has in-
creased by 150 percent in the past 10 years, a trend
also seen in Europe.1,2 In North America, 40 percent
of patients starting dialysis in 1998 had diabetic ne-
phropathy. Among patients who require dialysis, those
with diabetes have a 22 percent higher mortality at
one year and a 15 percent higher mortality at five
years than patients without diabetes. In 1998, the es-
timated cost of care for a diabetic patient undergo-
ing dialysis was $51,000 per year, which was about
$12,000 more than the cost for a nondiabetic patient.1
The first sign of renal involvement in patients with
type 2 diabetes is most often microalbuminuria (uri-
nary albumin excretion, 20 to 200 µg per minute in
an overnight urine sample), which is classified as in-
cipient nephropathy (Table 1).3 Microalbuminuria af-
fects 20 to 40 percent of patients 10 to 15 years after
the onset of diabetes. Progression to macroalbumin-
uria (urinary albumin excretion, >200 µg per min-
From the Unit of Nephrology, Ospedali Riuniti di Bergamo; and the
Clinical Research Center for Rare Diseases, Mario Negri Institute for Phar-
macological Research — both in Bergamo, Italy. Address reprint requests
to Dr. Schieppati at Mario Negri Institute, Via Gavazzeni 11, 24100 Ber-
gamo, Italy.
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ute), or overt nephropathy, occurs in 20 to 40 per-
cent of patients over a period of 15 to 20 years after
the onset of diabetes. Once macroalbuminuria is
present, creatinine clearance declines at a rate that
varies widely from patient to patient; the average
reduction is 10 to 12 ml per minute per year in
untreated patients.4,5 Hypertension and proteinuria
may accelerate the decline in the glomerular filtration
rate and the progression to end-stage renal disease.
STRATEGIES AND EVIDENCE
Screening for Microalbuminuria
Early recognition of renal changes increases the
chance to prevent the progression from incipient to
overt nephropathy. A routine dipstick urinalysis should
be performed at the time of diagnosis, because of the
difficulty in precisely dating the onset of type 2 dia-
betes. If the test is positive for protein, analysis of a
24-hour urine sample is recommended for quantifi-
cation of urinary protein excretion (Fig. 1). Since a
negative dipstick test for protein does not rule out mi-
croalbuminuria, a more sensitive method should be
used (e.g., the Micral test or radioimmunoassay for
albumin) and repeated every year, if the result is neg-
ative. If the result is positive, microalbuminuria can
be confirmed and quantified by measuring the ratio
of albumin to creatinine in a morning urine sample or
by measuring the rate of albumin excretion in a 24-
hour or overnight urine sample. Overnight samples
can be used to distinguish true microalbuminuria from
postural or exercise proteinuria, which are common in
young patients. Isolated microalbuminuria or macroal-
buminuria usually indicates the presence of diabetic
nephropathy, but the presence of other abnormalities
on urinalysis suggests another renal disease.
Screening for and monitoring of background or
proliferative retinopathy are especially important in all
patients with urinary abnormalities.3 If retinopathy is
present, albuminuria can be attributed with confidence
to diabetic nephropathy; if there is no evidence of ret-
inopathy, one should look for other causes of albu-
minuria (Fig. 1).
Glycemic Control
Hyperglycemia is a risk factor for diabetic nephrop-
athy,6 and in patients with overt nephropathy, the
mean level of glycosylated hemoglobin is correlated
with the loss of renal function.7 The United Kingdom
Prospective Diabetes Study8 showed that intensive
control of blood glucose with sulfonylureas or insu-
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

type 2 diabetes and in up to 40 percent of those with

TABLE 1. STAGES OF RENAL INVOLVEMENT ACCORDING
THE URINARY ALBUMIN LEVEL IN PATIENTS
WITH TYPE 2 DIABETES MELLITUS.
STAGE
NONTIMED URINARY
ALBUMIN SAMPLE
ADJUSTED
FOR
URINARY
CREATININE
UNADJUSTED LEVEL
µg/ml mg/g
Normoalbuminuria <20 <30
Microalbuminuria (incipi- 20–200 30–300
ent nephropathy)*
Macroalbuminuria (overt >200 >300
nephropathy)*
*The values for microalbuminuria and macroalbuminuria are based on
the assumption that any factors that might increase the rate of urinary al-
bumin excretion, including exercise, excessive protein intake, congestive heart
failure, hematuria, uncontrolled hypertension or diabetes, urinary tract in-
fection, and contamination of the urine specimen with vaginal fluid, have been
eliminated or controlled for.
lin reduces the risk of diabetic nephropathy and other
microvascular complications, although not macrovas-
cular complications, in patients with type 2 diabetes.
In a randomized study conducted in Japan, intensive
control of type 2 diabetes with three or more insulin
injections per day resulted in a lower rate of new or
progressive nephropathy over a period of six years than
did conventional therapy with one or two injections
per day (7.7 percent vs. 28 percent).9
In the subgroup of participants in the United King-
dom Prospective Diabetes Study who were overweight
(defined as >120 percent of ideal body weight),10 the
effect of the biguanide metformin in reducing the risk
of renal failure was similar to that of other hypogly-
cemic agents, but metformin resulted in a significantly
lower risk of myocardial infarction than did the other
agents. However, metformin should not be used to
lower the glucose level when renal function is impaired
(serum creatinine level, »1.5 mg per deciliter [133
µmol per liter] in men and »1.4 mg per deciliter
[124 µmol per liter] in women) or when creatinine
clearance is abnormal, because of the associated in-
crease in the risk of lactic acidosis.
Blood-Pressure Control
Thirty percent of patients with type 2 diabetes have
hypertension at the time of the diagnosis of diabetes;
when nephropathy develops, almost 70 percent have
high blood pressure.11 Renal vascular disease contrib-
utes to hypertension in 20 percent of patients with
TO overt nephropathy.12 High blood pressure accelerates
the progressive increase in albumin levels in patients
with type 2 diabetes who have initially normal albu-
min levels and accelerates the loss of renal function in
TIMED URINARY
ALBUMIN SAMPLE
those with overt nephropathy.13 Both effects are pre-
vented or limited by antihypertensive therapy.14
Agents that inhibit the renin–angiotensin system
appear to be particularly effective in reducing the risk
OVERNIGHT 24-HR of the development or progression of overt nephrop-
µg/min mg/24 hr athy. The diabetes substudy of the Heart Outcomes
Prevention Evaluation (HOPE) study15 showed that
<20 <30
at similar blood pressures, an angiotensin-converting–
20–200 30–300
enzyme (ACE) inhibitor resulted in a 24 percent great-
>200 >300 er decrease in the rate of progression to overt nephrop-
athy than did placebo in patients with type 2 diabetes
and normoalbuminuria or microalbuminuria. In the
Irbesartan in Patients with Type 2 Diabetes and Mi-
croalbuminuria Study,16 treatment with irbesartan at
a dose of 300 mg per day decreased the level of urinary
albumin excretion by 38 percent from base line, and,
over a three-year follow-up period, reduced the risk
of progression to macroalbuminuria by 70 percent as
compared with placebo.
Six small trials, involving a total of 352 patients with
type 2 diabetes and overt nephropathy, showed that
ACE inhibitors were more effective than other anti-
hypertensive drugs (angiotensin II–receptor antago-
nists were not included) in reducing proteinuria.17
However, the six studies did not have sufficient statis-
tical power to detect an effect on the decline in the
glomerular filtration rate. The Reduction of Endpoints
in NIDDM with the Angiotensin II Antagonist Lo-
sartan (RENAAL) study showed that as compared
with conventional treatment alone (i.e., treatment
without ACE inhibitors), losartan combined with con-
ventional treatment decreased the level of urinary pro-
tein excretion by 35 percent and reduced the risk of
end-stage renal disease by 28 percent.18 In the Irbe-
sartan Diabetic Nephropathy Trial, the risk of the
combined end point of a doubling of the base-line
serum creatinine level, the onset of end-stage renal
disease, or death from any cause was 20 percent lower
in patients treated with irbesartan than in those treat-
ed with conventional therapy and 23 percent lower
than in those treated with amlodipine.19 These stud-
ies also showed a reduction in the rate of heart fail-
ure with angiotensin II antagonists but no differenc-
es in the overall rate of death or the rate of death
from cardiovascular causes.
Hyperkalemia is a recognized risk of antagonists of
the renin–angiotensin system, but pooled data from
large clinical trials suggest that the risk is low.18-20 Only
1.5 percent of patients treated with ACE inhibitors or
angiotensin II–receptor antagonists were withdrawn
from trials because of hyperkalemia, and no deaths

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 CLINICA L PR AC TICE

Perform dipstick test

for macroalbuminuria
(nontimed urine collection)

Positive Negative

Perform confirmatory test

(timed urine collection)
Perform dipstick test
for microalbuminuria
(nontimed urine collection)
Eliminate confounders
Positive Negative
Positive Negative

Perform confirmatory test

Screen for retinopathy (timed urine collection)
Rescreen
every
Positive Negative year
Eliminate confounders

Overt Continue evaluation Positive Negative

nephropathy for nondiabetic
renal disease
Incipient
nephropathy

Start
treatment
Start
treatment

Figure 1. Screening for Nephropathy in Patients with Type 2 Diabetes.

Dipstick tests for macroalbuminuria or microalbuminuria may have false negative results in patients treated with angio-
tensin-converting–enzyme inhibitors, angiotensin II–receptor antagonists, or nondihydropyridine calcium-channel
blockers, since these drugs may reduce the rate of urinary albumin excretion. The confirmatory test for macroalbumin-
uria or microalbuminuria should be repeated after factors that could invalidate the measurements have been eliminated
or controlled for. Microalbuminuria should be confirmed by at least two tests over a period of three to six months.

were reported in association with hyperkalemia in any
treatment group.18-20
AREAS OF UNCERTAINTY
Role of Other Antihypertensive Agents
Dihydropyridine calcium-channel blockers (e.g., ni-
fedipine and amlodipine) may worsen proteinuria and
accelerate the progression of disease in patients with
nondiabetic or diabetic nephropathy.21-23 These find-
ings are at variance with the effects of the nondihy-
dropyridine calcium-channel blockers, diltiazem and
verapamil, which may reduce overt proteinuria and
improve glomerular size selectivity in patients with
nephropathy due to type 2 diabetes.24 According to a
meta-analysis, at any level of blood-pressure control,
patients with diabetes who were treated with dihy-
dropyridine calcium-channel blockers had more severe
proteinuria and a more rapid decline in the glomerular
filtration rate than those treated with other antihyper-
tensive agents.25 However, in the RENAAL study, the
effect of losartan in reducing the risk of renal events
was not diminished by concomitant use of dihydropyr-
idine calcium-channel blockers.18
Beta-blockers may also be beneficial in the treat-
ment of diabetic nephropathy. In the United Kingdom
Prospective Diabetes Study, beta-blockers and ACE
inhibitors were equally effective in lowering the inci-
dence of microalbuminuria and macroalbuminuria in
patients with type 2 diabetes.26 A small study involving
patients with overt nephropathy also found that beta-
blockers and ACE inhibitors had similar protective ef-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
fects on renal function.27 In the RENAAL study, losar-
tan did not offer additional renal protection in pa-
tients who were already receiving treatment with beta-
blockers.18 The question of whether beta-blockers
offer as much renal protection as angiotensin II–
receptor antagonists needs to be answered by a direct
comparison of the two classes of drugs. No large stud-
ies have compared the effects of diuretics, beta-block-
ers, or calcium-channel blockers with the effects of
ACE inhibitors or angiotensin II–receptor antagonists
in patients with diabetes who have overt nephropathy.
Combination of Antihypertensive Drugs
The antiproteinuric effects of inhibitors of the re-
nin–angiotensin system are increased by sodium re-
striction and by concomitant administration of diuret-
ics or nondihydropyridine calcium-channel blockers.
In patients with type 2 diabetes who have microalbu-
minuria, the combined treatment with lisinopril and
candesartan was more effective in reducing blood pres-
sure and albuminuria than either drug alone.28
Blood-Pressure Goals
The optimal range of blood pressure in patients with
type 2 diabetes is unclear. In recent trials involving pa-
tients with type 2 diabetes, there were no more car-
diovascular events when diastolic blood pressure was
70 to 84 mm Hg than when it was 85 mm Hg or
higher.14 However, if diastolic blood pressure was less
than 70 mm Hg, the rates of cardiovascular events in-
creased by 11 percent for each additional reduction of
5 mm Hg, with an attendant increase in mortality.29
Treatment of Dyslipidemia
Dyslipidemia is common in patients with diabetes,
especially in those with overt nephropathy. A meta-
analysis of 13 controlled trials (involving a total of 362
subjects, 253 of whom had diabetes) showed that stat-
ins decreased proteinuria and preserved the glomer-
ular filtration rate in patients with chronic renal disease
— effects that are not entirely explained by a reduc-
tion in blood cholesterol.30
Protein Restriction
A randomized trial involving patients with type 1 di-
abetes and overt nephropathy showed that, as com-
pared with a high intake of protein and phosphorus,
restriction of protein and phosphorus (0.6 g of pro-
tein per kilogram of body weight per day and 500 to
1000 mg of phosphorus per day) reduced the decline
in the glomerular filtration rate, lowered blood pres-
sure, and stabilized renal function in some patients.31
Restriction of protein intake to 0.8 g per kilogram
per day, which is consistent with the recommended
daily allowance, also reduces the rate of progression to
end-stage renal disease in patients with type 1 dia-
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TABLE 2. RECOMMENDED INTERVENTIONS TO SLOW
THE PROGRESSION OF RENAL DISEASE IN PATIENTS
WITH TYPE 2 DIABETES.*
INTERVENTION TARGET
Blood-pressure control <130/80 mm Hg
Inhibition of renin–angiotensin Urinary protein excretion,
system <0.3 g/24 hr
Correction of dyslipidemia LDL cholesterol, <100 mg/dl
(2.6 mmol/liter)
Glycemic control Glycosylated hemoglobin, <7%
*Cessation of smoking, loss of weight, exercise, and reduction of protein,
salt, and alcohol intake are also recommended, as appropriate. LDL de-
notes low-density lipoprotein.
betes.32 There have been no large randomized trials
of protein restriction in patients with type 2 diabetes
mellitus.
Multidrug Treatment
The combination of ACE inhibitors, angiotensin
II–receptor antagonists, diuretics, and nondihydro-
pyridine calcium-channel blockers (to reduce blood
pressure to less than 125/75 mm Hg) and statins (to
lower the level of low-density lipoprotein cholesterol
to less than 100 mg per deciliter [2.6 mmol per liter]),
in conjunction with intensified metabolic control to
achieve a glycosylated hemoglobin level of less than
7.5 percent, was assessed in an uncontrolled study in-
volving 20 patients with chronic nephropathy and per-
sistent, nephrotic-range proteinuria (3 of whom had
type 2 diabetes).33 Fourteen patients, including the
three with diabetes, had a remission, as defined by a
rate of urinary protein excretion that remained lower
than 1 g per 24 hours and a decline in the glomerular
filtration rate of less than 1 ml per minute per 1.73 m2
of body-surface area per year (i.e., the physiologic
rate of renal-function loss associated with aging). In
a small, randomized, though unblinded, trial involving
patients with type 2 diabetes and microalbuminuria,
the rate of progression to overt nephropathy was low-
er among those assigned to an intensive intervention
program (including treatment of hyperglycemia, hy-
pertension, dyslipidemia, and microalbuminuria) than
among those assigned to conventional treatment; in-
tensive treatment also resulted in lower rates of ret-
inopathy and autonomic neuropathy.34
Smoking Cessation
Smoking, besides increasing the risk of cardiovas-
cular events, is an independent risk factor for the de-
velopment of nephropathy in patients with type 2 di-
 C LINICA L PR AC TICE

TABLE 3. SUGGESTED MEDICATIONS FOR HYPERTENSION IN PATIENTS WITH TYPE 2 DIABETES.*

DRUG DOSE RANGE SIDE EFFECTS† COMMENTS

ACE inhibitors Cough, hyperkalemia, rash, loss Cardioprotective effect in patients with
Captopril 25–150 mg/day in 2 or 3 divided doses of taste; rare effects (<1% of pa- cardiac ischemic disease, heart failure, or
Enalapril 5–40 mg/day in 1 or 2 divided doses tients): angioedema, leukopenia both; effectiveness definitively proved in
Lisinopril 5–40 mg/day in 1 or 2 divided doses patients with type 1 diabetic nephropa-
Ramipril 1.25–5 mg/day thy; dose should be adjusted according
Trandolapril 1–4 mg/day to renal function

Angiotensin II–receptor Hyperkalemia; rare effect (<1% of Renoprotective effect in patients with type
 antagonists patients): angioedema 2 diabetic nephropathy; dose does not
Losartan 25–100 mg/day in 1 or 2 divided doses need to be adjusted according to renal
Valsartan 80–320 mg/day function
Irbesartan 150–300 mg/day
Beta-blockers Bronchospasm, bradycardia, delayed Cardioprotective effect in patients with
Atenolol 25–100 mg/day atrioventricular conduction, heart cardiac ischemic disease, heart failure,
Metoprolol 50–300 mg/day failure, masked hypoglycemia; less or both
Propranolol 40–180 mg/day in 2 divided doses serious effects: impaired peripher-
al circulation, decreased exercise
tolerance, impotence
Diuretics Increased cholesterol and uric acid; Increase in antihypertensive and antipro-
rare effects: blood dyscrasia, pho- teinuric effects of ACE inhibitors and
tosensitivity, pancreatitis, hypona- angiotensin II–receptor antagonists;
tremia may increase antihypertensive effect of
all other drugs
Thiazide Hypokalemia, increased glucose Preferred in patients with normal renal
Chlorthalidone 12.5–50 mg/day function (serum creatinine, <1.5 mg/dl
Hydrochlorothiazide 12.5–50 mg/day [133 µmol/liter] in men and <1.4
mg/dl [124 µmol/liter] in women)
Loop Hypokalemia Preferred in patients with renal insufficien-
Furosemide 40–500 mg/day in 2 or 3 divided doses cy, fluid overload, or both; dose should
be adjusted according to renal function;
may help prevent or limit hyperkalemia
induced by ACE inhibitors or angioten-
sin II–receptor antagonists
Potassium-sparing Hyperkalemia in patients with renal May increase the antiproteinuric effect
Spironolactone 25 mg/day insufficiency, those treated with of ACE inhibitors and angiotensin II–
ACE inhibitors, angiotensin II– receptor antagonists; cardioprotective
receptor antagonists, or both; effect in patients with heart failure
gynecomastia
Alpha- and beta-blockers Postural hypotension, broncho- Cardioprotective effect in patients with
Carvedilol 12.5–50 mg/day in 2 divided doses spasm cardiac ischemic disease, heart failure, or
both; dose should be adjusted according
to renal function
Nondihydropyridine Constipation, bradycardia, delayed Avoid combined therapy with beta-block-
calcium-channel atrioventricular conduction, gin- ers because of their effect on atrioven-
blockers‡ gival hyperplasia tricular conduction
Diltiazem 120–360 mg/day in 1 or 2 divided doses
Verapamil 90–480 mg/day in 1 or 2 divided doses

*Angiotensin-converting–enzyme (ACE) inhibitors or angiotensin II–receptor antagonists should be used as first-line therapy, unless there is a contra-
indication. If first-line agents are contraindicated or do not adequately control blood pressure, beta-blockers or diuretics should be used.
†The listed side effects are those that are most common, unless otherwise indicated.
‡Dihydropyridine calcium-channel blockers, other adrenergic inhibitors, and direct vasodilators should be used if the listed drugs, even in combination,
do not achieve the target blood pressure.

abetes and is associated with an accelerated loss of renal
function. Smoking cessation alone may reduce the risk
of disease progression by 30 percent.35
Can Diabetic Nephropathy Be Prevented?
Among diabetic participants in the HOPE study
who did not have microalbuminuria at base line, treat-
ment with an ACE inhibitor resulted in a nonsignif-
icant reduction in the risk of microalbuminuria.15
Insofar as diabetic nephropathy is best prevented by
preventing diabetes, it is relevant that recent studies
suggest that dietary modification and increased phys-
ical activity can substantially reduce the risk of type 2
diabetes.36,37 Post hoc analyses of data from HOPE,38
the Captopril Prevention Project,39 and the West of
Scotland Coronary Prevention Study40 showed reduc-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
tions in the incidence of diabetes with long-term ACE-
inhibitor treatment38,39 or statin therapy,40 but these
findings require confirmation.
GUIDELINES
Clinical-practice guidelines issued by the American
Diabetes Association41 and the Canadian Diabetes As-
sociation42 for the management of type 2 diabetes rec-
ommend screening for microalbuminuria at the time
of the diagnosis of diabetes (with subsequent yearly
screening) and tight control of blood pressure, with
a systolic pressure of less than 130 mm Hg and a di-
astolic pressure of less than 80 mm Hg as desirable
targets. Other recommended measures include tight
glycemic control (glycosylated hemoglobin, <7 per-
cent), protein intake that does not exceed 0.8 g per
kilogram per day, and lifestyle modifications (cessa-
tion of smoking, weight loss, exercise, and reduction
of salt and alcohol intake). However, these and other
guidelines were published before the results of clin-
ical trials with angiotensin II–receptor antagonists.
Thus, these guidelines recommend ACE inhibitors
both in patients with incipient nephropathy and in
those with overt nephropathy, unless otherwise con-
traindicated. Guidelines aimed at reducing the risk of
cardiovascular disease recommend the use of statins as
needed to maintain low-density lipoprotein cholester-
ol at a level below 100 mg per deciliter.43 As noted
earlier, this approach may also have a renal benefit.
CONCLUSIONS AND RECOMMENDATIONS
Early detection of nephropathy in patients with di-
abetes is feasible and has important practical implica-
tions for improving the outcome. Screening should
start with a routine urinalysis; if the results are normal,
a more sensitive test for microalbuminuria is warrant-
ed. Quantitative determination of albuminuria is re-
quired to assess the stage of nephropathy.
Once incipient or overt nephropathy has been
detected, treatment is aimed at reducing the risk of dis-
ease progression and preventing cardiovascular com-
plications. Treatment should include lifestyle modifi-
cations (such as weight loss, exercise, and reduction of
protein, salt, and alcohol intake), smoking cessation,
tight glucose control (target glycosylated hemoglobin,
<7 percent), and control of blood pressure (Table 2).
All these approaches would be appropriate in the pa-
tient described in the case vignette.
Inhibition of the renin–angiotensin system with an
ACE inhibitor or angiotensin II–receptor antagonist
is warranted to decrease both blood pressure and al-
buminuria; the dose should be titrated upward to the
moderate or high range, as tolerated, to achieve a sys-
tolic pressure below 130 mm Hg and a diastolic pres-
sure below 80 mm Hg. Although data from clinical
trials provide stronger support for the use of angioten-
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sin II–receptor antagonists than for the use of other
agents in patients with type 2 diabetes and microalbu-
minuria or macroalbuminuria, in the absence of a di-
rect comparison of the two strategies, we consider ei-
ther of these classes of medication to be a reasonable
first choice. Serum potassium and creatinine should be
checked in all patients seven days after the initiation of
treatment with drugs that block the renin–angio-
tensin system and after any increase in the dose of
such drugs. A beta-blocker or diuretic — or if these
agents are inadequate, a nondihydropyridine calcium-
channel blocker — should be added if ACE inhibitors
or angiotensin II–receptor antagonists are insufficient
to maintain blood pressure in the desired range (Ta-
ble 3). We consider adding dihydropyridine calcium-
channel blockers or alpha-blockers only when the tar-
get for blood pressure is not met with the use of these
other approaches.
We use the same approaches in hypertensive patients
with normoalbuminuria, in order to delay or prevent
nephropathy. If tolerated, drugs that inhibit the renin–
angiotensin system are also recommended for normo-
tensive patients with microalbuminuria or macroalbu-
minuria; reduction of the albumin level is the main
goal in such patients.
Restriction of dietary protein (a maximum of 0.8 g
per kilogram of body weight per day, corresponding
to about 10 percent of total daily caloric intake) has
been rigorously studied only in patients with type 1
diabetes, but it may also be beneficial in those with
type 2 diabetes. Although studies of statins have not
been designed specifically to examine their use in pa-
tients with renal disease, available data suggest that
these medications may not only reduce the risk of
cardiovascular disease but also slow the loss of renal
function.10
REFERENCES
1. Renal Data System. USRDS 2000 annual data report. Bethesda, Md.:
National Institute of Diabetes and Digestive and Kidney Diseases, 2001.
(Accessed March 18, 2002, at http://www.usrds.org/adr_2000.htm.)
2. European Dialysis and Transplant Association. Report on management
of renal failure in Europe, XXVI, 1995. Nephrol Dial Transplant 1996;11:
Suppl 7:1-32.
3. Ruggenenti P, Remuzzi G. The diagnosis of renal involvement in non-
insulin-dependent diabetes mellitus. Curr Opin Nephrol Hypertens 1997;
6:141-5.
4. UK Prospective Diabetes Study (UKPDS). IX. Relationships of urinary
albumin and N-acetylglucosaminidase to glycaemia and hypertension at di-
agnosis of type 2 (non-insulin-dependent) diabetes mellitus and after
3 months’ diet therapy. Diabetologia 1993;36:835-42.
5. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus.
N Engl J Med 1999;341:1127-33.
6. The Diabetes Control and Complications Trial Research Group. The ef-
fect of intensive treatment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus. N Engl
J Med 1993;329:977-86.
7. Mulec H, Blohmè G, Grande B, Bjorck S. The effect of metabolic con-
trol on rate of decline in renal function in insulin-dependent diabetes mel-
litus with overt diabetic nephropathy. Nephrol Dial Transplant 1998;13:
651-5.
8. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glu-
 C LINICA L PR AC TICE
cose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998;352:837-53. [Erratum, Lancet 1999;354:602.]
9. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy pre-
vents the progression of diabetic microvascular complications in Japanese
patients with non-insulin-dependent diabetes mellitus: a randomized pro-
spective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.
10. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in overweight pa-
tients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65. [Erra-
tum, Lancet 1998;352:1557.]
11. Mogensen CE. Microalbuminuria, blood pressure and diabetic renal dis-
ease: origin and development of ideas. In: Mogensen CE, ed. The kidney and
hypertension in diabetes mellitus. 5th ed. Boston: Kluwer, 2000:655-706.
12. Courrèges JJ, Bacha J, Aboud E. Prévalence et profil d’une atteinte
rénovasculaire chez le diabétique de type II hypertendu sévère. Arch Mal
Cour Vaiss 1997;90:1059-63.
13. Ordonez JD, Hiatt RA. Comparison of type II and type I diabetics
treated for end-stage renal disease in a large prepaid health plan population.
Nephron 1989;51:524-9.
14. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in
adults with hypertension and diabetes: a consensus approach. Am J Kidney
Dis 2000;36:646-61.
15. Heart Outcomes Prevention Evaluation Study Investigators. Effects of
ramipril on cardiovascular and microvascular outcomes in people with di-
abetes mellitus: results of the HOPE study and MICRO-HOPE substudy.
Lancet 2000;355:253-9. [Erratum, Lancet 2000;356:860.]
16. Parving H-H, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen
S, Arner P. The effect of irbesartan on the development of diabetic ne-
phropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8.
17. Parving H-H, Hovind P, Rossing K, Andersen S. Evolving strategies
for renoprotection: diabetic nephropathy. Curr Opin Nephrol Hypertens
2001;10:515-22.
18. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and ne-
phropathy. N Engl J Med 2001;345:861-9.
19. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of
the angiotensin-receptor antagonist irbesartan in patients with nephropa-
thy due to type 2 diabetes. N Engl J Med 2001;345:851-60.
20. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angioten-
sin-converting–enzyme inhibition on diabetic nephropathy. N Engl J Med
1993;329:1456-62. [Erratum, N Engl J Med 1993;330:152.]
21. Bakris GL. Renal effects of calcium antagonists in diabetes mellitus:
an overview of studies in animal models and in humans. Am J Hypertens
1991;4:Suppl:487S-493S.
22. Ruggenenti P, Perna A, Benini R, Remuzzi G. Effects of dihydropyr-
idine calcium channel blockers, angiotensin-converting enzyme inhibition
and blood pressure control on chronic, nondiabetic nephropathies. J Am
Soc Nephrol 1998;9:2096-101.
23. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs. amlodipine
on renal outcomes in hypertensive nephrosclerosis: a randomized con-
trolled trial. JAMA 2001;285:2719-28.
24. Smith AC, Toto R , Bakris GL. Differential effects of calcium channel
blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kid-
ney Int 1998;54:889-96.
25. Weidmann P, Schneider M, Bohlen L. Therapeutic efficacy of different
antihypertensive drugs in human diabetic nephropathy: an updated meta-
analysis. Nephrol Dial Transplant 1995;10:Suppl 9:39-45.
26. UK Prospective Diabetes Study Group. Efficacy of atenolol and cap-
topril in reducing risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 39. BMJ 1998;317:713-20.
N Engl J Med, Vol. 346, No. 15 · April 11, 2002 · www.nejm.org · 1151
Downloaded from www.nejm.org on March 22, 2008 . Copyright © 2002 Massachusetts Medical Society. All rights reserved.
27. Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving H-H.
Long-term effect of lisinopril and atenolol on kidney function in hyperten-
sive NIDDM subjects with diabetic nephropathy. Diabetes 1997;46:1182-
8.
28. Mogensen CE, Neldam S, Tikkenen I, et al. Randomised controlled
trial of dual blockade of renin-angiotensin system in patients with hyper-
tension, microalbuminuria, and non-insulin dependent diabetes: the Can-
desartan and Lisinopril Microalbuminuria (CALM) study. BMJ 2000;321:
1440-4.
29. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive
blood-pressure lowering and low-dose aspirin in patients with hyperten-
sion: principal results of the Hypertension Optimal Treatment (HOT) ran-
domised trial. Lancet 1998;351:1755-62.
30. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the pro-
gression of renal disease: a meta-analysis. Kidney Int 2001;59:260-9.
31. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of
restricting dietary protein on the progression of renal failure in patients
with insulin-dependent diabetes mellitus. N Engl J Med 1991;324:78-84.
32. Hansen HP, Tauber-Lassen E, Jensen BR , Parving H-H. Effect of di-
etary protein restriction on prognosis in type 1 diabetic patients with dia-
betic nephropathy. Presented at the European Diabetic Nephropathy Study
Group 14th Annual Meeting, County Durham, United Kingdom, May
2001. abstract.
33. Ruggenenti P, Schieppatti A, Remuzzi G. Progression, remission, re-
gression of chronic renal diseases. Lancet 2001;357:1601-8.
34. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial
intervention in patients with type 2 diabetes mellitus and microalbumin-
uria: the Steno type 2 randomised study. Lancet 1999;353:617-22.
35. Ritz E, Ogata H, Orth SR. Smoking: a factor promoting onset and
progression of diabetic nephropathy. Diabetes Metab 2000;26:Suppl 4:54-
63.
36. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2
diabetes mellitus by changes in lifestyle among subjects with impaired glu-
cose tolerance. N Engl J Med 2001;344:1343-50.
37. Diabetes Prevention Program Research Group. Reduction in the inci-
dence of type 2 diabetes with lifestyle intervention or metformin. N Engl
J Med 2002;346:393-403.
38. The Heart Outcomes Prevention Evaluation Study Investigators. Ef-
fects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardio-
vascular events in high-risk patients. N Engl J Med 2000;342:145-53. [Er-
ratum, N Engl J Med 2000;342:748.]
39. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-
converting-enzyme inhibition compared with conventional therapy on car-
diovascular morbidity and mortality in hypertension: the Captopril Preven-
tion Project (CAPP) randomised trial. Lancet 1999;353:611-6.
40. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development
of diabetes mellitus: evidence for a protective effect in the West of Scotland
Coronary Prevention Study. Circulation 2001;103:357-62.
41. American Diabetes Association clinical practice recommendations
2001. Diabetes Care 2001;24:Suppl 1:S1-S33. (Also available at http://
journal.diabetes.org/CareSup1Jan01.htm.)
42. Meltzer S, Leiter L, Daneman D, et al. 1998 Clinical practice guide-
lines for the management of diabetes in Canada. CMAJ 1998;159:Suppl 8:
S1-S29.
43. Executive summary of the Third Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel
III). JAMA 2001;285:2486-97.
Copyright © 2002 Massachusetts Medical Society.