PRIMARY CARE
Review Article
Primary Care
N EPHROPATHY IN P ATIENTS WITH
T YPE 2 D IABETES M ELLITUS
EBERHARD RITZ, M.D., AND STEPHAN REINHOLD ORTH, M.D.
I
N the not-so-distant past, type 2 diabetes melli-
tus was thought to be a relatively benign condi-
tion, at least in the elderly, with relatively little
effect on life expectancy or renal function.1 It has
now become obvious that type 2 diabetes must be
taken every bit as seriously as type 1 diabetes, in part
because of its renal complications.2 However, some
recent and encouraging evidence indicates that dia-
betic nephropathy and deterioration of renal func-
tion are to a certain extent preventable.
EPIDEMIOLOGY
According to the reports of the U.S. Renal Data
System,3,4 in the past two decades there has been a
continual increase in the incidence of end-stage re-
nal disease among patients with diabetes, predomi-
nantly those with type 2 diabetes. In the United
States, the proportion of patients with both end-stage
renal disease and diabetes rose from 27 percent to
36 percent between 1982 and 1992. It is particularly
common among the elderly and nonwhites (i.e.,
blacks, Asians, and Native Americans). A similar trend
has occurred in other developed countries as well
(Table 1), making end-stage renal disease in patients
with type 2 diabetes a medical problem of worldwide
dimensions.4
Although in the past the risk of renal complica-
tions was thought to be considerably lower among
patients with type 2 diabetes than among those with
type 1 diabetes,1 there is now abundant evidence that
the risk of nephropathy (Fig. 1) with progression to
end-stage renal disease is similar in the two groups.5
Because there are more patients with type 2 than
type 1 diabetes, it is not surprising that one sees more
patients with type 2 diabetes who have end-stage re-
nal disease, but why is it that the incidence of end-
From the Department of Internal Medicine, Renal Unit, Ruperto Carola
University, Bergheimer Str. 56a, D-69115 Heidelberg, Germany, where re-
print requests should be addressed to Dr. Ritz.
©1999, Massachusetts Medical Society.
Downloaded from www.nejm.org on June 21, 2009 . Copyright © 1999 Massachusetts Medical Society. All rights reserved.
stage renal disease in such patients has recently in-
creased so dramatically? One reason is that as treat-
ment of hypertension and coronary heart disease has
improved, more patients with type 2 diabetes live long
enough for nephropathy and end-stage renal disease
to develop.2 Hence, end-stage renal disease in patients
with type 2 diabetes may be viewed as a disease of
medical progress.
Because of their excessive cardiovascular risk, the
survival of these patients is dramatically reduced even
before end-stage renal disease develops, but it drops
to extremely low levels once end-stage renal disease
occurs.4,6 The five-year survival rates are 6 percent in
Germany and 27 percent in Australia4 — similar to
the rates among patients with metastasized gastroin-
testinal carcinoma. This factor alone justifies intensive
efforts to prevent nephropathy and end-stage renal
disease.
RENAL LESIONS
Although patients with type 2 diabetes and micro-
albuminuria frequently have the classic lesions of the
Kimmelstiel–Wilson syndrome, a sizable proportion
have nonspecific vascular and interstitial lesions with
minimal glomerular changes or none at all.7 Fur-
thermore, some patients have renal ischemia as a re-
sult of atherosclerotic renal-artery stenosis or choles-
terol microembolism. Approximately 20 percent of
patients with type 2 diabetes who have end-stage re-
nal disease have a nondiabetic form of renal disease.2
GENETIC BASIS
The risk of nephropathy is strongly determined
by genetics. Familial clustering of diabetic nephrop-
athy,8 high rates of hypertension and cardiovascular
events among the relatives of patients with type 2
diabetes who have nephropathy,9 and higher-than-
normal blood-pressure levels and rates of albuminuria
among the offspring of these patients10 have all been
described. The risk of nephropathy has been linked
to specific chromosomal sites.11,12 The genes involved
have not been identified. At least among whites,13
the presence of the insertion or deletion polymor-
phism of the angiotensin-converting enzyme (ACE )
gene is not a major predictor of renal risk, although
it apparently influences the rate of progression.14 Sev-
eral genes or gene products have been linked to dia-
betic nephropathy.15,16 A polymorphism of the b3
subunit of the G protein at position 825 is related
to obesity and hypertension. The G b3 825T allele is
more frequent among patients with type 2 diabetes
with progression to end-stage renal disease than
among nondiabetic patients.17
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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

TABLE 1. INCIDENCE OF END-STAGE RENAL TABLE 2. FACTORS THAT INCREASE THE RISK
FAILURE AMONG PATIENTS WITH DIABETES.* OF PROGRESSION TO END-STAGE
RENAL FAILURE AMONG PATIENTS
WITH TYPE 2 DIABETES.
COUNTRY 1984 1994
Elevated blood pressure
no. of cases/
million population/yr Albuminuria or proteinuria
Poor glycemic control (high level of insulin
United States 29.2 107.0 resistance)
Japan 23.4 66.0 Smoking
Australia 4.0 14.0 High dietary intake of protein?
Norway 6.5 15.4 (11.1) Hyperlipidemia?
Germany (southwest) — 52.0 (47.0)
Italy (Lombardy) 6.5 (2.9) 13.0 (7.0)

*The numbers in parentheses are the numbers of

cases of type 2 diabetes. Data were obtained from
Ritz et al.4

TABLE 3. MEASURES TO PREVENT

PROGRESSION OF OVERT NEPHROPATHY
100 IN PATIENTS WITH TYPE 2 DIABETES.
Prevalence of Proteinuria (%)

Achieve glycemic control (glycosylated hemoglobin

80 concentration close to 7 percent); avoid hypogly-
cemia.
Maintain blood pressure in the mid-normal range
60 (125/75 mm Hg), preferably with the use of
Type 2 angiotensin-converting–enzyme inhibitors (pos-
sibly also angiotensin II–receptor blockers).
40
Reduce the level of proteinuria (therapeutic goal is
a protein concentration of less than 1 g per day).
20 Type 1 Stop smoking.
Restrict dietary protein intake to approximately
0.8 g per kilogram of body weight per day (pref-
0 erentially by reducing the intake of animal pro-
0 5 10 15 20 25 teins), except among patients with preterminal
renal failure.
A Years after Diagnosis of Diabetes
Prevalence of Renal Failure (%)

100

80 RISK FACTORS

60
40
20
0 tice, the finding of a family history of cardiovascular
0 1 2 3
B Years after Onset of Proteinuria
Figure 1. Cumulative Prevalence of Persistent Proteinuria among
Patients with Type 1 or Type 2 Diabetes, According to the Dura-
tion of Diabetes (Panel A), and Cumulative Prevalence of Renal
Failure among Patients with Type 1 or Type 2 Diabetes, Accord-
ing to the Duration of Proteinuria (Panel B).
A serum creatinine concentration of more than 1.4 mg per dec-
iliter (124 µmol per liter) was considered to indicate renal failure.
Data were obtained from Hasslacher et al.5
Type 2
Cross-sectional 9,18,19 and longitudinal 20 studies have
identified some factors associated with a high risk of
Type 1
nephropathy: elevated blood pressure and glycosylat-
ed hemoglobin and cholesterol concentrations, smok-
ing, advanced age, high level of insulin resistance, male
sex (the risk is lower among women, at least before
menopause), black 21 or Native American race, and
possibly high dietary protein intake. In clinical prac-
4 5
events is a simple but powerful indicator of renal risk.9
Table 2 summarizes the most important remediable
factors that promote progression in patients with es-
tablished diabetic nephropathy. Preventive measures
are listed in Table 3.
Glycemia
Although there has been little doubt that the qual-
ity of glycemic control affects the risk of kidney dis-
ease in patients with type 1 diabetes,22 there was
prolonged controversy over whether the same is true
in patients with type 2 diabetes. Type 2 diabetes has

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 PRIMA RY C A R E
an image problem. In contrast to the difficult-to-
control hyperglycemia of patients with type 1 diabetes,
the asymptomatic, persistent hyperglycemia of elder-
ly patients with type 2 diabetes was long viewed as
relatively benign. The results of recent controlled,
prospective studies contradict this belief and provide
evidence that the risk of the development and pro-
gression of albuminuria can be substantially reduced
by improving glycemic control.23,24 The U.K. Prospec-
tive Diabetes Study showed that the way in which
glycemic control was achieved did not matter —
whether by insulin or oral antihyperglycemic agents
such as sulfonylureas or metformin.24 A recent re-
view includes detailed recommendations concerning
target blood glucose concentrations.25
Smoking
The adverse effects of smoking on diabetic and
nondiabetic renal disease are well established 26 but
not widely appreciated. Patients with type 2 diabetes
who smoke have a greater risk of microalbuminuria
than patients who do not smoke, and their rate of pro-
gression to end-stage renal disease is about twice as
rapid.27 At least among patients with type 1 diabetes,
there is also convincing evidence that the loss of renal
function is slower in those who stopped smoking.28
Protein Intake
The evidence that high dietary protein intake in-
creases the risk of both nephropathy and the progres-
sion to end-stage renal disease is tenuous. Among
patients with type 1 diabetes, those who had lower
protein intakes had a lower prevalence of microalbu-
minuria.29 Although evidence from controlled studies
is not available, it may be prudent to advise patients
with type 2 diabetes against a high dietary protein
intake (more than 0.8 to 1.0 g per kilogram of body
weight per day). Dietary protein restriction has also
been reported to retard progression in patients with
type 1 diabetes.30 The effect of protein restriction is
not impressive, however, relative to that of antihyper-
tensive treatment. Furthermore, in diabetic patients
with advanced nephropathy, reduction of dietary pro-
tein carries the risk of catabolism.
Blood Pressure
Subjects who have a high genetic risk of diabetic
nephropathy but who do not yet have diabetes have
higher blood pressures than subjects with no family
history of the disease,11 and frank hypertension is fre-
quent in subjects who have insulin resistance but not
diabetes.31 In at least 80 percent of patients, hyperten-
sion or an abnormal circadian blood-pressure profile
is also found at the time of the diagnosis of type 2
diabetes.9 Both hypertension32,33 and an abnormal cir-
cadian blood-pressure profile34 are strongly correlated
with the presence of albuminuria18,19 and are power-
ful predictors of cardiovascular and renal events.
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The evidence provided by Danish investigators that
antihypertensive treatment with beta-blockers and di-
uretics attenuated the progressive loss of renal func-
tion in patients who had type 1 diabetes and ne-
phropathy was a major breakthrough.35 The same has
now been shown to be the case in patients who have
type 2 diabetes and nephropathy.25,36 Questions re-
main about the target blood pressure and most ap-
propriate antihypertensive agents.
The Modification of Diet in Renal Disease Study
provided convincing evidence that in patients with
proteinuric renal disease, lowering of blood pressure
to within the upper limit of normal according to the
World Health Organization definition further low-
ers the rate of loss of renal function.37 As a conse-
quence, the National Kidney Foundation recommend-
ed that the target blood-pressure values should be
approximately 125/75 mm Hg in patients with ei-
ther nondiabetic or diabetic renal disease.38 Whether
this target is advisable for patients who have diabetes
and renal ischemia remains unresolved.
Patients with diabetes who have microalbuminuria
have not yet begun to lose glomerular filtration, but
they are at high risk for renal complications. Microal-
buminuria should be seen as an indicator of the need
for antihypertensive treatment, and patients should
therefore be tested regularly — at least once a year
— for it.32,33 Microalbuminuria is defined as a urinary
albumin excretion rate of 30 to 300 mg per 24 hours
(or 20 to 200 µg per milliliter or 20 to 200 µg per
minute) on two of three measurements. The test re-
sults cannot be interpreted correctly in the presence
of confounding factors such as urinary tract infec-
tion, fever, uncontrolled hyperglycemia or hyperten-
sion, and congestive heart failure.
Patients with diabetes who have microalbuminuria
also have an extremely high risk of cardiovascular
events. Antihypertensive treatment reduces albumi-
nuria and diminishes the risk of progression of albu-
minuria even in normotensive patients with diabetes.
A 1995 consensus statement therefore recommend-
ed antihypertensive treatment, preferably with ACE
inhibitors, irrespective of a patient’s blood pressure
once microalbuminuria has been documented.32 This
recommendation appears rational in view of recent
evidence that the protein is nephrotoxic in tubular
fluid39 and that the rate of protein excretion is a pow-
erful predictor of progression.40 In our view, decreas-
ing the level of proteinuria is a desirable therapeutic
goal in and of itself.
In the recent U.K. Prospective Diabetes Study,41
even moderate lowering of blood pressure led to ma-
jor reductions in the risk of cardiovascular and renal
events (Table 4). The accompanying editorial stated
that “antihypertensive treatment is more effective than
tight glucose control and the beneficial effect comes
sooner.”42 In the Hypertension Optimal Treatment
Study, the risk of major cardiovascular events was 50
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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
TABLE 4. EFFECTS OF TIGHT AND LESS TIGHT CONTROL OF BLOOD
AMONG 1148 PATIENTS WITH TYPE 2 DIABETES.*
VARIABLE
Target blood pressure — mm Hg
Actual blood pressure — mm Hg
Reduction in the risk of end points in the tight-
control group as compared with the less-tight-
control group — % (95% confidence interval)
Death
Diabetes-related end points
Stroke
Microvascular end points
*Data were obtained from the U.K. Prospective Diabetes Study,41 which lasted 8.4 years.
percent lower among patients with type 2 diabetes
whose target diastolic blood pressure was 80 mm Hg
than among patients whose target diastolic blood
pressure was 90 mm Hg.43,44
There has been concern about the potential risks
of such aggressive blood-pressure lowering, particu-
larly in elderly patients with type 2 diabetes. Reduc-
ing diastolic blood pressure below 85 mm Hg was
thought to increase cardiovascular risk in this group,
but no convincing evidence of this possibility was
found.43 It is nevertheless prudent to rule out the
presence of stenotic lesions, particularly of the carotid
arteries, before treatment to lower blood pressure is
begun. Blood pressure should be lowered slowly, and
patients should be monitored closely, particularly
given the reductions in cerebral and renal45 autoregu-
lation in hypertensive elderly patients with diabetes.
Blood pressure should be monitored with patients
in both the sitting and the upright positions to ex-
clude the possibility of orthostatic hypotension, since
autonomic denervation is frequent among patients
with type 2 diabetes who have nephropathy and poly-
neuropathy.
Patients with diabetes tend to retain sodium, and
their hypertension is exquisitely volume-sensitive.25
It is therefore advisable to restrict sodium intake (with
occasional monitoring of urinary sodium excretion)
and to administer diuretics: thiazides in combination
with potassium-sparing agents (e.g., 12.5 to 25 mg
of hydrochlorothiazide plus 25 to 50 mg of triam-
terene) before renal failure has occurred, and loop
diuretics (e.g., 40 to 125 mg of furosemide two to
three times daily) with or without thiazides after re-
nal failure has set in. Diuretics interfere with insulin
sensitivity, but the effect is moderate at low doses
or when they are taken in combination with ACE
inhibitors. Sodium loading blunts the antihyperten-
sive and antiproteinuric action of ACE inhibitors. In
our experience, failure to administer appropriate dos-
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PRESSURE
TIGHT LESS TIGHT
BLOOD-PRESSURE BLOOD-PRESSURE
CONTROL (N=758) CONTROL (N=390)
<150/85 <180/105
144/82 154/87
¡32 (¡51 to ¡6)
¡24 (¡38 to ¡8)
¡44 (¡65 to ¡11)
¡37 (¡56 to ¡11)
es of diuretics and failure to give short-acting loop
diuretics more frequently than once per day are the
most common causes of a poor response to ACE in-
hibitors.
To protect the nephrons, blood pressure must be
lowered. Lowering blood pressure is more important
than the type of antihypertensive agent used.25 Dur-
ing more than eight years of observation in the U.K.
Prospective Diabetes Study, beta-blockers and ACE
inhibitors were found to be similarly effective in pa-
tients with type 2 diabetes who had few renal com-
plications.41 ACE inhibitors reduce the level of pro-
teinuria more than do equivalent doses of other
antihypertensive agents, but this superior effect is pro-
gressively reduced as blood pressure declines.46 Never-
theless, there is impressive experimental and clinical47-49
evidence that ACE inhibitors (and, possibly, the more
recently developed angiotensin II–receptor block-
ers) have specific renoprotective properties in pa-
tients with diabetic or nondiabetic renal disease who
have proteinuria. These agents antagonize the stim-
ulation of the kidney by angiotensin II.50,51 In a pla-
cebo-controlled study of normotensive patients with
type 2 diabetes and microalbuminuria, Ravid et al.52
found that enalapril slowed the increase in albumin
excretion. It is not known, however, whether enala-
pril is superior to other antihypertensive agents or
whether ACE inhibition prevents microalbuminuria.53
Numerous studies have shown that in patients who
have type 2 diabetes, hypertension, and microalbu-
minuria, ACE inhibitors prevent an increase in albu-
min excretion and may reduce it.25
Evidence from prospective, placebo-controlled stud-
ies is not available to indicate whether ACE inhibi-
tors reduce the risk of end-stage renal disease in pa-
tients with type 2 diabetes. Nevertheless, in view of
the similar, high risk of renal complications among
patients with type 1 and those with type 2 diabetes5
it is reasonable to extrapolate from studies of patients
 PR IMA RY C A R E
with type 1 diabetes.47 There is also no information
to indicate whether angiotensin II–receptor block-
ers are renoprotective in patients who have type 2 di-
abetes and advanced nephropathy. In direct compar-
isons, the antiproteinuric action of ACE inhibitors
and angiotensin II–receptor blockers was similar in
patients with nondiabetic or diabetic renal disease.54
Two large international studies of angiotensin II–
receptor blockers in patients who have type 2 diabe-
tes and renal failure are currently under way.
ACE inhibitors and angiotensin II–receptor block-
ers are relatively safe. Because of the small (less than
5 percent) potential risks of hyperkalemia and unrec-
ognized renal-artery stenosis, serum creatinine and
potassium concentrations should be monitored, par-
ticularly at the start of treatment. In patients with
type 2 diabetes, some ACE inhibitors improve glu-
cose uptake in peripheral tissue 25 but may also occa-
sionally cause hypoglycemic episodes.
As compared with ACE inhibitors, calcium-chan-
nel blockers are generally less effective in reducing
albuminuria.25 However, there are differences among
the calcium-channel blockers. In patients with type 1
or type 2 diabetes, short-acting agents even increased
proteinuria in some studies.55,56 The effects of the
long-acting compound amlodipine,57 and particular-
ly verapamil and diltiazem, on proteinuria58 and the
glomerular filtration rate57 are similar to those of ACE
inhibitors. In patients who have type 2 diabetes and
nephropathy, ACE inhibitors and calcium-channel
blockers were both superior to beta-blockers in re-
ducing proteinuria and attenuating the decrease in
creatinine clearance.58
There has been much concern about the cardio-
vascular safety of calcium-channel blockers in pa-
tients who have type 2 diabetes and nephropathy. In
a study of patients who had type 2 diabetes and hy-
pertension, Estacio et al.59 reported twice as many
fatal and nonfatal myocardial infarctions among those
who were given nisoldipine than among those who
were given enalapril. We interpret these findings to
indicate that calcium-channel blockers are apparent-
ly inferior to ACE inhibitors with respect to cardiac
end points. They should therefore not be adminis-
tered as monotherapy. But whether they increase the
underlying cardiac risk in such patients is uncertain.
Such an increase is unlikely, since treatment with ni-
trendipine reduced the risk of overall mortality and
cardiovascular events more among elderly patients
who had hypertension and diabetes than among non-
diabetic elderly patients with hypertension.60
On the basis of theoretical arguments and clinical
observations, several authors have suggested that the
combination of calcium-channel blockers and ACE in-
hibitors is superior to monotherapy with either drug.61
In practice, a combination of antihypertensive agents
is often necessary to achieve target blood-pressure
values.37,38
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TABLE 5. COMMON PROBLEMS IN PATIENTS WITH TYPE 2 DIABETES
AND ADVANCED DIABETIC NEPHROPATHY.
Microvascular complications
Retinopathy (nonproliferative and proliferative)
Polyneuropathy (including autonomic polyneuropathy)
Cystopathy (detrusor paresis)
Gastroparesis
Diarrhea or constipation
Impotence
Foot (neuropathic) problems
Macrovascular (atherosclerotic) complications
Coronary heart disease
Cerebrovascular disease (ischemic)
Arterio-occlusive disease (legs and distal arteries)
Ischemic nephropathy (renal-artery stenosis and cholesterol embolism)
RENAL FAILURE
Patients who have type 2 diabetes and renal failure
should consult a nephrologist; however, several points
are of particular importance for primary care physi-
cians. Especially in elderly female patients with re-
duced muscle mass, measurement of serum creati-
nine may grossly underestimate the reduction in the
glomerular filtration rate. In this situation, measure-
ment of endogenous creatinine clearance is recom-
mended.
Microvascular and macrovascular complications are
particularly frequent in high-risk patients who have
type 2 diabetes and renal failure. Table 5 can be used
as a checklist for routine examinations. Coronary heart
disease may be completely asymptomatic in such pa-
tients, and funduscopy should be performed at least
once yearly. Because these patients are at high risk for
cardiac disease, treatment with statins is also justi-
fied.62 Foot problems occur with frightening frequen-
cy, so care givers must inspect patients’ feet regularly.
Timely creation of vascular access, preferably with
the use of native vessels, is crucial to prepare for un-
complicated dialysis once uremia develops. Too of-
ten patients with type 2 diabetes are hospitalized for
uremic emergencies, which are associated with high
morbidity and mortality.6 Acute renal decompensa-
tion is frequently due to the administration of radi-
ocontrast agents for cardiac studies, although this
complication is largely preventable if the dose of the
radiocontrast agent is adjusted for renal function,
the patient is kept hydrated, and the dose of diuret-
ics and ACE inhibitors is reduced or treatment is
temporarily stopped.63,64 Finally, although most pa-
tients with type 2 diabetes are treated with hemodi-
alysis or continuous peritoneal dialysis as outpatients,
the results of renal transplantation in such patients
are close to those in nondiabetic patients, if they do
not have vascular complications. Therefore, kidney
transplantation should be considered for patients
with type 2 diabetes.65
Vol ume 341 Numb e r 15 · 1131
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
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