Diabetic Nephropathy—The Family

Physician’s Role
MICHELLE A. ROETT, MD, MPH; SARAH LIEGL, MD; and YALDA JABBARPOUR, MD, Georgetown University
Medical Center, Washington, District of Columbia

Nearly one-half of persons with chronic kidney disease have diabetes mellitus. Diabetes accounted for 44 percent of
new cases of kidney failure in 2008. Diabetic nephropathy, also called diabetic kidney disease, is associated with sig-
nificant macrovascular risk, and is the leading cause of kidney failure in the United States. Diabetic nephropathy usu-
ally manifests after 10 years’ duration of type 1 diabetes, but may be present at diagnosis of type 2 diabetes. Screening
for microalbuminuria should be initiated five years after diagnosis of type 1 diabetes and at diagnosis of type 2 diabe-
tes. Screening for microalbuminuria with a spot urine albumin/creatinine ratio identifies the early stages of nephrop-
athy. Positive results on two of three tests (30 to 300 mg of albumin
per g of creatinine) in a six-month period meet the diagnostic cri-
teria for diabetic nephropathy. Because diabetic nephropathy may
also manifest as a decreased glomerular filtration rate or an increased
serum creatinine level, these tests should be included in annual
monitoring. Preventive measures include using an angiotensin-
converting enzyme inhibitor or angiotensin II receptor blocker in
normotensive persons. Optimizing glycemic control and using an
angiotensin-converting enzyme inhibitor or angiotensin II receptor
blocker to control blood pressure slow the progression of diabetic

ILLUSTRATION BY SCOTT BODELL

nephropathy, but implementing intensive glycemic and blood pres-
sure control is associated with more adverse outcomes. Low-protein
diets may also decrease adverse renal outcomes and mortality in per-
sons with diabetic nephropathy. (Am Fam Physician. 2012;85(9):883-
889. Copyright © 2012 American Academy of Family Physicians.)

D
Patient information: iabetic nephropathy (also called risk of major cardiovascular events and
▲

A handout on this topic diabetic kidney disease) is the all-cause mortality.4 The overall prevalence
is available at http://
familydoctor.org/ leading cause of kidney failure of micro- and macroalbuminuria is up to
familydoctor/en/diseases- in the United States. According 35 percent in both types of diabetes.1 How-
conditions/diabetic- to the Centers for Disease Control and Pre- ever, persons with type 2 diabetes exhibit
nephropathy.html. vention, in 2008, approximately 44 percent the highest prevalence, particularly Native
of all new cases of kidney failure were caused American, Asian, Hispanic, and black per-
by diabetes mellitus; 48,374 persons with sons, who are at higher risk of ESRD than
diabetes began treatment for end-stage renal non-Hispanic white persons.5 Diabetic
disease (ESRD); and 202,290 persons with nephropathy may progress from microalbu-
ESRD caused by diabetes were on long-term minuria to macroalbuminuria with progres-
dialysis or had a renal transplant.1 In a 2010 sive loss of glomerular filtration rate (GFR)
U.S. Renal Data System report, 29.1 percent until ESRD.6 After being diagnosed with
of persons with self-reported diabetes had diabetes, 2.0 percent of persons per year
stage 2 or 3 chronic kidney disease.2 progress to microalbuminuria; 2.8 percent
Risk factors associated with development per year progress from microalbuminuria to
of microalbuminuria include higher blood macroalbuminuria; and 2.3 percent per year
pressure, higher blood glucose level, dyslip- progress from macroalbuminuria to having
idemia, and smoking.3 Micro- and macro­ an elevated plasma creatinine level or need-
albuminuria are associated with increased ing renal replacement therapy.7
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2012 American Academy of Family Physicians. For the private, noncommer-
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 SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Persons with type 1 diabetes mellitus should be screened for microalbuminuria starting five years after C 6
diagnosis.
Persons with type 2 diabetes (without macroalbuminuria) should be screened for microalbuminuria at C 6, 9
diagnosis and annually thereafter.
Persons with type 1 or 2 diabetes and microalbuminuria should continue to be tested for albuminuria C 6
annually to monitor disease progression and response to therapy.
Normotensive persons with diabetes and microalbuminuria should be given an ACE inhibitor or angiotensin II C 10, 24, 25
receptor blocker to reduce progression to macroalbuminuria.
Combination therapy with ACE inhibitors and angiotensin II receptor blockers should be avoided in persons C 26
with diabetes, atherosclerosis, and evidence of end-organ damage.
ACE inhibitors should be discontinued if the patient’s creatinine level increases more than 30 percent above C 29
baseline in the first two months of therapy (even in persons with an elevated baseline creatinine level
of greater than 1.4 mg per dL [123.76 µmol per L]) or if hyperkalemia persists (serum potassium level of
greater than 5.6 mEq per L [5.6 mmol per L]).
Adding hydrochlorothiazide to an ACE inhibitor in persons with diabetes, microalbuminuria, and C 30
hypertension is recommended to increase the likelihood of normalized albuminuria.
The American Diabetes Association recommends limiting protein intake in persons with diabetes to 0.8 to C 6
1 g per kg per day in earlier stages of chronic kidney disease and to 0.8 g per kg per day in later stages to
improve urine albumin excretion and estimated GFR.
Supplemental folic acid (2.5 mg), vitamin B6 (pyridoxine, 25 mg), and cyanocobalamin (1 mg) should be avoided B 36
in persons with type 1 or 2 diabetes and macroalbuminuria because of a higher risk of decline in GFR, and
increased risk of myocardial infarction, stroke, and all-cause mortality (number needed to harm = 11).

ACE = angiotensin-converting enzyme; GFR = glomerular filtration rate.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Screening Macroalbuminuria, or overt nephropathy, is defined

Several studies have analyzed the effectiveness and cost- as an albumin/creatinine ratio of more than 300 mg of
effectiveness of diabetic nephropathy screening. Dia- albumin per g of creatinine.10 At this level, protein is eas-
betic nephropathy typically manifests after 10 years’ ily detected on routine urinalysis or urine dipstick. Sev-
duration of type 1 diabetes, whereas approximately eral conditions, including marked hyperglycemia and
3 percent of persons with newly diagnosed type 2 dia- hypertension, may cause transient elevations of urinary
betes have overt nephropathy.8 Screening for microalbu- albumin (Table 1).9,11,13 Because up to 36 percent of per-
minuria should begin five years after diagnosis of type 1 sons with type 2 diabetes have renal insufficiency with-
diabetes.6 Given the poor reliability of estimating length out micro- or macroalbuminuria, annual screening for
of disease at diagnosis of type 2 diabetes, consensus diabetic nephropathy should also include measurement
guidelines recommend that these persons be screened of serum creatinine and estimation of GFR.6,9,14
for microalbuminuria starting at diagnosis.6,9 However,
patient-oriented evidence to support this recommenda- Diagnosis
tion (i.e., less ESRD in screened persons) is lacking.6,10 Laboratory evaluation of diabetic nephropathy is sum-
Persons with type 1 or 2 diabetes and microalbuminuria marized in Table 2.9,10 Persistent microalbuminuria
should continue to be tested for albuminuria annually is the earliest sign of diabetic nephropathy. Once a
to monitor disease progression and response to therapy.6 screening test detects microalbuminuria, it should be
The diagnostic reference standard for defining micro- confirmed with additional spot urine tests over the next
albuminuria is detection of 30 to 300 mg of albumin in three to six months. Two out of three samples falling
a 24-hour urine sample.10 A spot urine albumin/creati- within the microalbuminuria (30 to 300 mg of albu-
nine ratio, preferably in a first-morning void, correlates min per g of creatinine) or macroalbuminuria (more
well with a 24-hour urine albumin excretion rate and than 300 mg of albumin per g of creatinine) range con-
accurately predicts renal events.11,12 Because this test is firm the classification.10 The National Kidney Founda-
easily administered, it is the first-line annual screening tion recommends that all persons with chronic kidney
test for most persons with diabetes. Microalbuminuria is disease undergo renal ultrasonography to distinguish
defined as an albumin/creatinine ratio of 30 to 300 mg of potentially reversible causes of kidney disease.15 Sev-
albumin per g of creatinine.10 eral conditions, including albuminuria in the absence

884  American Family Physician www.aafp.org/afp Volume 85, Number 9 ◆ May 1, 2012
 Diabetic Nephropathy
Table 1. Differential Diagnosis of Albuminuria

Congestive heart failure

Exercise within 24 hours of test
Hypertension (if refractory hypertension, consider renal disease difference in doubling of creatinine or eventual need for
other than diabetic nephropathy) dialysis (Table 4).13,21,22 The final A1C was 6.4 to 6.9 per-
Marked hyperglycemia cent in the intensive-control groups, and 7.3 to 8.4 per-
Renal disease other than diabetic nephropathy should be cent in the standard-control groups.13,21,22 The ACCORD
considered in the following situations:
(Action to Control Cardiovascular Risk in Diabetes)
• Absence of diabetic retinopathy
trial had to be halted early because of increased all-cause
• Low or rapidly decreasing glomerular filtration rate
mortality in the intensive-control group.21,23
• More than 30 percent reduction in glomerular filtration rate
within two to three months after initiation of an angiotensin-
The American Diabetes Association continues to rec-
converting enzyme inhibitor or angiotensin II receptor blocker ommend an A1C goal of 7.0 percent, and suggests lower
• Presence of active urinary sediment targets if they can be achieved without significant hypo-
• Rapidly increasing proteinuria or nephrotic syndrome glycemic or adverse events. Less stringent adherence to
• Signs or symptoms of other systemic disease the 7.0 percent guideline is also acceptable for persons
Urinary tract infection (e.g., pyuria, hematuria, fever) with extensive comorbidities, micro- or macrovascular
complications, history of severe hypoglycemia, limited
Information from references 9, 11, and 13.
life expectancy, or long-standing diabetes refractory to
appropriate management.6

BLOOD PRESSURE CONTROL

of retinopathy, should prompt consideration of renal
biopsy to identify nondiabetic causes of renal disease10 In addition to glycemic control with an A1C goal of
(Table 19,11,13). 7.0 percent or less, lowering blood pressure to 130/80
mm Hg or less has been shown to slow the progression
Preventing Progression of nephropathy.24 More than two-thirds of adults with
One in eight persons with type 1 diabetes and microalbu- diabetes have a blood pressure of 140/90 mm Hg or
minuria reverts to normal urine albumin excretion with- greater, or use prescription medications for hyperten-
out treatment.10 The mainstays of treatment to prevent sion.1 Observational studies have shown that estimated
progression of diabetic nephropathy have
traditionally included achieving adequate
glycemic control and lowering blood pres- Table 2. Laboratory Evaluation of Persons with Diabetic
sure with an angiotensin-converting enzyme Nephropathy
(ACE) inhibitor or angiotensin II receptor
Test Significant results
blocker (Table 3).6,8,10,16-19 Weight loss, smok-
ing cessation, and decreased dietary protein Albumin in a 24-hour urine Microalbuminuria: 30 to 300 mg
have also been recommended.20 The pri- sample (mg of albumin per Macroalbuminuria: > 300 mg
24 hours)
mary treatment goal is prevention of ESRD,
Estimated glomerular filtration Glomerular filtration rate hyperfiltration,
because micro- and macroalbuminuria rate with elevated glomerular filtration rate
alone are asymptomatic conditions. in early stages followed by linear decline
until end-stage renal disease
GLYCEMIC CONTROL Random spot albumin/ Microalbuminuria: 30 to 300 mg
Because approximately one-half of persons creatinine ratio (mg of Macroalbuminuria: > 300 mg
albumin per g of creatinine)
with stage 3 or 4 chronic kidney disease
Renal biopsy (if unclear Light microscopy: glomerular sclerosis
have A1C levels higher than 7.0 percent,2 etiology) with nodular mesangial expansion and
guidelines from the American Diabetes proliferation (Kimmelstiel-Wilson nodules)
Association and others have recommended Electron microscopy: glomerular basement
aggressive blood glucose control with the membrane thickening
goal of preventing diabetic nephropathy.6 Timed four-hour or overnight Microalbuminuria: 20 to 200 mcg
urine collection (mcg of Macroalbuminuria: > 200 mcg
However, three large, well-designed, ran- albumin per minute)*
domized controlled trials comparing inten-
sive glycemic control with standard control *—Because postural proteinuria may be more common during adolescence, screen-
found a reduction in progression to mac- ing with overnight urine collection is especially important in this age group.

roalbuminuria with intensive control, but Information from references 9 and 10.
increased hypoglycemic episodes, and no

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Diabetic Nephropathy
Table 3. Preventing Progression of Diabetic
Nephropathy

Lifestyle changes
GFR typically declines at rates of greater than 10 mL Low-protein diet, smoking cessation, weight loss
per minute per 1.73 m 2 per year in persons with dia- Treatment of associated conditions
betes, poorly controlled hypertension, and macroalbu- Anemia: screen and treat persons with any stage of chronic
minuria, but much more slowly (1 to 4 mL per minute kidney disease
per 1.73 m 2 per year) in those with effective blood pres- Blood glucose control: A1C ≤ 7.0 percent
sure control.10 Blood pressure control*: ≤ 130/80 mm Hg
In a systematic review, ACE inhibitors reduced the First-line:
risk of microalbuminuria in persons with diabetes and • ACE inhibitor in persons with type 1 diabetes, hypertension,
and any stage of albuminuria
both with and without hypertension compared with pla-
• ACE inhibitor or angiotensin II receptor blocker in persons
cebo and calcium channel blockers.25 In a recent large with type 2 diabetes, hypertension, and microalbuminuria
randomized controlled trial, 4,733 participants were • Angiotensin II receptor blocker in persons with type 2
assigned to either intensive control (systolic blood pres- diabetes, hypertension, creatinine level > 1.5 mg per dL
sure goal of less than 120 mm Hg) or standard control (132.60 µmol per L), and macroalbuminuria
(systolic blood pressure goal of less than 140 mm Hg). • ACE inhibitor or angiotensin II receptor blocker in
normotensive persons with diabetes and microalbuminuria
The intensive-control group had a lower incidence of
or macroalbuminuria
macroalbuminuria but significantly higher rates of seri- Second-line: diuretics, calcium channel blockers, beta blockers
ous adverse events such as hypotension, bradycardia, Cardiovascular disease
elevated serum creatinine level, and declining estimated Dyslipidemia
GFR. There were no differences in the rates of nonfatal Stage 3 chronic kidney disease (estimated glomerular filtration
myocardial infarction, nonfatal stroke, death from car- rate < 60 mL per minute per 1.73 m2):
diovascular causes, or ESRD, or in the need for dialysis. • Routine testing and treatment of secondary
This study did not support a systolic blood pressure goal hyperparathyroidism, hyperkalemia, acid-base disturbances
of less than 120 mm Hg for persons with diabetes.16 • Consider comanagement with nephrologist
Treatment with ACE inhibitors or angiotensin II Referral to nephrologist
receptor blockers for hypertension is more effective in Acute kidney injury
reducing the decline in kidney function than treatment Rapid progression of chronic kidney disease
with other blood pressure–lowering drugs. Persons Stage 4 chronic kidney disease (estimated glomerular filtration
rate < 30 mL per minute per 1.73 m2)
with diabetes, microalbuminuria, and with or with-
out hypertension should be given an ACE inhibitor or ACE = angiotensin-converting enzyme.
angiotensin II receptor blocker to reduce progression to
*—Serum creatinine and potassium levels should be monitored if ACE
macroalbuminuria.10,24,25 inhibitors, angiotensin II receptor blockers, or diuretics are used for
A large randomized trial showed that in persons blood pressure control.
with diabetes, atherosclerosis, and end-organ damage, Information from references 6, 8, 10, and 16 through 19.
ACE inhibitors and angiotensin II receptor blockers
were equally effec-
tive in prevent- with angiotensin II receptor blockers, both agents had
In a small, randomized con-
ing progression of similar effects on renal outcomes (i.e., ESRD, doubling
trolled trial, a low-protein
diabetic nephropa- of creatinine, progression of micro­a lbuminuria to mac-
diet slowed progression
thy. However, the roalbuminuria, and remission from microalbuminuria
to end-stage renal disease
combination of an to normoalbuminuria). ACE inhibitors significantly
or death in persons with
ACE inhibitor and reduced all-cause mortality at the maximal tolerated
diabetic nephropathy.
an angiotensin II dose compared with lower doses, but angiotensin II
receptor blocker receptor blockers did not.27 Similar results were noted
is not recommended because it provided no additional in a Cochrane review of 50 trials involving 13,215 per-
benefit and actually led to higher serum creatinine levels sons.28 ACE inhibitors should be discontinued if the cre-
and an increased rate of dialysis.26 atinine level increases by 30 percent above baseline in
In a meta-analysis of 4,008 persons with diabetic the first two months of therapy (even in persons with an
nephropathy from 36 trials comparing ACE inhibitors elevated baseline creatinine level of greater than 1.4 mg
with placebo; 3,331 persons from four trials compar- per dL [123.76 µmol per L]) or if hyperkalemia persists
ing angiotensin II receptor blockers with placebo; and (serum potassium level of greater than 5.6 mEq per L
206 persons from three trials comparing ACE inhibitors [5.6 mmol per L]).29

886  American Family Physician www.aafp.org/afp Volume 85, Number 9 ◆ May 1, 2012
 Table 4. Summary of Evidence for Prevention of Renal Outcomes with Intensive Glycemic Control

Number of Development of Doubling of serum Need for renal

Trial participants macroalbuminuria creatinine replacement therapy All-cause mortality

ACCORD*21 10,251 6.0 percent in intensive 58.6 percent in intensive 2.7 percent in intensive 5.0 percent in intensive
control vs. 8.2 percent control vs. 58.5 percent control vs. 3.0 control vs. 4.0 percent
in standard control in standard control percent in standard in standard control
(P < .0001; NNT = 45) (P = NSS) control (P = NSS) (P < .05)

ADVANCE22 11,140 2.9 percent in intensive 1.2 percent in intensive 0.4 percent in intensive 8.9 percent in intensive
control vs. 4.1 percent control vs. 1.1 percent control vs. 0.6 control vs. 9.6 percent
in standard control in standard control percent in standard in standard control
(P < .001; NNT = 83) (P = NSS) control (P = NSS) (P = NSS)

Veterans 1,791 2.9 percent in intensive 8.8 percent in intensive Not studied 11.4 percent in intensive
Affairs control vs. 5.1 percent control vs. 8.8 percent control vs. 10.6
Diabetes†13 in standard control in standard control percent in standard
(P = .04; NNT = 45) (P = NSS) control (P = NSS)

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation; NNT = number needed to treat; NSS = not statistically significant.
*—Did not include consideration of the development of microalbuminuria in the new or worsening nephropathy category.
†—Did not make a conclusion about new or worsening nephropathy.
Information from references 13, 21, and 22.

In a randomized double-blind controlled trial, 332 DIET

persons who had hypertension, type 2 diabetes, and Dietary restrictions, including low-protein and low-iron
albuminuria were treated with benazepril (Lotensin) diets, also may have a beneficial effect in slowing the pro-
combined with either amlodipine (Norvasc) or hydro- gression of diabetic nephropathy, but evidence is limited
chlorothiazide. Both medication combinations signifi- for translating disease-oriented markers, such as urine
cantly reduced the urine albumin/creatinine ratio and albumin excretion rate or GFR, into patient-oriented
blood pressure, and resulted in similar delayed pro- outcomes, such as progression to ESRD or mortality. The
gression to overt proteinuria. In the same study, per- American Diabetes Association recommends limiting
sons who had microalbuminuria and hypertension protein intake in persons with diabetes to 0.8 to 1 g per
were more likely to revert to normoalbuminuria when kg per day in earlier stages of chronic kidney disease and
taking the hydrochlorothiazide/ACE inhibitor com- to 0.8 g per kg per day in later stages to improve urine
bination, suggesting that initial treatment with this albumin excretion and estimated GFR.6
combination might be most beneficial in persons with In a small randomized controlled trial, a low-protein
microalbuminuria.30 diet (0.6 g per kg per day) slowed progression to ESRD
Several other medication combinations also have been or death compared with a normal-protein diet (0.89 g
evaluated. Based on the ADVANCE (Action in Diabetes per kg per day).17 Improvements in proteinuria also were
and Vascular Disease: Preterax and Diamicron Modi- demonstrated in a systematic review of eight random-
fied Release Controlled Evaluation) trial, perindopril ized trials evaluating low- versus normal-protein diets in
(Aceon) and indapamide reduce new-onset albumin- 519 persons with type 1 or 2 diabetes and nephropathy,
uria, progression of nephropathy, and mortality, with and in a randomized trial comparing a soy protein diet
no difference in rates of ESRD.22,31 Smaller studies show (35 percent animal, 35 percent textured soy, and 30 per-
successful decreases in albumin/creatinine ratio by add- cent vegetable proteins) with a control diet (70 percent
ing spironolactone (Aldactone) to lisinopril (Zestril) in animal and 30 percent vegetable proteins).18,19
persons with type 2 diabetes and microalbuminuria; A cohort study of 191 persons with diabetes referred to a
adding avosentan (not available in the United States) to nephrologist for advanced renal disease showed that a 50
an ACE inhibitor or angiotensin II receptor blocker in percent carbohydrate-restricted, low-iron, polyphenol-
persons with type 2 diabetes and macroalbuminuria; enriched diet was superior to a conventional protein-
and adding aliskiren (Tekturna) to losartan (Cozaar) restricted diet for avoiding renal replacement therapy
in persons with type 2 diabetes and macroalbuminuria. independent of blood pressure, average A1C level, initial
However, specific patient-oriented evidence is lack- renal dysfunction, or use of ACE inhibitors.35 In a ran-
ing.32-34 Table 3 summarizes recommendations for drug domized double-blind placebo-controlled trial of 238
therapy in persons with diabetic nephropathy.6,8,10,16-19 persons with type 1 or 2 diabetes and macroalbuminuria,

May 1, 2012 ◆ Volume 85, Number 9 www.aafp.org/afp American Family Physician 887

Diabetic Nephropathy

Table 5. Summary of Interventions and Outcomes for Diabetic Nephropathy

Outcome

Intervention Disease-oriented Patient-oriented

Blood pressure control Lower incidence of macroalbuminuria, Higher rates of hypotension and bradycardia with
(< 140/80 mm Hg) elevated serum creatinine level, declining intensive blood pressure control (< 120/80 mm
estimated GFR Hg); no differences in the rates of nonfatal
myocardial infarction, nonfatal stroke, death from
cardiovascular causes, or end-stage renal disease, or
the need for dialysis

Intensive glycemic control Reduced progression from microalbuminuria Increased hypoglycemia, no difference in doubling of
to macroalbuminuria creatinine and eventual need for dialysis

Low-protein diet Decreased urine albumin excretion rate, May lower rate of progression to end-stage renal
improved GFR disease and death compared with a normal-protein
diet (based on limited evidence)

Supplementation with Decline in GFR Increased risk of myocardial infarction, stroke, and
folic acid, vitamin B6 all-cause mortality
(pyridoxine), and
cyanocobalamin
(not recommended)

Use of angiotensin-converting Reduced risk of progression from Reduced all-cause mortality

enzyme inhibitor normoalbuminuria, reduced progression
from microalbuminuria to macroalbuminuria

Use of angiotensin II receptor Reduced risk of progression from None

blocker normoalbuminuria, reduced progression
from microalbuminuria to macroalbuminuria

GFR = glomerular filtration rate.

persons receiving supplemental folic acid (2.5 mg), vita- director for the Georgetown University/Providence Hospital Family Medi-
min B6 (pyridoxine, 25 mg), and cyanocobalamin (1 mg) cine Residency Program at Fort Lincoln Family Medicine Center, Colmar
Manor, Md.
had a significantly greater decline in GFR, and increased
risk of myocardial infarction, stroke, and all-cause mor- SARAH LIEGL, MD, is an assistant professor in the Department of Family
Medicine at Georgetown University Medical Center, and residency faculty
tality compared with persons receiving placebo (number
at the Georgetown University/Providence Hospital Family Medicine Resi-
needed to harm = 11).36 Table 5 summarizes patient- and dency Program at Fort Lincoln Family Medicine Center.
disease-oriented evidence regarding development of dia-
YALDA JABBARPOUR, MD, is an assistant professor in the Department of
betic nephropathy. Family Medicine at Georgetown University Medical Center. At the time
this manuscript was written, she was chief resident of the Georgetown
Data Sources: A PubMed search was conducted for diabetic nephropa-
University/Providence Hospital Family Medicine Residency Program at
thy–related topics, including clinical reviews, randomized controlled
Fort Lincoln Family Medicine Center.
trials, and meta-analyses. Search terms included diabetic nephropathy,
microalbuminuria, macroalbuminuria, diabetic kidney disease, renal Address correspondence to Michelle A. Roett, MD, MPH, FAAFP,
replacement therapy, diabetes, diet, and glycemic and blood pressure Georgetown University/Providence Hospital Family Medicine Residency
control. Relevant publications from the Cochrane database, Essential Evi- Program, Fort Lincoln Family Medicine Center, 4151 Bladensburg Rd.,
dence, National Guideline Clearinghouse, U.S. Preventive Services Task Colmar Manor, MD 20722 (e-mail: mar2@georgetown.edu). Reprints
Force, the Centers for Disease Control and Prevention, and the American are not available from the authors.
Diabetes Association also were reviewed. Search date: January 31, 2011.
Author disclosure: No relevant financial affiliations to disclose.

The Authors
REFERENCES
MICHELLE A. ROETT, MD, MPH, FAAFP, is an associate professor in the
Department of Family Medicine at Georgetown University Medical Cen- 1. Centers for Disease Control and Prevention. National diabetes fact sheet,
ter, Washington, DC, and the medical director and an associate program 2011. Atlanta, Ga.: U.S. Department of Health and Human Services,

888  American Family Physician www.aafp.org/afp Volume 85, Number 9 ◆ May 1, 2012
 Diabetic Nephropathy

Centers for Disease Control and Prevention; 2011. http://www.cdc.gov/ 21. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardio-
diabetes/pubs/pdf/ndfs_2011.pdf. Accessed February 19, 2011. vascular Risk in Diabetes Study Group. Effects of intensive glucose low-
2. United States Renal Data System. USRDS 2010 Annual Data Report: ering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the 22. Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative

United States. Bethesda, Md.: National Institutes of Health, National Group. Intensive blood glucose control and vascular outcomes in
Institute of Diabetes and Digestive and Kidney Diseases; 2010. http:// patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
www.usrds.org/atlas10.aspx. Accessed February 14, 2012. 23. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and
3. Hovind P, Tarnow L, Rossing P, et al. Predictors for the development of the prevention of cardiovascular events: implications of the ACCORD,
microalbuminuria and macroalbuminuria in patients with type 1 diabe- ADVANCE, and VA diabetes trials: a position statement of the American
tes: inception cohort study. BMJ. 2004;328(7448):1105-1108. Diabetes Association and a scientific statement of the American
4. Gerstein HC, Mann JF, Yi Q, et al.; HOPE Study Investigators. Albumin- College of Cardiology Foundation and the American Heart Association
uria and risk of cardiovascular events, death, and heart failure in dia- [published correction appears in Circulation. 2009;119(25):e605].
betic and nondiabetic individuals. JAMA. 2001;286(4):421-426. Circulation. 2009;119(2):351-357.
5. Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; DEMAND 24. Chobanian AV, Bakris GL, Black HR, et al.; National Heart, Lung, and
investigators. Prevalence and risk factors for microalbuminuria in a Blood Institute Joint National Committee on Prevention, Detection,
referred cohort of type II diabetic patients: a global perspective. Kidney Evaluation, and Treatment of High Blood Pressure; National High Blood
Int. 2006;69(11):2057-2063. Pressure Education Program Coordinating Committee. The Seventh
6. American Diabetes Association. Executive summary: standards of medi- Report of the Joint National Committee on Prevention, Detection, Eval-
cal care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S4-S10. uation, and Treatment of High Blood Pressure: the JNC 7 report [pub-
lished correction appears in JAMA. 2003;290(2):197]. JAMA. 2003;
7. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR;
289(19):2560-2572.
UKPDS Group. Development and progression of nephropathy in type 2
diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). 25. Strippoli GF, Craig M, Craig JC. Antihypertensive agents for prevent-
Kidney Int. 2003;63(1):225-232. ing diabetic kidney disease. Cochrane Database Syst Rev. 2005;
(4):CD004136.
8. Rossing P, Hougaard P, Parving HH. Progression of microalbuminuria in
type 1 diabetes: ten-year prospective observational study. Kidney Int. 26. Mann JF, Schmieder RE, McQueen M, et al.; ONTARGET investigators.
2005;68(4):1446-1450. Renal outcomes with telmisartan, ramipril, or both, in people at high
9. Molitch ME, DeFronzo RA, Franz MJ, et al.; American Diabetes Asso- vascular risk (the ONTARGET study): a multicentre, randomised, double-
ciation. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1): blind, controlled trial. Lancet. 2008;372(9638):547-553.
S79-S83. 27. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angioten-
10. KDOQI clinical practice guidelines and clinical practice recommen-
sin converting enzyme inhibitors and angiotensin II receptor antagonists
dations for diabetes and chronic kidney disease. Am J Kidney Dis. on mortality and renal outcomes in diabetic nephropathy: systematic
2007;49(2 suppl 2):S12-S154. review. BMJ. 2004;329(7470):828.
11. Lambers Heerspink HJ, Gansevoort RT, Brenner BM, et al. Comparison 28. Strippoli GF, Bonifati C, Craig ME, Navaneethan SD, Craig JC. Angioten-
of different measures of urinary protein excretion for prediction of renal sin converting enzyme inhibitors and angiotensin II receptor antagonists
events. J Am Soc Nephrol. 2010;21(8):1355-1360. for preventing the progression of diabetic kidney disease. Cochrane
Database Syst Rev. 2006;(4):CD006257.
12. Witte EC, Lambers Heerspink HJ, de Zeeuw D, Bakker SJ, de Jong PE, Gan-
sevoort R. First morning voids are more reliable than spot urine samples 29. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associ-
to assess microalbuminuria. J Am Soc Nephrol. 2009;20(2):436-443. ated elevations in serum creatinine: is this a cause for concern? Arch
13. Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Glucose Intern Med. 2000;160(5):685-693.
control and vascular complications in veterans with type 2 diabetes 30. Bakris GL, Toto RD, McCullough PA, Rocha R, Purkayastha D, Davis P;
[published correction appears in N Engl J Med. 2009;361(10):1024- GUARD (Gauging Albuminuria Reduction With Lotrel in Diabetic Patients
1025, 1028]. N Engl J Med. 2009;360(2):129-139. With Hypertension) Study Investigators. Effects of different ACE inhibitor
14. Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the combinations on albuminuria: results of the GUARD study. Kidney Int.
absence of albuminuria and retinopathy among adults with type 2 dia- 2008;73(11):1303-1309.
betes mellitus. JAMA. 2003;289(24):3273-3277. 31. de Galan BE, Perkovic V, Ninomiya T, et al.; ADVANCE Collaborative
15. National Kidney Foundation. K/DOQI clinical practice guidelines for
Group. Lowering blood pressure reduces renal events in type 2 diabe-
chronic kidney disease: evaluation, classification, and stratification. Am tes. J Am Soc Nephrol. 2009;20(4):883-892.
J Kidney Dis. 2002;39(2 suppl 1):1-266. 32. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of
16. Cushman WC, Evans GW, Byington RP, et al.; ACCORD Study Group. angiotensin receptor blockade or mineralocorticoid antagonism to max-
Effects of intensive blood-pressure control in type 2 diabetes mellitus. imal angiotensin-converting enzyme inhibition in diabetic nephropathy.
N Engl J Med. 2010;362(17):1575-1585. J Am Soc Nephrol. 2009;20(12):2641-2650.
17. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary 33. Wenzel RR, Littke T, Kuranoff S, et al.; SPP301 (Avosentan) Endothe-
protein restriction on prognosis in patients with diabetic nephropathy. lin Antagonist Evaluation in Diabetic Nephropathy Study Investigators.
Kidney Int. 2002;62(1):220-228. Avosentan reduces albumin excretion in diabetics with macroalbumin-
18. Azadbakht L, Atabak S, Esmaillzadeh A. Soy protein intake, car-
uria. J Am Soc Nephrol. 2009;20(3):655-664.
diorenal indices, and C-reactive protein in type 2 diabetes with 34. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study
nephropathy: a longitudinal randomized clinical trial. Diabetes Care. Investigators. Aliskiren combined with losartan in type 2 diabetes and
2008;31(4):648-654. nephropathy. N Engl J Med. 2008;358(23):2433-2446.
19. Pan Y, Guo LL, Jin HM. Low-protein diet for diabetic nephropathy: a 35. Facchini FS, Saylor KL. A low-iron-available, polyphenol-enriched, car-
meta-analysis of randomized controlled trials. Am J Clin Nutr. 2008; bohydrate-restricted diet to slow progression of diabetic nephropathy.
88(3):660-666. Diabetes. 2003;52(5):1204-1209.
20. Morales E, Valero MA, León M, Hernández E, Praga M. Beneficial
36. House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy
effects of weight loss in overweight patients with chronic proteinuric on progression of diabetic nephropathy: a randomized controlled trial.
nephropathies. Am J Kidney Dis. 2003;41(2):319-327. JAMA. 2010;303(16):1603-1609.

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