Clinical Evidence Concise

A Publication of BMJ Publishing Group

Diabetic Nephropathy

Am Fam Physician. 2005 Dec 1;72(11):2299-2302.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The evidence is available at http://www.clinicalevidence.com/ceweb/conditions/pac/0606/0606.jsp.

What are the effects of treatments in persons with type 1 diabetes and early nephropathy?

BENEFICIAL

Angiotensin-Converting Enzyme Inhibitors (Progression To Late Nephropathy).

One systematic review found that, compared with placebo or controls, angiotensin-converting enzyme (ACE) inhibitors (captopril, lisinopril, enalapril, perindopril, and ramipril) reduced progression to macroalbuminuria and increased regression to normoalbuminuria in normotensive persons with type 1 diabetes and microalbuminuria. We found no randomized controlled trials (RCTs) comparing angiotensin-II receptor antagonists and ACE inhibitors in persons with type 1 diabetes and early nephropathy.

Glycemic Control (Progression to Late Nephropathy).

One systematic review found that, compared with conventional control, intensive glycemic control reduced progression of nephropathy in persons with type 1 diabetes and either normal albumin excretion or microalbuminuria. The review showed no significant difference between intensive glycemic control and conventional control in the incidence of severe hypoglycemia. The review showed a higher incidence of diabetic keto-acidosis in persons treated with continuous subcutaneous insulin infusion compared with conventional multiple injection treatment.

UNKNOWN EFFECTIVENESS

Angiotensin-II Receptor Antagonists.

We found no RCTs comparing the effects of angiotensin-II receptor antagonists with placebo on outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and early nephropathy. Long-term placebo-controlled RCTs would not be ethical because of the established benefits of ACE inhibitors and the similarity between these two drug classes. We found no RCTs comparing angiotensin-II receptor antagonists with ACE inhibitors in persons with type 1 diabetes and early nephropathy.

Protein Restriction.

We found no RCTs comparing the effects of low-protein diet with usual diet on the outcomes of progression to late nephropathy, all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and early nephropathy.

Tight Control of Blood Pressure.

We found no RCTs comparing the effects of tight control of blood pressure with conventional control on the outcomes of progression to late nephropathy, all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and early nephropathy.

What are the effects of treatments in persons with type 1 diabetes and late nephropathy?

BENEFICIAL

Captopril.

One RCT that included persons with type 1 diabetes and late nephropathy found that, compared with placebo, captopril (an ACE inhibitor) reduced the combined outcomes of renal transplant, end-stage renal disease, or death over three years. We found no RCTs comparing angiotensin-II receptor antagonists with ACE inhibitors in persons with type 1 diabetes and late nephropathy.

UNKNOWN EFFECTIVENESS

Angiotensin-II Receptor Antagonists.

We found no RCTs comparing the effects of angiotensin-II receptor antagonists with placebo on outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and late nephropathy. Conducting long-term placebo-controlled RCTs would not be ethical because of the established benefits of ACE inhibitors and the similarity between these two drug classes. We found no RCTs comparing angiotensin-II receptor antagonists with ACE inhibitors in persons with type 1 diabetes and late nephropathy.

Protein Restriction.

One small RCT found that, compared with usual protein intake, a low-protein diet reduced the cumulative incidence of end-stage renal disease or death over four years in persons with type 1 diabetes and late nephropathy. This RCT was small, and neither participants nor study investigators could be blinded to the randomization because of the nature of the intervention.

Glycemic Control

We found no RCTs comparing the effects of intensive glycemic control with conventional glycemic control on the outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and late nephropathy.

Tight Control of Blood Pressure.

We found no RCTs comparing the effects of tight blood pressure control with conventional control on the outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 1 diabetes and late nephropathy.

What are the effects of treatments in persons with type 2 diabetes and early nephropathy?

BENEFICIAL

ACE Inhibitors

One RCT found that, compared with placebo, enalapril reduced progression to late nephropathy in persons with type 2 diabetes and early nephropathy. One RCT comparing ramipril with placebo using subgroup analysis in persons with diabetes and early nephropathy found that ramipril reduced the combined outcomes of myocardial infarction, stroke, or cardiovascular death. One RCT found no significant difference between low-dose ramipril and placebo in all-cause mortality, end-stage renal disease, stroke, heart failure, or myocardial infarction. One systematic review that included persons with diabetes and nephropathy, but that did not stratify the results by the type of diabetes, found that, compared with placebo, ACE inhibitors reduced progression to late nephropathy in persons with diabetes and microalbuminuria over three years. One RCT that included persons with type 2 diabetes and early nephropathy found no significant difference between the ACE inhibitor enalapril and the angiotensin-II receptor antagonist telmisartan over five years in the change in glomerular filtration rate, all-cause mortality, stroke, heart failure, or myocardial infarction.

Angiotensin-II Receptor Antagonists.

One RCT that included persons with type 2 diabetes, hypertension, and microalbuminuria found that, compared with placebo, 300 mg of the angiotensin-II receptor antagonist irbesartan reduced progression from early to late nephropathy over two years. However, it found no significant decrease with 150 mg of irbesartan. One RCT that included persons with type 2 diabetes and early nephropathy found no significant difference between the angiotensin-II receptor antagonist telmisartan and enalapril over five years in change in glomerular filtration rate, all-cause mortality, stroke, heart failure, or myocardial infarction.

Tight Control of Blood Pressure (Progression to Late Nephropathy)

One RCT found that, in persons with type 2 diabetes, early nephropathy, and normal baseline blood pressure, a lower diastolic blood pressure target (10 mm Hg below baseline) reduced progression from microalbuminuria to overt albuminuria over five years compared with a moderate diastolic blood pressure target (80 to 89 mm Hg).

UNKNOWN EFFECTIVENESS

Protein Restriction

We found no RCTs evaluating the effects of protein restriction on the outcomes of progression to late nephropathy, all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 2 diabetes and early nephropathy.

Glycemic Control

We found no RCTs evaluating the effects of glycemic control on the outcomes of progression to late nephropathy, all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 2 diabetes and early nephropathy.

What are the effects of treatments in persons with type 2 diabetes and late nephropathy?

BENEFICIAL

Angiotensin-II Receptor Antagonists

We found two RCTs comparing the effects of angiotensin-II receptor antagonists with placebo on the outcomes of progression to end-stage renal disease, cardiovascular events, and all-cause mortality. One RCT that included persons with type 2 diabetes and late nephropathy found that, compared with placebo, losartan reduced progression to end-stage renal disease over 3.4 years. The trial found no significant difference in fatal or nonfatal cardiovascular events or death from any cause. Another RCT that included persons with type 2 diabetes and late nephropathy found no significant difference between irbesartan and placebo in progression to end-stage renal disease or death from any cause over 2.6 years. The trial also found that irbesartan reduced the incidence of congestive heart failure compared with placebo. It found no significant difference in a composite cardiovascular outcome, cardiovascular death, myocardial infarction, cerebrovascular accident, or cardiac revascularization. In both RCTs, the angiotensin-II receptor antagonist was discontinued if hyperkalemia occurred.

Protein Restriction

We found no RCTs evaluating the effects of protein restriction on the outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 2 diabetes and late nephropathy.

Glycemic Control.

We found no RCTs on glycemic control on the outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 2 diabetes and late nephropathy.

Tight Control of Blood Pressure

We found no RCTs evaluating the effects of tight blood pressure control on the outcomes of all-cause mortality, incidence of end-stage renal disease, or incidence of cardiovascular events (e.g., stroke, heart failure, myocardial infarction) in persons with type 2 diabetes and late nephropathy.

Definition

Diabetic nephropathy is a clinical syndrome characterized by albuminuria on at least two occasions that are separated by three to six months, in persons with diabetes. Diabetic nephropathy usually is accompanied by hypertension, progressive rise in proteinuria, and decline in renal function. In type 1 diabetes, five stages have been proposed. Of these, stages 1 and 2 are equivalent to pre-clinical nephropathy and are detected only by imaging or biopsy. Stage 3 is synonymous with early nephropathy. Stage 4 also is known clinically as late nephropathy. Stage 5 represents the progression to end-stage renal disease.

Incidence

In 1997, the worldwide prevalence of diabetes was 124 million, and this number is expected to increase to 221 million in 2010.1 In the United Kingdom, 1.4 million persons had been diagnosed with diabetes in 1998, and estimates suggest that 1 million more have undiagnosed diabetes.2 After having diabetes for 20 years, the cumulative risk of proteinuria is 27 percent in type 2 and 28 percent in type 1 diabetes.3 In types 1 and 2 diabetes, the overall prevalence of microalbuminuria and macroalbuminuria is approximately 30 to 35 percent.4 In addition, the incidence of diabetic nephropathy is increasing, in part because of the growing type 2 diabetes epidemic and increased life expectancies. For example, in the United States, the incidence rate has increased by 150 percent in the past decade.5

Etiology

Duration of diabetes, older age, male sex, smoking status, and poor glycemic control have been found to be risk factors for developing nephropathy.6,7 In addition, certain ethnic groups seem to be at greater risk for developing diabetic nephropathy (see Prognosis). Microalbuminuria is less pathognomonic in patients with type 2 diabetes because hypertension, which commonly complicates type 2 diabetes, also can cause microalbuminuria. Hypertension also can cause renal insufficiency; therefore, the time to development of renal insufficiency can be shorter in type 2 diabetes than in type 1. For persons with an atypical course, renal biopsy may be advisable. In addition, there are some differences in the progression of type 1 and type 2 diabetic nephropathy. In type 2 diabetes, albuminuria is more often present at diagnosis. Hypertension also is more common in type 2 diabetic nephropathy. Finally, microalbuminuria is less predictive of late nephropathy in patients with type 2 diabetes compared with type 1.8

Prognosis

Persons with microalbuminuria are at increased risk for progression to macroalbuminuria and end-stage renal disease. The course of renal function is similar between types 1 and 2 diabetes. The natural history of diabetic nephropathy is better defined in type 1 than in type 2 diabetes. In type 2 diabetes, the course can be more difficult to predict, primarily because the date of onset of diabetes is less commonly known and because comorbid conditions can contribute to renal disease. Without specific interventions, about 80 percent of persons with type 1 diabetes and 20 to 40 percent of persons with type 2 diabetes who have microalbuminuria will develop macroalbuminuria.9 Diabetic nephropathy is associated with poor outcomes. Diabetic nephropathy is the most common cause of end-stage renal disease in the United Kingdom, accounting for 20 percent of all cases,10 whereas in the United States, diabetes accounts for 48 percent of all new cases of end-stage renal disease.11 Persons with type 1 diabetes and proteinuria have been found to have a 40-fold greater risk of all-cause mortality than persons without proteinuria.12 The prognostic significance of proteinuria is less extreme in type 2 diabetes, although persons with proteinuria have a fourfold risk of death compared with persons without proteinuria.13 In addition, increased cardiovascular risk has been associated with albuminuria in persons with diabetes.14 Blacks, Native Americans, and Hispanics have a much higher risk of developing end-stage renal disease in the setting of diabetes compared with whites.9,15 In the United States, blacks with diabetes develop end-stage renal disease at a considerably more rapid rate than whites with diabetes.16 In the United Kingdom, the rates for initiating treatment for end-stage renal disease are 4.2 times higher for Afro-Caribbeans and 3.7 times higher for Indo-Asians compared with whites.17 The Pima tribe of Native Americans, located in the southwestern United States, have much higher rates of diabetic nephropathy compared with whites, and they also develop end-stage renal disease at a faster rate.18

search date: November 2004

Adapted with permission from Shlipak M. Diabetic nephropathy. Clin Evid Concise 2005;13:149–54.

 

REFERENCES

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2. Diabetes UK. Who gets diabetes and what causes it? Accessed online September 12, 2005, at: http://www.diabetes.org.uk/diabetes/get.htm.

3. Hasslacher C, Ritz E, Wahl P, et al. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant. 1989;4:859–63.

4. Parving HH, Osterby R, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. The kidney. Philadelphia: WB Saunders, 2000:1731–73.

5. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002;346:1145–51.

6. Marcantoni C, Ortalda V, Lupo A, et al. Progression of renal failure in diabetic nephropathy. Nephrol Dial Transplant. 1998;13(suppl 8):S16–9.

7. Ballard DJ, Humphrey LL, Melton LJ III, et al. Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota. Diabetes. 1988;37:405–12.

8. Powers A. Diabetes mellitus. In: Braunwald E, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of internal medicine. New York: McGraw-Hill, 2001.

9. Molitch ME, DeFronzo RA, Franz MJ, et al. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79–83.

10. Ansell D, Feest T. UK renal registry report. Bristol: United Kingdom Renal Registry, 2001.

11. USRDS. 2000 annual data report. Bethesda, Md.: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2000.

12. Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1985;28:590–6.

13. Morrish NJ, Stevens LK, Head J, et al. A prospective study of mortality among middle-aged diabetic patients (the London Cohort of the WHO Multinational Study of Vascular Disease in Diabetics) I: causes and death rates. Diabetologia. 1990;33:538–41.

14. Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia. 1999;42:263–85.

15. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the US: 1990–1998. Diabetes Care. 2000;23:1278–83.

16. Hsu CY, Lin F, Vittinghoff E, et al. Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States. J Am Soc Nephrol. 2003;14:2902–7.

17. Roderick PJ, Raleigh VS, Hallam L, et al. The need and demand for renal replacement therapy in ethnic minorities in England. J Epidemiol Community Health. 1996;50:334–9.

18. Lemley KV. A basis for accelerated progression of diabetic nephropathy in Pima Indians. Kidney Int Suppl. 2003:S38–42.

This is one in a series of chapters excerpted from Clinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence Concise is published in print twice a year and is updated monthly online. Each topic is revised every 12 months, and subscribers should view the most up-to-date version at http://www.clinicalevidence.com. If you are interested in contributing to Clinical Evidence, send an e-mail to CEcommissioning@bmj-group.com. This series is part of the AFP’s CME. See “Clinical Quiz” on page 2173.


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