American Journal of Kidney Diseases
Volume 46, Issue 4 , Pages 766-773, October 2005

Diabetes and the Kidney

  • Andrew S. O’Connor, DO, MPH
    • ,
  • Jeffrey R. Schelling, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Jeffrey R. Schelling, MD, Rammelkamp Center for Education and Research, Department of Medicine, Case Western Reserve University, 2500 MetroHealth Dr, Cleveland, OH 44109

Rammelkamp Center for Education and Research, Department of Medicine, Case Western Reserve University, Cleveland, OH

Received 18 February 2005; accepted 12 May 2005. published online 22 August 2005.

Article Outline

 

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Diabetes 

Definitions 

•Metabolic disorder of multiple causes characterized by chronic hyperglycemia and disorders of carbohydrate, fat, and protein metabolism

•Results from defects in insulin secretion (type 1), insulin action (type 2), or combination of these factors

•World Health Organization and American Diabetes Association diagnostic criteria:
■Fasting plasma glucose ≥126 mg/dL (≥7.0 mmol/L) or fasting whole-blood glucose level ≥110 mg/dL (≥6.1 mmol/L), or a

■2-hour post–glucose-load plasma glucose ≥200 mg/dL (≥11.1 mmol/L; 180 mg/dL [10.0 mmol/L] if whole blood), or a

■Random plasma glucose >200 mg/dL (>11.1 mmol/L) on >1 occasion

■“Prediabetic” stage: fasting plasma glucose between 100 and 126 mg/dL (5.6 and 7.0 mmol/L) increasingly recognized as risk factor for end-organ complications; evidence supports lifestyle interventions to prevent or delay onset of diabetes


Incidence 

•18.2 million people in United States have diabetes (National Health and Nutrition Examination Survey 1999 to 2000), and up to one third of these cases are undiagnosed

•Approximately 1 in 400 to 500 children and adolescents have type 1 diabetes

•With increases in obesity rates in adolescents, type 2 diabetes becoming common, especially in minority groups

•8.7% of adults have diabetes; rate increases to 18% of adults aged ≥60 years

•By 2030, anticipate 366 million cases of type 2 diabetes worldwide and 30 million US cases

Risk Factors for Development 

Type 1 Diabetes 

•Defined by autoimmunity; autoantigens include islet-cell proteins, glutamic acid decarboxylase, insulin, and proinsulin

•Viral infections may initiate a poorly understood immune response, which induces β-cell damage

•Genetics/family history:
■Lifetime risk for 1 monozygotic twin is 20% to 30% if the other has diabetes

■18 different risk alleles have been identified


Type 2 Diabetes 

•Environment:
■Most patients are overweight or obese, suggesting role for environmental factors, especially “Westernization” of diet with highly processed foods high in fat and simple sugars


•Genetics/family history:
■High degrees of concordance within families and between twins

■Single gene mutations have been identified for multiple mature-onset diabetes of the young (MODY) phenotypes


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Additional Reading 

1. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002

2. Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047-1053, 2004

3. Field LL: Genetic linkage and association studies of type I diabetes: Challenges and rewards. Diabetologia 45:21-35, 2002

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Diabetic Nephropathy (DN): General 

Definition 

•Progressive decline in glomerular filtration rate (GFR) in context of long-standing diabetes, usually accompanied by nephrotic-range proteinuria and other end-organ complications, such as retinopathy

Stages 

•Normoalbuminuria with elevated GFR (within 5 to 10 years):
■Usually associated with glomerular and tubular hypertrophy and enlarged kidneys on ultrasound evaluation

■Hyperfiltration may be maladaptive


•Microalbuminuria/incipient diabetic nephropathy (within 5 to 15 years):
■Defined as 30 to 300 mg albumin/g creatinine

■May be measured quantitatively or semiquantitatively with dipsticks


•Macroalbuminuria/overt proteinuria (10 to 20 years):
■Defined as >300 mg albumin/g creatinine


•Decline in GFR (15 to 25 years)

•End-stage renal disease (ESRD) within 5 years of developing nephrotic-range proteinuria

Epidemiology 

•DN remains leading cause of ESRD in United States:
■In 2002, 45% of incident ESRD due to DN, resulting from increased prevalence of type 2 diabetes

■41% of prevalent ESRD from DN


•Incidence of DN in type 1 diabetic patients has been declining, which may be related to early and aggressive control of blood glucose and blood pressure

•Incidence of diabetic nephropathy from type 2 diabetes is variable, but probably increasing due to increased rates of obesity, metabolic syndrome, and type 2 diabetes

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Additional Reading 

1. Mogensen CE, Christensen CK, Vittinghus E: The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32:S64-S78, 1983 (suppl 2)

2. Nelson RG, Bennett PH, Beck GJ, et al: Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 335:1636-1642, 1996

3. US Renal Data System: USRDS 2004 Annual Data Report. Am J Kidney Dis 45:S8-S280, 2005 (suppl 1)

4. Hovind P, Tarnow L, Rossing P, et al: Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: Inception cohort study. BMJ 328:1105-1109, 2004

5. Hovind P, Tarnow L, Rossing K, et al: Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 26:1258-1264, 2003

6. Bennett PH, Lee ET, Lu M, Keen H, Fuller JH: Increased urinary albumin excretion and its associations in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 44:S37-S45, 2001 (suppl 2)

7. Hsu CY, Vittinghoff E, Lin F, Shlipak MG: The incidence of end-stage renal disease is increasing faster than the prevalence of chronic renal insufficiency. Ann Intern Med 141:95-101, 2004

8. Xue JL, Ma JZ, Louis TA, Collins AJ: Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 12:2753-2758, 2001

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DN Pathology 

General 

•Diabetic kidneys generally increased in size (between 10% and 30% above age-, sex-, and race-matched controls) on ultrasound and gross pathologic evaluation due to glomerular and tubular hypertrophy, rather than hyperplasia

Indications for Biopsy 

•Accelerated disease kinetics compared with earlier description in “Diabetic Nephropathy: General” section

•Absence of extrarenal end-organ damage

•Concomitant nondiabetic lesions are rare, although higher incidences have been reported in selected populations characterized by atypical clinical presentations

Glomerular 

•Glomerular basement membrane thickening:
■May occur as early as 2 years after diabetes diagnosis

■Irregular by electron microscopy, usually no glomerular basement membrane deposits

■Subendothelial “hyaline caps” associated with progressive glomerular disease


•Podocyte numbers may decrease, with individual podocyte foot processes broadening to cover expanded surface area

•Mesangial matrix expansion (diffuse diabetic glomerulosclerosis) is most common lesion; hyalinization of parietal surface of Bowman capsule (capsular drop lesions) seen less commonly

•Kimmelstiel-Wilson nodules (nodular diabetic glomerulosclerosis): eosinophilic, at glomerular periphery

•Arteriolar hyalinosis; involves afferent and efferent arterioles, efferent hyalinization is relatively specific for DN

Tubulointerstitial 

•Early cellular component, with tubular hypertrophy and decrease in ratio of capillaries to tubules

•Tubulointerstitial lesions (interstitial fibrosis and tubular atrophy) have been described, which correlates with degree of renal dysfunction and, by extrapolation, progression to ESRD

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Additional Reading 

1. Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batlle D: Renal pathology patterns in type II diabetes mellitus: Relationship with retinopathy. The Collaborative Study Group. Nephrol Dial Transplant 13:2547-2552, 1998

2. Olsen S, Mogensen CE: How often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature. Diabetologia 39:1638-1645, 1996

3. Pagtalunan ME, Miller PL, Jumping-Eagle S, et al: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99:342-348, 1997

4. Katz A, Caramori ML, Sisson-Ross S, Groppoli T, Basgen JM, Mauer M: An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients. Kidney Int 61:2058-2066, 2002

5. D’Amico G: Tubulointerstitium as predictor of progression of glomerular diseases. Nephron 83:289-295, 1999

6. Gilbert RE, Cooper ME: The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury? Kidney Int 56:1627-1637, 1999

7. Nath KA: Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20:1-17, 1992

8. Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional correlations in renal disease. II. The correlations. Hum Pathol 1:631-641, 1970

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Recommendations for DN Screening 

Timing of Initial Screen 

Type 1 Diabetic Patients 

•In patients with appropriate glycemic control, initially screen 5 years after diabetes diagnosis

•Patients with risk factors for DN progression (see next section) should be screened earlier

•Onset of puberty is independent risk factor for DN, so adolescents should be screened at time of puberty

Type 2 Diabetic Patients 

•At diagnosis, up to 7% of type 2 diabetic patients already have DN, which may reflect delay in diabetes diagnosis by 4 to 7 years

•Therefore, initially screen for DN upon diabetes diagnosis

Negative Initial Screen 

•If initial screen is negative, annual screening should be followed

Urine Microalbuminuria 

•Most accepted screening test

•Methods of microalbuminuria screening (composite based on American Diabetes Association and National Kidney Foundation guidelines):
■Analysis of untimed “spot” samples is acceptable; first-morning-void specimens are preferred

■Albumin excretion from 24-hour urine collection also acceptable, but cumbersome and often inaccurate due to inadequate collection

■Patients can be screened with microalbuminuria dipsticks, but require subsequent quantitative assay for correlation after positive dipstick reading


•Albuminuria screening should not be performed when patients have acute conditions that may independently increase urinary albumin excretion, such as:
■Urinary tract infection

■Acute illness, especially with fever

■Recent heavy exercise

■Hypertensive urgency/emergency

■Hyperglycemia


GFR Estimates 

•Useful for staging and therapeutic plans

•Creatinine clearance from 24-hour urine collection has been standard until recently; however, as with quantitative albuminuria, timed collections are cumbersome and often inaccurate

•GFR estimate from equations is preferred alternative, and current recommendations are that equations based on Modification of Diet in Renal Disease (MDRD) study should be used rather than Cockcroft-Gault equation; however, MDRD equation may underestimate GFR in normal range

•Because equations are based on serum creatinine values, calibration of serum creatinine assays to national reference standard is important

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Additional Reading 

1. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T: Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 28:164-176, 2005

2. American Diabetes Association: Standards of medical care in diabetes. Diabetes Care 28:S4-S36, 2005 (suppl 1)

3. Stephenson JM, Fuller JH: Microalbuminuria is not rare before 5 years of IDDM. EURODIAB IDDM Complications Study Group and the WHO Multinational Study of Vascular Disease in Diabetes Study Group. J Diabetes Complications 8:166-173, 1994

4. Schultz CJ, Konopelska-Bahu T, Dalton RN, et al: Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group. Diabetes Care 22:495-502, 1999

5. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR: Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225-232, 2003

6. Harris MI, Klein R, Welborn TA, Knuiman MW: Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 15:815-819, 1992

7. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 39:S1-S266, 2002 (suppl 1)

8. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999

9. Stevens LA, Levey AS: Clinical implications of estimating equations for glomerular filtration rate. Ann Intern Med 141:959-961, 2004

10. Rule AS, Larson TS, Bergstralh EJ, et al: Using serum creatinine to estimate glomerular filtration rate: Accuracy in good health and in chronic renal disease. Ann Intern Med 141:929-937, 2004

11. Coresh J, Astor B, McQuillan G, et al: Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 39:920-929, 2002

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Risk Factors for DN Progression 

Hyperglycemia 

•Diabetes Control and Complications Trial (DCCT):
■Intensive glucose control decreased incidence of microalbuminuria and macroalbuminuria among type 1 diabetic patients


■Epidemiology of Diabetes Intervention and Complications (EDIC):
■Follow-up of DCCT cohort that showed that initial tight glucose control had sustained benefit on incidence of microalbuminuria years later


•UK Prospective Diabetes Study Group (UKPDS):
■In type 2 diabetic patients, hemoglobin A1c (HgbA1c) <7.0% associated with decreased risk for microvascular complications and progression of diabetic nephropathy


Hypertension 

•Common in diabetic patients, even without documented renal disease; prevalence increases with declining GFR

•Systolic blood pressure predicts DN progression

•UKPDS: Reduced risk for microalbuminuria in type 2 diabetic patients with blood pressure <140/80 mm Hg

Proteinuria 

•In type 1 diabetes, increased baseline urinary albumin excretion, even within normal range, is risk for micro- and macroalbuminuria in type 1 diabetes

•In type 2 diabetic patients, initial hyperfiltration predicted micro- and macroalbuminuria, which was followed by gradual GFR decline

•Conversely, some studies have shown that microalbuminuria is poor predictor of DN progression in diabetes types 1 and 2

•Macroalbuminuria is strong predictor of DN progression in diabetes types 1 and 2

Family History/Genetic Predisposition 

•Substantial evidence for familial predisposition to DN in diabetes types 1 and 2

•Studies containing large numbers of well-phenotyped patients are underway to identify DN susceptibility genes

Male Sex 

•Independent risk for DN progression, although mechanism is unclear

Risks for CKD Progression, May Apply to DN 

•Hyperlipidemia

•Tobacco use:
■Risk for microalbuminuria in diabetes types 1 and 2

■Longitudinal studies show relationship with CKD progression


•Decreased birth weight:
■Associated with decreased nephron number, earlier onset, and more rapid progression of nephropathy


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Additional Reading 

1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977-986, 1993

2. Writing Team for the Diabetes and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290:2159-2167, 2003

3. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837-853, 1998

4. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR: Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225-232, 2003

5. Mogensen CE: Microalbuminuria and hypertension with focus on type 1 and type 2 diabetes. J Intern Med 254:45-66, 2003

6. Bakris GL, Williams M, Dworkin L, et al: Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 36:646-661, 2000

7. Tarnow L, Rossing P, Gall MA, Nielsen FS, Parving HH: Prevalence of arterial hypertension in diabetic patients before and after the JNC-V. Diabetes Care 17:1247-1251, 1994

8. Biesenbach G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 9:1097-1102, 1994

9. Breyer JA, Bain RP, Evans JK, et al: Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. The Collaborative Study Group. Kidney Int 50:1651-1658, 1996

10. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317:703-713, 1998

11. Mogensen CE, Christensen CK, Vittinghus E: The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32:S64-S78, 1983 (suppl 2)

12. Hovind P, Tarnow L, Rossing P, et al: Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: Inception cohort study. BMJ 328:1105-1109, 2004

13. Nelson RG, Bennett PH, Beck GJ, et al: Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 335:1636-1642, 1996

14. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS: Regression of microalbuminuria in type 1 diabetes. N Engl J Med 348:2285-2293, 2003

15. Mogensen CE: Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int 31:673-689, 1987

16. Freedman BI, Tuttle AB, Spray BJ: Familial predisposition to nephropathy in African-Americans with non-insulin-dependent diabetes mellitus. Am J Kidney Dis 25:710-713, 1995

17. Quinn M, Angelico MC, Warram JH, Krolewski AS: Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39:940-945, 1996

18. Covic AM, Iyengar SK, Olson JM, et al: A family-based strategy to identify genes for diabetic nephropathy. Am J Kidney Dis 37:638-647, 2001

19. Knowler WC, Coresh J, Elston RC, et al: The Family Investigation of Nephropathy and Diabetes (FIND): Design and methods. J Diabetes Complications 19:1-9, 2005

20. Jacobsen P, Rossing K, Tarnow L, et al: Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int Suppl 71:S101-S105, 1999

21. Seliger SL, Davis C, Stehman-Breen C: Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 10:219-225, 2001

22. Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 158:998-1004, 1998

23. Chaturvedi N, Fuller JH, Taskinen MR: Differing associations of lipid and lipoprotein disturbances with the macrovascular and microvascular complications of type 1 diabetes. Diabetes Care 24:2071-2077, 2001

24. Appel GB, Radhakrishnan J, Avram MM, et al: Analysis of metabolic parameters as predictors of risk in the RENAAL study. Diabetes Care 26:1402-1407, 2003

25. Orth SR: Smoking and the kidney. J Am Soc Nephrol 13:1663-1672, 2002

26. Keller G, Zimmer G, Mall G, Ritz E, Amann K: Nephron number in patients with primary hypertension. N Engl J Med 348:101-108, 2003

27. Brenner BM, Chertow GM: Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis 23:171-175, 1994

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Strategies for Preventing/Slowing DN Progression 

Glucose Control 

•Multiple intervention trials show benefit of maintaining HgbA1c <7.0%

•Multiple agents may be effective:
■Insulin—DCCT and EDIC:
○Of the diabetes regimens, best evidence for preventing nephropathy with insulin

○EDIC study demonstrated sustained benefit of glucose control in decreasing micro- and macroalbuminuria, as well as new development of hypertension


■Thiazolidinediones:
○May be beneficial for decreasing albuminuria in type 2 diabetic patients

○May cause fluid retention in subjects with decreased left ventricular ejection fraction


■Metformin:
○Excellent for glucose and lipid control

○Use with caution in diabetic subjects with chronic kidney disease because of case reports of metformin-induced fatal metabolic acidosis



•Insulin half-life is prolonged with decreased GFR, so dosing of all agents should be adjusted in renal dysfunction to avoid hypoglycemia

Blood Pressure Control 

•130/80 mm Hg is reasonable goal, but may require 3 to 4 drugs

•Substantial data showing benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for DN progression:
■Recent comparison of ACE inhibitors and ARBs suggests that these agents have equivalent long-term benefits in early DN (GFR ≥70 mL/min [≥1.17 mL/s])

■In ACE inhibitor– and ARB-treated patients, serum potassium and creatinine should be closely monitored for 2 to 3 months; if documented stable renal function, annual monitoring of electrolytes is appropriate

■If patients start on nonsteroidal anti-inflammatory drugs, develop a state of hypoperfusion, or demonstrate progressive GFR decline from DN, more frequent monitoring of electrolytes and creatinine is appropriate

■Serum creatinine increase of 30% above baseline (after institution of blood pressure control) that subsequently stabilizes in a period of 2 to 3 months predicts improved long-term outcome

■UKPDS—β-blocker as effective as ACE inhibitor


Lipids 

•Treatment with statins to achieve low-density lipoprotein cholesterol <100 mg/dL (<2.59 mmol/L), or <70 mg/dL (<1.81 mmol/L) for patients with cardiovascular disease history

Dietary Protein Restriction 

•Controversial

•Difficult to achieve without comprehensive dietary team

Weight Loss 

•Improves insulin sensitivity, potentially slows DN progression

Smoking Cessation

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Additional Reading 

1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977-986, 1993

2. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int 47:1703-1720, 1995

3. Writing Team for the Diabetes and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 287:2563-2569, 2002

4. Writing Team for the Diabetes and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290:2159-2167, 2003

5. Nesto RW: Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association: Response to Elasy and Griffin. Diabetes Care 27:2096, 2004 (letter)

6. Bakris G, Viberti G, Weston WM, Heise M, Porter LE, Freed MI: Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens 17:7-12, 2003

7. Bailey CJ, Turner RC: Metformin. N Engl J Med 334:574-579, 1996

8. Bakris GL, Weir MR, Shanifar S, et al: Effects of blood pressure level on progression of diabetic nephropathy: Results from the RENAAL study. Arch Intern Med 163:1555-1565, 2003

9. Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351:1755-1762, 1998

10. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338:645-652, 1998

11. Bakris GL: A practical approach to achieving recommended blood pressure goals in diabetic patients. Arch Intern Med 161:2661-2667, 2001

12. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456-1462, 1993

13. Viberti G, Wheeldon NM: Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: A blood pressure-independent effect. Circulation 106:672-678, 2002

14. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861-869, 2001

15. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851-860, 2001

16. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870-878, 2001

17. Barnett AH, Bain SC, Bouter P, et al: Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 351:1952-1961, 2004

18. Bakris GL, Siomos M, Richardson D, et al: ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure. VAL-K Study Group. Kidney Int 58:2084-2092, 2000

19. Bakris GL, Weir MR: Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: Is this a cause for concern? Arch Intern Med 160:685-693, 2000

20. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 317:713-720, 1998

21. Grundy SM, Cleeman JI, Merz CN, et al: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110:227-239, 2004

22. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis. Ann Intern Med 124:627-632, 1996

23. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH: Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int 62:220-228, 2002

24. Chen J, Muntner P, Hamm LL, et al: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 140:167-174, 2004

25. Gross ML, Amann K: Progression of renal disease: New insights into risk factors and pathomechanisms. Curr Opin Nephrol Hypertens 13:307-312, 2004

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Renal Replacement Therapy in DN 

•Diabetic patients are fastest growing proportion of ESRD population

•Mortality rate for diabetic ESRD patients remains very high, mainly related to cardiovascular disease

•Hemodialysis versus peritoneal dialysis:
■Relative mortality data remain controversial

■No clear benefit of 1 modality versus another


•Hemodialysis:
■Long-term economic and morbidity benefits of native vein arteriovenous fistula > graft > catheter

■Diabetic patients have significantly worse vascular access–related outcomes:
○Significantly greater primary arteriovenous fistula rates have been achieved in diabetic patients with coordinated approach

○Requires appropriate referral, preaccess planning (vein preservation, venous mapping), and collaboration with skilled surgeon

○Centers for Medicare and Medicaid Services has launched “Fistula First” campaign to achieve Kidney Disease Outcomes Quality Initiative recommendation of arteriovenous fistulas in 50% of incident dialysis patients


■Achievement of national guidelines for access outcomes often requires a multidisciplinary team approach


•Transplantation
■Patients with DN progression should receive education regarding benefits of transplantation and timely referral for evaluation

■Survival rates and quality of life for transplantation recipients superior to that for other forms of renal replacement therapy

■Kidneys from living-unrelated donors have similar functional outcomes to deceased donor organs:
○Increased potential pool of donors may assist with current long waiting times


■Economic benefits to kidney transplantation

■Pancreas transplant for type 1 diabetes

■Potential for resolution of diabetic nephropathy, retinopathy, and improvement in cardiovascular outcomes

■Potential for recurrent DN with poor glycemic control


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Additional Reading 

1. Locatelli F, Pozzoni P, Del Vecchio L: Renal replacement therapy in patients with diabetes and end-stage renal disease. J Am Soc Nephrol 15:S25-S29, 2004 (suppl 1)

2. Vonesh EF, Snyder JJ, Foley RN, Collins AJ: The differential impact of risk factors on mortality in hemodialysis and peritoneal dialysis. Kidney Int 66:2389-2401, 2004

3. National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Vascular Access: Update 2000. Am J Kidney Dis 37:S137-S181, 2001 (suppl 1)

4. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725-1730, 1999

5. D’Cunha PT, Besarab A: Vascular access for hemodialysis: 2004 and beyond. Curr Opin Nephrol Hypertens 13:623-629, 2004

6. Lee T, Barker J, Allon M: Associations with predialysis vascular access management. Am J Kidney Dis 43:1008-1013, 2004

7. Malovrh M: Approach to patients with end-stage renal disease who need an arteriovenous fistula. Nephrol Dial Transplant 18:v50-v52, 2003 (suppl 5)

8. Allon M, Bailey R, Ballard R, et al: A multidisciplinary approach to hemodialysis access: Prospective evaluation. Kidney Int 53:473-479, 1998

9. Silva MB Jr, Hobson RW, Pappas PJ, et al.: A strategy for increasing use of autogenous hemodialysis access procedures: Impact of preoperative noninvasive evaluation. J Vasc Surg 27:302-307, 1998

10. Park YH, Min SK, Lee JN, et al: Comparison of survival probabilities for living-unrelated versus cadaveric renal transplant recipients. Transplant Proc 36:2020-2022, 2004

11. Shames BD, D’Alessandro AM, Pirsch JD, et al: Living-unrelated renal transplantation at the University of Wisconsin. Clin Transpl 149-156, 2001

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 Originally published online as doi:10.1053/j.ajkd.2005.05.032 on August 22, 2005.

PII: S0272-6386(05)00897-8

doi:10.1053/j.ajkd.2005.05.032

American Journal of Kidney Diseases
Volume 46, Issue 4 , Pages 766-773, October 2005

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