Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S30-S37, July 2008

Slowing the progression of kidney disease in patients with diabetes

Based on material presented at a Boehringer Ingelheim-Sponsored Meeting held in Madrid, Spain, May 4–5, 2007.

  • Ellen Burgess, MD

      Affiliations

    • Corresponding Author InformationCorresponding author: Ellen Burgess, MD, University of Calgary, 1403-29 Street NW, Calgary, Alberta, T2N 2T9 Canada. Tel: 001 403 944 1598; fax: 001 403 283 2494.

Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

Article Outline

Abstract 

Diabetic nephropathy is a leading cause of renal failure requiring replacement therapy. Diabetic nephropathy is typically characterized by persistent microalbuminuria progressing to nephrotic syndrome, a progressive decline in glomerular filtration rate, and hypertension. Diabetic nephropathy prevention strategies may involve early angiotensin-converting enzyme (ACE) inhibitor treatment and the control of diabetes to reduce glomerular hypertension and hyperfiltration. Treatment strategies include the use of ACE inhibitors or angiotensin receptor blockers (ARBs), and cholesterol-lowering agents. Early intervention is key to the prevention of more severe renal outcomes. Although intensive and early control of blood pressure (BP) is key to renoprotection, the class of antihypertensive has an important bearing on outcome. There is evidence for the efficacy of ARBs in preventing the progression from microalbuminuria to overt nephropathy (urine protein excretion >500 mg/day) from the IRbesartan in patients with diabetes and MicroAlbuminuria (IRMA 2) Study using irbesartan and the INcideNt to OVert: Angiotensin II receptor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy (INNOVATION) Study using telmisartan. For the management of overt nephropathy, the findings of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) demonstrate that losartan and irbesartan, respectively, reduce the time to doubling of serum creatinine levels and development of end-stage renal disease.

Keywords: Angiotensin receptor blockers, microalbuminuria, proteinuria, type 2 diabetic nephropathy

 

Back to Article Outline

Introduction 

Diabetes, or more specifically type 2 diabetes, is the leading cause of end-stage renal disease (ESRD) in Western countries.1, 2 Persistent microalbuminuria is the early sign of diabetic renal disease, and progression to macroalbuminuria predicts progression to ESRD.3, 4, 5 Once a patient with type 2 diabetes develops >3 g/day of proteinuria, the decline in renal function appears inevitable; a number of studies have shown that the glomerular filtration rate (GFR) declines at a rate of about 5.3 to 5.7 ml/min/y.6, 7 A retrospective cohort study conducted in Minnesota found that 10 years after the diagnosis of persistent proteinuria, the cumulative risk of chronic renal failure was 11% in patients with type 2 diabetes.8 In a longitudinal study among 364 Pima Indians, the cumulative incidence of ESRD was 40% at 10 years and 61% at 15 years after the onset of proteinuria.9 The incidence of ESRD was significantly related to the duration of diabetes and proteinuria, extent of hyperglycemia, diabetes treatment, and retinopathy at the time of proteinuria recognition, but not to blood pressure (BP).

Once proteinuria occurs, the progression of nephropathy is similar in patients with either type 1 or type 2 diabetes10, 11; however, much of our understanding of the progression of renal impairment comes from the study of type 1 diabetes. Figure 1 shows the typical progression of diabetic nephropathy. There are five stages; microalbuminuria (albumin excretion rate: 30 to 300 mg/24 hours) occurs in Stage II and proteinuria (albumin excretion rate: >300 mg/24 hours) is evident during Stage III. Nephrotic syndrome and ESRD/chronic renal failure occur in the last stages.12 Hypertension, which frequently co-exists with type 2 diabetes, is a risk factor for the development of microalbuminuria and renal disease.12, 13 It is thought that early interruption of this 5-stage progression can affect the outcome. Early detection by screening for microalbuminuria using laboratory tests such as radioimmunoassay is, therefore, extremely important.14

  • View full-size image.
  • Figure 1. 

    The typical course of diabetic nephropathy. Reproduced with permission from Pylypchuk G, Beaubien E. Diabetic nephropathy. Prevention and early referral. Can Fam Physician 2000;46:636–42.12

During the early stage of nephropathy (microalbuminuria), an increase in glomerular pressure occurs (from around 35 mm Hg [normal value] to about 45 mm Hg) (glomerular hypertension), which leads to hyperfiltration. This change is partly caused by an increase in systemic blood pressure (SBP), and partly due to dilation of the afferent glomerular arteriole and constriction of the efferent glomerular arteriole. The constriction of the efferent arteriole is very important in increasing glomerular pressure and is due to an effect of angiotensin II.15 The distribution of anionic charge density on the glomerular basement membrane (GBM) is progressively modified, and the size of GBM pores gradually increase; this results in an increase in the permeability of the GBM and allows the negatively charged albumin, and later the larger positively charged macromolecules, to cross the GBM.16, 17 Prevention strategies usually involve effective control of hyperglycemia, and hypertension, which can help to address glomerular hypertension and hyperfiltration. Treatment strategies include the use of angiotensin receptor blockers (ARBs) to reduce the risk of ESRD and the need for renal replacement therapy such as dialysis.18

Back to Article Outline

The Role of Antihypertensives on Glomerular Filtration 

The importance of glomerular capillary pressure and the role of angiotensin II in the evolution of renal impairment suggest that agents acting on the renin-angiotensin system (RAS) should have an important renoprotective role, and may provide cardioprotection in patients with type 2 diabetes and microalbuminuria.1 Animal models have confirmed that angiotensin-converting enzyme (ACE) inhibitors and ARBs can vasodilate the efferent arteriole and reduce the intraglomerular pressure.15 Clinical studies confirm the renal benefit of these drugs.19 When an ACE inhibitor or ARB is started, there is a slight reduction in the GFR. It was initially hoped that this would be enough to stop the deterioration of renal function in patients with proteinuria; however, the deterioration in renal function was slowed but continued, presumably due to nonhemodynamic effects.19

Back to Article Outline

Association Between Albuminuria and Cardiovascular Disease 

As well as being a predictor of chronic renal disease, microalbuminuria is also a prognostic marker of cardiovascular morbidity and mortality. A multivariate analysis of mortality from coronary heart disease in patients with type 2 diabetes showed that microalbuminuria was the leading predictor, with an odds ratio (OR) of 10.02; this was followed by smoking (OR, 6.52), diastolic hypertension (OR, 3.20), and serum cholesterol (OR, 2.32).20 In patients with type 2 diabetes, there is a clear relationship between the degree of proteinuria and the incidence of coronary heart disease and stroke that is independent of other cardiovascular risks. In a 7-year follow-up study conducted in Finland in patients with type 2 diabetes (n = 1,056), the incidence of stroke was 7.2% in those without proteinuria (<150 mg/L), 11.1% in those with borderline proteinuria (150 to 300 mg/L), and 23.0% in those with clinical proteinuria (>300 mg/L) (Figure 2).21 By comparison, the corresponding rates in nondiabetic subjects (n = 1,375) were 1.6%, 3.2%, and 8.5%, respectively. Similarly, the incidence of coronary heart disease was considerably greater in patients with type 2 diabetes, and this increased with the degree of proteinuria, such that with urinary protein >300 mg/L there was a 34.8% incidence of coronary heart disease in this cohort. The chances of a patient surviving a cardiovascular event were also significantly reduced in those patients with borderline or clinical proteinuria (Figure 2).21

  • View full-size image.
  • Figure 2. 

    The effect of the degree of proteinuria on the risk of cardiovascular mortality (Left) and stroke or CHD events (Right) in patients with type 2 diabetes. CHD, coronary heart disease; U-Prot, urinary protein concentration. Reproduced with permission from Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke 1996;27:2033–39.21

Clearly, many patients with diabetes die from cardiovascular disease before ESRD occurs, but this fact should not detract from the importance of effectively managing chronic renal disease and stabilizing renal function. In many countries, diabetic nephropathy is the most frequent cause of ESRD requiring hemodialysis. In Canada, for example, the average annual incidence rate of dialysis has been shown to be 130 per 100,000 in patients with diabetes compared with 11 per 100,000 in nondiabetic patients.22 Rates of ESRD are high in the U.S., although they have stabilized in recent years; the U.S. Renal Data System showed that 340 and 338 out of every million U.S. citizens experienced renal failure in 2002 and 2003, respectively.23, 24 The primary cause of ESRD is diabetes, and in 2000 it accounted for 45.2% of all new cases.23, 24 Using observed and modeled data from 5,097 subjects in the United Kingdom Prospective Diabetes Study (UKPDS 64), annual transition rates from total absence of nephropathy to microalbuminuria, persistently elevated serum creatinine, or renal replacement therapy and death were determined (Figure 3).25 Ten years after the diagnosis of diabetes, the prevalence of microalbuminuria, macroalbuminuria, and elevated plasma creatinine or renal replacement therapy was 24.9%, 5.3%, and 0.8%, respectively. Furthermore, patients with elevated serum creatinine levels or those undergoing renal replacement therapy had an annual death rate of 19.2% (95% confidence interval [CI], 14.0% to 24.4%).

  • View full-size image.
  • Figure 3. 

    Annual transition rates in diabetic nephropathy: results of the United Kingdom Prospective Diabetes Study (UKPDS 64). Reproduced with permission from Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holmes RR, UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225–32.25

Back to Article Outline

Pharmacological Stabilization of Renal Function 

Control of Microalbuminuria 

ARBs have been shown to be renoprotective in diabetic patients with microalbuminuria. In 2001, the IRbesartan in patients with diabetes and MicroAlbuminuria (IRMA 2) Study established the benefit of ARB treatment of early renal disease.26 A total of 590 patients with hypertension (SBP >135 mm Hg and/or diastolic blood pressure [DBP] >85 mm Hg), type 2 diabetes, microalbuminuria (20 to 200 μg/min), and normal renal function (serum creatinine concentration ≤1.5 mg/dL for men and ≤1.1 mg/dL for women) were randomized to double-blind treatment with irbesartan 150 or 300 mg, or placebo, and were followed for 2 years. The primary endpoint was the time to the occurrence of overt proteinuria (urinary albumin excretion rate >200 μg/min and ≥30% compared with baseline). Using irbesartan 300 mg, there was a statistically significant reduction in the incidence of overt proteinuria compared with placebo (hazard ratio, 0.30; 95% CI, 0.14 to 0.61; P < .001). Some normalization of the urinary albumin excretion rate is achievable with intensive control of blood glucose levels.27 This was clearly the case in the IRMA 2 Study, where there was regression of microalbuminuria to the urinary normal albumin excretion rate <20 μg/min following treatment with irbesartan 300 mg daily only (34% vs. 21% in the control group; P = .006).26

In a subgroup analysis, the effect of withdrawing irbesartan treatment on the albuminuria was examined.28 If BP control was the mechanism of action, then the urinary albumin excretion rate would revert to baseline after stopping treatment; however, if the effect on urinary albumin excretion persisted, long-term renoprotection was due to possible changes in glomerular structure or biochemical normalization. This was the situation with the higher irbesartan dose, where there was a persistent reduction in the urinary albumin excretion rate of 47% (Figure 4).28 Thus, it also appears that the dose of this ARB is important in the maintenance of renoprotection.

  • View full-size image.
  • Figure 4. 

    Effect of irbesartan 150 or 300 mg or placebo on changes in UAE rate during and after discontinuation of treatment in patient with type 2 diabetes and microalbumurinia. UAE, urinary albumin excretion. © 2003 American Diabetes Association. Reprinted with permission from Andersen S, Brochner-Mortensen J, Parving H-H, Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 2003;26:3296–302.28

Similar evidence of renoprotection in early disease using telmisartan has been demonstrated in the INcideNt to OVert: Angiotensin II receptor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy (INNOVATION) Study.29 This study was conducted in 527 Japanese patients with type 2 diabetes and microalbuminuria (urinary albumin:creatinine 100 to 300 mg/g) and normal renal function (serum creatinine concentration ≤1.5 mg/dL for men and ≤1.1 mg/dL for women), but not necessarily hypertensive. The patients received telmisartan 40 mg or 80 mg or placebo and were followed up for a mean of 1.3 years. Telmisartan reduced the transition to overt nephropathy in a dose-dependent manner: transition rates after 1 year with telmisartan 80 mg (n = 168), telmisartan 40 mg (n = 172), and placebo (n = 174) were 16.7%, 22.6%, and 49.9%, respectively (each telmisartan dose vs. placebo P < .0001) (Figure 5).29 Transition rates were also determined in the subgroup of patients who were not hypertensive at baseline. In these normotensive patients, the transition rates for telmisartan 80 mg (n = 51), telmisartan 40 mg (n = 58), and placebo (n = 540) were 11%, 21%, and 44.2 %, respectively (each telmisartan dose vs. placebo P < .01).

  • View full-size image.
  • Figure 5. 

    Effect of telmisartan 40 or 80 mg or placebo on the transition from microalbuminuria to overt nephropathy in Japanese patient with type 2 diabetes and with or without hypertension. NNT, number needed to treat to prevent one transition; RRR, relative risk reduction. © 2007 American Diabetes Association. Reprinted with permission from Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care 2007;30:1577–8.29

Control of Overt Proteinuria 

The renoprotective benefit of an ARB in more advanced chronic kidney disease was evaluated in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study.30 The patients in this study had a minimum urinary albumin:creatinine of ≥300 mg/g or a urinary protein excretion rate ≥0.5 g/day at baseline. The aim was to determine whether or not the addition of losartan to conventional therapy would increase the time to the composite endpoint of ESRD, a doubling of serum creatinine level, or death. The RENAAL Study showed that the addition of losartan resulted in significant reduction in these endpoints (individually or as a composite) (Table).30 The additional renoprotective effect of losartan could not be attributed to additional control of BP as comparable reductions were observed in the patients receiving either antihypertensive.

Table. Effect of the addition of losartan to conventional therapy on the composite endpoint and components of the composite
EndpointLosartan (%)Placebo (%)P valueRisk Reduction (%)95% CI
Composite43.547.1.02162, 28
Doubling of serum creatinine21.626.0.006258, 39
ESRD19.625.5.0022811, 42
Death21.020.3.88−2−27, 19
ESRD or death34.039.4.01205, 32

CI, confidence interval; ESRD, end-stage renal disease.

Reproduced with permission from Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–69.30

Additional analysis of the data from the RENAAL Study showed that, after adjusting for age, gender, race, weight, smoking, baseline BP, total cholesterol, serum creatinine, albuminuria, hemoglobin, and glycosylated hemoglobin, there was a 5.2-fold (95% CI, 4.3 to 6.3) increased risk for reaching the composite endpoint in patients with high baseline albuminuria (≥3.0 g/g creatinine) compared with the patients with low albuminuria (<1.5 g/g creatinine).31 There was also an 8.1-fold (95% CI, 6.1 to 10.8) increased risk of progressing to ESRD. Hence, early treatment with losartan 100 mg daily was associated with better outcomes.

Furthermore, a 50% reduction in albuminuria in the first 6 months of treatment was associated with a 36% reduction in risk for developing the composite endpoint and 45% reduction for ESRD. In addition, the risk of hospitalization for heart failure as well as a composite endpoint of other cardiovascular endpoints was reduced in association with the reduction in albuminuria, such that a 50% reduction in albuminuria was associated with a 50% reduction in the risk of heart failure, and an 18% reduction in other cardiovascular endpoints. Hence, the reduction in albuminuria has become an important surrogate goal of therapy for nephrologists.

A trial to compare telMisartan 80 mg vs. losArtan 100 mg, in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO) has recently been completed; this was a 1-year, prospective, randomized, double-blind, double-dummy, forced-titration, multicenter, parallel-group trial. The patients were hypertensive at baseline (SBP >130 mm Hg, DBP >80 mm Hg, or in receiving of antihypertensive medications), had proteinuria (urinary protein:creatinine ≥700 mg/g), and impaired renal function (serum creatinine ≤3.2 mg/dL in men and ≤3.0 mg/dL in women).32 The aim of this study was to determine whether telmisartan 80 mg (n = 419) was effective against progression of renal disease in hypertensive diabetic patients compared with losartan 100 mg (n = 441) treatment. After 1 year of treatment, proteinuria reduction (the primary endpoint) was significantly greater with telmisartan than losartan (−29% vs. −20%, respectively; P < .05).33

In the Irbesartan in Diabetic Nephropathy Trial (IDNT), the efficacy of the ARB was compared with that of the calcium-channel blocker amlodipine over a mean follow-up period of 2.6 years in a total of 1,715 patients with proteinuria ≥900 mg/day.34 As with the RENAAL Study, the primary endpoint was the time to the composite endpoint of a doubling of serum creatinine level, ESRD (serum creatinine level of 600 μmol/L), or death. Treatment with irbesartan was associated with a 20% relative risk (RR) reduction of the primary composite endpoint (P = .02), and a 23% RR reduction compared with amlodipine (P = .006). There was no statistically significant difference in the risk reduction in patients receiving placebo or amlodipine.

Back to Article Outline

Impact of Renoprotective Studies on Treatment Guidelines 

Current guidelines recognize the importance of intensive BP control in patients with type 2 diabetes. For example, the American Diabetes Association35 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure36 recommend a BP of <130/80 mm Hg. The RENAAL, IDNT, and IRMA 2 trials have consistently shown the renoprotective benefit of ARBs. In light of these findings, the American Diabetes Association recommend that ARBs be used in patients with type 2 diabetes, albuminuria, and chronic kidney disease (serum creatinine <1.5 mg/dL).37 Maximal renoprotection may be achieved by the use of several antihypertensive agents in order to reach rigorous BP targets.

Back to Article Outline

Cardiovascular Benefit of Renoprotection With ARBs 

Meta-analysis of the data from the RENAAL, IDNT, and IRMA 2 studies suggests that renoprotection confers cardiovascular protection. Among the 1,532 patients receiving placebo and 1,719 patients receiving ARBs, the total number of cardiovascular events was 430 (28.1%) and 408 (23.7%), respectively. The OR was 0.85, and the cardioprotection was statistically significantly in favor of ARB (P = .034). The association between reno- and cardiovascular protection may be linked to baseline levels of proteinuria. High urinary albumin:creatinine ratios (RR, 1.29 per natural log unit; 95% CI, 1.13 to 1.48; P = .0002) at baseline were highly predictive for cardiovascular events. For example, data from IDNT showed that a high urinary albumin:creatinine at baseline was highly predictive of cardiovascular events,38 and data from the RENAAL Study showed that baseline serum creatinine level strongly predicted a composite of myocardial infarction, stroke, or cardiovascular death.39

Back to Article Outline

Conclusion 

Angiotensin II clearly plays an important role in the progression of chronic kidney disease in patients with diabetes. Control of BP is an important component of renoprotection, and stringent control is essential. However, in addition to their hemodynamic advantages, some antihypertensive agents may provide nonhemodynamic benefits. Antihypertensive intervention at the level of the RAS affords renoprotective effects over and above their BP-lowering ability. In the case of patients with type 2 diabetes, clinical trials have shown that ARBs can reduce proteinuria, curtail the progression of chronic kidney disease, and reduce the incidence of ESRD. Cardiovascular disease is an added complication of diabetes, especially in the presence of diabetic nephropathy. Although studies in patients with type 2 diabetes and nephropathy did not evaluate cardiovascular outcomes as a primary endpoint, treatment using a meta-analysis showed that ARBs reduced the risk of cardiovascular events.

Back to Article Outline

References 

  1. Jerums G, MacIsaac RJ. Treatment of microalbuminuria in patients with type 2 diabetes mellitus. Treat Endocrinol. 2002;1:163–173
  2. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116:85–97
  3. Bakris GL, Whelton P, Weir M, Mimran A, Keane W, Schiffrin E. The future of clinical trials in chronic renal disease: outcome of an NIH/FDA/Physician Specialist Conference (Evaluation of clinical trial endpoints in chronic renal disease study group). J Clin Pharmacol. 2000;40:815–825
  4. Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G. Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies (“Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN)). Kidney Int. 1998;53:1209–1216
  5. Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis. 1999;33:1004–1010
  6. Gall MA, Nielsen FS, Smidt UM, Parving HH. The course of kidney function in type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy. Diabetologia. 1993;36:1071–1078
  7. Hasslacher C, Bostedt-Kiesel A, Kempe HP, Wahl P. Effect of metabolic factors and blood pressure on kidney function in proteinuric type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:1051–1056
  8. Humphrey LL, Ballard DJ, Frohnert PP, Chu CP, O'Fallon WM, Palumbo PJ. Chronic renal failure in non-insulin-dependent diabetes mellitus (A population-based study in Rochester, Minnesota). Ann Intern Med. 1989;111:788–796
  9. Nelson RG, Knowler WC, McCance DR, Sievers ML, Pettitt DJ, Charles MA, et al. Determinants of end-stage renal disease in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus and proteinuria. Diabetologia. 1993;36:1087–1093
  10. Ordonez JD, Hiatt RA. Comparison of type II and type I diabetics treated for end-stage renal disease in a large prepaid health plan population. Nephron. 1989;51:524–529
  11. Biesenbach G, Janko O, Zazgornik J. Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephron Dial Transplant. 1994;9:1097–1102
  12. Pylypchuk G, Beaubien E. Diabetic nephropathy (Prevention and early referral). Can Fam Physician. 2000;46:636–642
  13. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension. 1992;19:403–418
  14. Maher JF. Diabetic nephropathy: early detection, prevention and management. Am Fam Physician. 1992;45:1661–1668
  15. Anderson S, Brenner BM. The role of intraglomerular pressure in the initiation and progression of renal disease. J Hypertens. 1986;4:S236–S238
  16. Selby JV, FitzSimmons SC, Newman JM, Katz PP, Sepe S, Showstack J. The natural history and epidemiology of diabetic nephropathy (Implications for prevention and control). JAMA. 1990;263:1954–1960
  17. Goode NP, Shires M, Crellin DM, Aparicio SR, Davison AM. Alterations of glomerular basement membrane charge and structure in diabetic nephropathy. Diabetologia. 1995;38:1455–1465
  18. Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau D, Ludwig S, et al. 1998 clinical practice guidelines for the management of diabetes in Canada (Canadian Diabetes Association). CMAJ. 1998;159:S1–S29
  19. Navis G, Faber HJ, de Zeeuw D, de Jong PE. ACE inhibitors and the kidney (A risk-benefit assessment). Drug Saf. 1996;15:200–211
  20. Eastman RC, Keen H. The impact of cardiovascular disease on people with diabetes: the potential for prevention. Lancet. 1997;350:S29–S32
  21. Miettinen H, Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Proteinuria predicts stroke and other atherosclerotic vascular disease events in nondiabetic and non-insulin-dependent diabetic subjects. Stroke. 1996;27:2033–2039
  22. Lok CE, Oliver MJ, Rothwell DM, Hux JE. The growing volume of diabetes-related dialysis: a population based study. Nephrol Dial Transplant. 2004;19:3098–3103
  23. National Institute of Diabetes and Digestive and Kidney Disease. End-stage renal disease rate stabilizing, USRDS finds. http://kidney.niddk.nih.gov/about/Research_Updates/KidneyDiseaseSum06/1.htmAccessed: May 29, 2007
  24. US Renal Data System: 2002 Annual Data Report. Bethesda, Maryland: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2002;
  25. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holmes RR UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225–232
  26. Parving H-H, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Amer P Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–878
  27. Fioretto P, Bruseghin M, Berto I, Gallina P, Manzato E, Mussap M. Renal protection in diabetes: role of glycemic control. J Am Soc Nephrol. 2006;17:S86–S89
  28. Andersen S, Brochner-Mortensen J, Parving H-H Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care. 2003;26:3296–3302
  29. Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care. 2007;30:1577–1578
  30. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869
  31. De Zeeuw D, Remuzzi G, Parving H-H, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309–2320
  32. Weber M. The telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. J Hypertens. 2003;21:S37–S46
  33. Bakris G, Burgess E, Davidai G, Koval S, Weir M; the AMADEO Investigators. Influence of Glycemic Control on Proteinuria in Patients with Type 2 Diabetes and Overt Nephropathy and Hypertension: Results of the AMADEO Trial (poster 0601-P). Presented at the 67th Scientific Sessions of the American Diabetes Association, June 22–26, 2007.
  34. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860
  35. American Diabetes Association. Nephropathy in diabetes (Position statement). Diabetes Care. 2004;27:S79–S83
  36. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252
  37. American Diabetes Association. Diabetic nephropathy. Diabetes Care. 2003;26:S94–S98
  38. Anavekar NS, Gans DJ, Berl T, Rohde RD, Cooper W, Bhaumik A, et al. Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria. Kidney Int Suppl. 2004;66:S50–S55
  39. Eijkelkamp WB, Zhang Z, Brenner BM, Cooper ME, Devereux RB, Dahlof B, et al. Renal function and risk for cardiovascular events in type 2 diabetic patients with hypertension: the RENAAL and LIFE studies. J Hypertens. 2007;25:871–876

 Conflict of interest: none.

PII: S1933-1711(08)00042-9

doi:10.1016/j.jash.2008.03.007

Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S30-S37, July 2008

Article Tools

* Image Usage & Resolution