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Hypertension in Diabetic Nephropathy: Epidemiology, Mechanisms, and Management

  • Peter N. Van Buren
    Affiliations
    Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
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  • Robert Toto
    Correspondence
    Address correspondence to Robert Toto, MD, Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8523.
    Affiliations
    Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
    Search for articles by this author
      Hypertension is highly prevalent in patients with diabetic nephropathy. Diabetic nephropathy is the leading cause of CKD and end-stage kidney disease in the United States. The etiology of hypertension in diabetic nephropathy involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction. The management of hypertension in these patients is focused on treatments that target these mediators. Clinical trials have established that drugs that inhibit the renin-angiotensin-aldosterone system should be used as first-line agents on the basis of their ability to slow down progression of kidney disease and lower albuminuria. There is further interest into how the combination of drugs that inhibit this pathway at multiple steps will contribute further to the management of hypertension and diabetic nephropathy. This article presents an updated review of the mechanisms involved in hypertension in patients with diabetic nephropathy. It also reviews the past clinical trials using single agents as therapeutics and the more recent trials involving novel drugs or drug combinations used to treat these patients. Retrospective analyses of multiple studies are included to better examine the significance of the currently proposed blood pressure targets for patients with diabetic nephropathy.

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      References

        • Horl M.
        • Horl W.
        Hemodialysis associated hypertension: pathophysiology and therapy.
        Am J Kidney Dis. 2002; 39: 227-244
      1. Excerpts from the United States renal data system-2009 Annual Data Report: atlas of chronic kidney disease and end stage renal disease in the United States. Incidence and prevalence.
        Am J Kidney Dis. 2010; 55: S231-S240
      2. Excerpts from the United States Renal Data System-2009 Annual Data Report: atlas of chronic kidney disease and end stage renal disease in the United States. Chronic kidney disease in the NHANES population.
        Am J Kidney Dis. 2010; 55: S35-S48
        • Schwartz
        • Melvin M.
        • Leonard-Martin T.
        • et al.
        Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy.
        Nephrol Dial Transplant. 1998; 13: 2547-2552
        • National Kidney Foundation
        KDOQI™ Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease.
        Am J Kidney Dis. 2007; 49: S1-S180
        • Parving H.H.
        • Gall M.A.
        • Skøtt P.
        • et al.
        Prevalence and causes of albuminuria in non insulin-dependent diabetic patients.
        Kidney Int. 1992; 4: 758-762
        • Epstein M.
        • Sowers J.
        Diabetes mellitus and hypertension.
        Hypertension. 1992; 19: 403-418
        • Norgaard K.
        • Feldt-Rasmussen B.
        • Johnsen K.
        • et al.
        Prevalence of hypertension in type 1 (insulin dependent) diabetes mellitus.
        Diabetologia. 1990; 33: 407-410
        • Parving H.
        • Hommel E.
        • Mathiesen E.
        • et al.
        Prevalence of microalbuminuria, arterial hypertension, retinopathy, and neuropathy in patients with insulin dependent diabetes.
        Br Med J. 1988; 296: 156-160
        • Lurbe E.
        • Redon J.
        • Kesani A.
        Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes.
        N Engl J Med. 2002; 347: 797-805
        • Fagerudd J.A.
        • Tarnow L.
        • Jacobsen P.
        • et al.
        Predisposition to essential hypertension and development of diabetic nephropathy in IDDM patients.
        Diabetes. 1998; 47: 439-444
        • Ismail N.
        • Becker B.
        • Strzelczyk P.
        • et al.
        Renal disease and hypertension in non-insulin dependent diabetes mellitus.
        Kidney Int. 1999; 55: 1-28
        • Keller C.
        • Bergis K.
        • Filser D.
        • et al.
        Renal findings in patients with short-term type 2 diabetes.
        J Am Soc Nephrol. 1996; 7: 2627-2635
        • Bakris G.
        • Williams M.
        • Dworkin L.
        • et al.
        Preserving renal function in adults with hypertension and diabetes: a consensus approach.
        Am J Kidney Dis. 2000; 36: 646-661
        • Freedman B.
        • Bostrom M.
        • Daeihagh P.
        • Boweden D.
        Genetic factors in diabetic nephropathy.
        Clin J Am Soc Nephrol. 2007; 2: 1306-1316
        • Iynegar S.
        • Freedman B.
        • Sedor J.
        Mining the genome for susceptibility to diabetic nephropathy: the role of large-scale studies and consortia.
        Semin Nephrol. 2007; 27: 208-222
        • Rajagopalan S.
        • Kurz S.
        • Munzel T.
        • et al.
        Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation.
        J Clin Invest. 1996; 97: 1916-1923
        • Price D.
        • Porter L.
        • Gordon M.
        • et al.
        The paradox of the low renin state in diabetic nephropathy.
        J Am Soc Nephrol. 1999; 10: 2382
        • Price D.
        • De’Oliveira J.
        • Fisher N.
        • et al.
        The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type 2 diabetes mellitus.
        Am J Hypertens. 1999; 12: 348
        • Anderson F.
        • Jung F.
        • Ingelfinger J.R.
        Renal rennin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations.
        Am J Renal Phys. 1993; 265: F477-F486
        • Mizuiri S.
        • Yoshikawa H.
        • Tanegashima M.
        • et al.
        Renal ACE immunohistochemical localization in NIDDM patients with nephropathy.
        Am J Kidney Dis. 1998; 31: 301-307
        • Konoshita T.
        • Wakahara S.
        • Mizuno
        • et al.
        Tissue gene expression of rennin-angiotensin system in human type 2 diabetic nephropathy.
        Diabetes Care. 2006; 29: 848-852
        • Danilcyzk U.
        • Penninger J.
        Angiotensin-converting enzyme II in the heart and kidney.
        Circ Res. 2006; 98: 463-471
        • Tikellis C.
        • Johnston
        • Forbes J.
        • et al.
        Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy.
        Hypertension. 2003; 41: 392-397
        • De Chatel R.
        • Weidmann P.
        • Flammer J.
        • et al.
        Sodium, rennin, aldosterone, catecholamines, and blood pressure in diabetes mellitus.
        Kidney Int. 1977; 12: 412-421
        • Brands M.
        • Labazi H.
        Role of glomerular filtration rate in controlling blood pressure early in diabetes.
        Hypertension. 2008; 52: 188-194
        • Tuck M.
        • Corry D.
        • Trujillo A.
        Salt sensitive blood pressure and exaggerated vascular reactivity in the hypertension of diabetes mellitus.
        Am J Med. 1990; 88: 210-216
        • Imanishi M.
        • Yoshioka K.
        • Okumura M.
        • et al.
        sodium sensitivity related to albuminuria appearing before hypertension in type 2 diabetic patients.
        Diabetes Care. 2001; 24: 111-116
        • DeFronzo R.
        The effect of insulin on renal sodium metabolism.
        Diabetologia. 1981; 21: 165-171
        • Koomans H.
        • Roos J.
        • Dourhout Mees E.
        • et al.
        Soidum balance in renal failure: a comparison of patients with normal subjects under extremes of sodium intake.
        Hypertension. 1985; 7: 714-721
        • Gu J.W.
        • Anand V.
        • Shek E.
        • et al.
        Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells.
        Hypertension. 1998; 31: 1083-1087
        • Spallone V.
        • Gambardella S.
        • Maiello M.
        • et al.
        Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients.
        Diabetes Care. 1994; 17: 578-584
        • Liniger C.
        • Favre L.
        • Assal J.
        Twenty-four hour blood pressure and heart rate profiles of diabetic patients with abnormal cardiovascular reflexes.
        Diabetic Med. 1991; 8: 420-427
        • Nielsen F.
        • Hansen H.
        • Jacobsen P.
        Increased sympathetic activity during sleep and nocturnal hypertension in Type 2 diabetic patients with diabetic nephropathy.
        Diabetic Med. 1999; 16: 555-562
        • Facchini F.
        • Stoohs R.
        • Reaven G.
        Enhanced sympathetic nervous system activity: the linchpin between insulin resistance, hyperinsulinemia, and heart rate.
        Am J Hypertens. 1996; 9: 1013-1017
        • Achan V.
        • Broadhead M.
        • Malaki M.
        • et al.
        Asymetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethyl dimethylaminohydrolase.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1455-1459
        • Abbasi F.
        • Asagmi T.
        • Cooke J.
        • et al.
        Plasma concentrations of asymetric dimethylarginine are increased in patients with type 2 diabetes mellitus.
        Am J Cardiol. 2001; 88: 1201-1203
        • Kielstein J.
        • Boger R.
        • Bode-Boger S.
        Asymetric dimethylarginine concentrations differ in patients with end stage renal disease: relationship to treatment method and atherosclerotic disease.
        J Am Soc Nephrol. 1999; 10: 594-600
        • Zoccali C.
        • Bode-Boger S.
        • Mallamaci F.
        • et al.
        Plasma concentrations of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.
        Lancet. 2001; 358: 2113-2117
        • Tarnow L.
        • Hovind P.
        • Teerlink T.
        • et al.
        Elevated plasma asymetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes.
        Diabetes Care. 2004; 27: 765-769
        • Matsuguma K.
        • Ueda S.
        • Yamagashi S.
        • et al.
        Molecular mechanism for elevation of asymetric dimethylarginine and its role for hypertension in chronic kidney disease.
        J Am Soc Nephrol. 2006; 17: 2176-2183
        • Muniyappa R.
        • Quon M.
        Insulin action and insulin resistance in vascular endothelium.
        Curr Opin Nutr Metab Care. 2007; 10: 523
        • Donatelli M.
        • Colletti I.
        • Bucalo M.
        • et al.
        Plasma endothelin levels in NIDDM patients with macroangiopathy.
        Diabetes Res. 1994; 25: 159-164
        • Koyama H.
        • Tabata T.
        • Nishzawa T.
        • et al.
        Plasma endothelin levels in patients with uremia.
        Lancet. 1989; 1: 991-992
        • Dhaun N.
        • Ferro C.
        • Davenport A.
        • et al.
        Hemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease.
        Nephrol Dial Transplant. 2007; 22: 3228
        • Prabhakar Sharma
        Role of nitric oxide in diabetic nephropathy.
        Semin Nephrol. 2004; 24: 333-334
        • Fitzgerald S.M.
        • Brands M.W.
        Nitric Oxide may be required to prevent hypertension at the onset of diabetes.
        Am J Physiol. 2000; 279: E762-E768
        • Brownlee M.
        Biochemistry and molecular cell biology of diabetic complications.
        Nature. 2001; 414: 813-820
        • Spittle M.
        • Hoenrich N.
        • Handelman G.
        • et al.
        Oxidative stress and inflammation in hemodialysis patients.
        Am J Kidney Dis. 2001; 38: 1408-1413
        • Ceballos-Picot I.
        • Witko-Sarsat V.
        • Merad-Boudia M.
        • et al.
        Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure.
        Free Radic Biol Med. 1996; 21: 845-853
        • Vaziri N.
        • Oveisi F.
        • Ding Y.
        Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension.
        Kidney Int. 1998; 53: 1748
        • Prabhakar S.
        • Starnes J.
        • Shi S.
        • et al.
        Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production.
        J Am Soc Nephrol. 2007; 18: 2945-2952
        • Griendling K.
        • Ollerenshaw J.
        • Minieri C.
        • et al.
        Angiotensin II stimulates NADH and NADPH activity in cultured vascular smooth muscle cells.
        Circ Res. 1994; 74: 1141-1148
        • Ogawa S.
        • Mori T.
        • Nako
        • et al.
        Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy.
        Hypertension. 2006; 47: 699-705
        • Li L.
        • Fink G.
        • Watts S.
        • et al.
        Endothelin 1 increases vascular superoxide via endothelin a-NADPH oxidase pathway in low renin hypertension.
        Circulation. 2003; 107: 1053-1058
        • Palmer B.
        Impaired autoregulation: implications for the genesis of hypertension and hypertension induced renal injury.
        Am J Med Sci. 2001; 321: 388-400
        • Gnudi L.
        • Viberti G.
        • Raij L.
        • et al.
        GLUT-1 overexpression: link between hemodynamic and metabolic factors in glomerular injury.
        Hypertension. 2003; 42: 19-24
        • American Diabetes Association
        Diabetic nephropathy.
        Diabetes Care. 2002; 25: S82-S89
        • Mogensen C.E.
        Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy.
        Br Med J. 1982; 285: 685-688
        • Parving H.H.
        • Andersen A.R.
        • Smidt U.M.
        • et al.
        Effect of antihypertensive treatment on kidney function in diabetic nephropathy.
        Br Med J. 1987; 294: 1443-1447
        • Parving H.H.
        • Smidt U.M.
        • Andersen A.R.
        • et al.
        Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy.
        Lancet. 1983; 321: 1175-1179
        • Lewis E.J.
        • Hunsicker L.G.
        • Bain R.P.
        • et al.
        • The Collaborative Study Group
        The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
        N Engl J Med. 1993; 329: 1456-1462
        • Parving H.H.
        • Hommel E.
        • Jensen B.R.
        • et al.
        Long-term beneficial effect of ACE inhibition on diabetic nephropathy in normotensive type 1 diabetic patients.
        Kidney Int. 2001; 60: 228-234
        • Lewis E.J.
        • Hunsicker L.G.
        • Clarke W.R.
        • 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
        • Brenner B.M.
        • Cooper M.E.
        • 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. 2001; 345: 861-869
        • Parving H.H.
        • Lehnert H.
        • Brochner-Mortensen J.
        • et al.
        The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
        N Engl J Med. 2001; 345: 870-878
        • Ruggenenti P.
        • Fassi A.
        • Ilieva A.
        • et al.
        Preventing microalbuminuria in type 2 diabetes.
        N Engl J Med. 2004; 351: 1941-1951
        • Haller H.
        • Ito S.
        • Janusszewicz A.
        • et al.
        Prevention of microalbuminuria in type 2 diabetes (roadmap trial).
        J Hypertens. 2010; 28: e323
        • Mauer M.
        • Zinman B.
        • Gardiner R.
        • et al.
        Renal and retinal effects of enalapril and losartan in type 1 diabetes.
        N Engl J Med. 2009; 361: 40-51
        • Barnett A.
        • Bain S.
        • Bouter P.
        • et al.
        Angiotensin receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
        N Engl J Med. 2004; 351: 1952-1962
        • Rossing K.
        • Jacobsen P.
        • Pietraszek L.
        • et al.
        Renoprotective effects of adding angiotensin II receptor blocker to a maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double blind crossover trial.
        Diabetes Care. 2003; 26: 2268-2274
        • Jacobsen P.
        • Andersen S.
        • Jensen B.
        • et al.
        Additive effect of ace inhibition and angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy.
        J Am Soc Nephrol. 2003; 14: 992-999
        • Jacobsen P.
        • Andersen S.
        • Rossing K.
        • et al.
        Dual blockade of the rennin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
        Kidney Int. 2003; 63: 1874-1880
        • Andersen N.H.
        • Poulsen P.L.
        • Knudsen S.T.
        • et al.
        Long-term dual blockade with candesartan and lisinopril in hypertensive patients with diabetes: the CALM II study.
        Diabetes Care. 2005; 28: 273-277
        • ON TARGET investigators
        Telmisartan, ramipril, or both in patients at high risk for vascular events.
        N Engl J Med. 2008; 358: 1547-1559
      3. Department of Veterans Affairs; Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy VA NEPHRON-D Study: Nephropathy iN Diabetes Study. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2010 Oct 26]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00555217 NLM Identifier NCT00555217.

        • Mann J.
        • Schmieder R.
        • McQueen
        • et al.
        Renal outcomes with telmisartan, ramipril, or both in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trial.
        Lancet. 2008; 372: 547-553
        • Urata H.
        • Strobel F.
        • Ganten D.
        Widespread distribution of human chymase.
        J Hypertens. 1994; 12: S17-S22
        • Persson F.
        • Rossing P.
        • Schjoedt K.
        • et al.
        Time course of the antiproteinuric and antihypertensive effects of the direct rennin inhibition in type 2 diabetes.
        Kidney Int. 2008; 73: 1419-1425
        • Parving H.H.
        • Persson F.
        • Lewis J.
        • et al.
        Aliskiren combined with losartan in type 2 diabetes and nephropathy.
        N Engl J Med. 2008; 358: 2433-2446
        • Persson F.
        • Rossing P.
        • Reinhard H.
        Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria.
        Diabetes Care. 2009; 32: 1873-1879
      4. Novartis; Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2010 Oct 26]. Available from http://www.clinicaltrials.gov/ct2/show/NCT00549757; NLM identifier 00549757.

        • Sato A.
        • Hayashi K.
        • Naruse M.
        • et al.
        Effectiveness of aldosterone blockade in patients with diabetic nephropathy.
        Hypertension. 2003; 41: 64-68
        • Schjoedt K.J.
        • Andersen S.
        • Rossing P.
        • et al.
        Aldosterone escape during blockade of the rennin angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate.
        Diabetologia. 2004; 47: 1936-1939
        • Bomback A.S.
        • Klemmer P.J.
        The incidence and implications of aldosterone breakthrough.
        Nat Clin Pract Nephrol. 2007; 3: 486-492
        • Schjoedt K.
        • Rossing K.
        • Juhl T.
        • et al.
        Beneficial impact of spironolactone in diabetic nephropathy.
        Kidney Int. 2005; 68: 2829-2836
        • Schjoedt K.
        • Rossing K.
        • Juhl T.
        • et al.
        Beneficial impact of spironolactone on nephritic range albuminuria in diabetic nephropathy.
        Kidney Int. 2006; 70: S36-S42
        • Mehdi U.
        • Adams-Huet B.
        • Raskin P.
        • et al.
        Addition of angiotensin receptor blocker or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy.
        J Am Soc Nephrol. 2009; 20: 2641-2650
        • Khosla N.
        • Kalaitzidis R.
        • Bakris G.
        Predictors of hyperkalemia risk following hypertension control with aldosterone blockade.
        Am J Nephrol. 2009; 30: 418-424
        • Mann J.
        • Green D.
        • Jamerson K.
        • et al.
        Avosentan for overt diabetic nephropathy.
        J Am Soc Nephrol. 2010; 21: 527-535
        • Saydah S.H.
        • Fradkin J.
        • Cowie C.C.
        Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes.
        JAMA. 2004; 291: 335-342
        • Joss F.
        • Ferguson C.
        • Brown C.
        • et al.
        Intensified treatment of patients with type 2 diabetes mellitus and overt nephropathy.
        QJM. 2004; 97: 219-227
        • Berl T.
        • Hunsicker L.
        • Lewis J.
        • et al.
        Impact of achieved blood pressure on cardiovascular outcomes in the irbesartan diabetic nephropathy trial.
        J Am Soc Nephrol. 2005; 16: 2170-2179
        • The ACCORD Study Group
        Effects of intensive blood pressure control in type 2 diabetes mellitus.
        N Engl J Med. 2010; 362: 1575-1585
        • Bakris G.
        • Weir M.
        • Shanifar S.
        • et al.
        Effects of blood pressure level on progression of diabetic nephropathy.
        Arch Int Med. 2003; 163: 1555-1565
        • De Galan B.
        • Perkovic V.
        • Ninomiya T.
        Lowering blood pressure reduces renal events in type 2 diabetes.
        J Am Soc Nephrol. 2009; 20: 883-892
        • Bakris G.
        • Sarafidis P.
        • Weir M.
        • et al.
        Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomized controlled trial.
        Lancet. 2010; 375: 1173-1181
        • Zillich A.
        • Garg J.
        • Basu S.
        • et al.
        Thiazide diuretics, potassium, and the development of diabetes: a quantitative review.
        Hypertension. 2006; 48: 219-224
      5. Van Buren PN, Huet-Adams B, Toto R. Effective antihypertensive therapies in high risk patients with diabetic nephropathy. J Investig Med. In press.

        • Kunz R.
        • Friedrich C.
        • Wolbers M.
        • et al.
        Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal disease.
        Ann Int Med. 2008; 148: 30-48