Progressive renal and cardiovascular disease: Optimal treatment strategies

Abstract

A 54-year-old white man was referred by his internist for evaluation of a serum creatinine of 1.9 mg/dL and nephrotic-range proteinuria (3.6 g/24 h). The patient had an approximate 10-year history of non–insulin-dependent diabetes mellitus and a 15-year history of hypertension. The patient also reported that he had a history of a mildly enlarged heart and an elevated cholesterol level but denied previous visual abnormalities, chest pain, shortness of breath, or peripheral edema. He reported that he has always been stocky but had gained approximately 10 pounds during the previous year. He stated that his glucose levels were reasonably controlled between 130-200 mg/dL with diet and oral medication, but that his blood pressure was hard to treat and his physician had prescribed many different medicines. On physical examination, he was a middle-aged, overweight white male who was 5′10” tall and weighed 230 pounds. His blood pressure was 162/98 mm Hg and did not vary between arms or with position. Funduscopic examination revealed arteriolar narrowing, a rare microaneurysm, and two small hemorrhages in his left retina. His lungs were clear. Cardiovascular examination disclosed normal carotid upstrokes, a regular heart rate and rhythm, an S4 gallop, and 1+ peripheral pulses without pedal edema. His abdominal examination was remarkable for truncal obesity and no hepatosplenomegaly or vascular bruits. He had intact sensation and motor function of all four extremities as well as normal deep tendon reflexes. Laboratory testing revealed a serum potassium of 4.8 mEq/L; BUN, 26 mg/dL; serum creatinine, 1.9 mg/dL; hematocrit, 38.8%; serum cholesterol, 287 mg/dL; 24-hour urinary protein, 3.6 g; and a creatinine clearance of 52 mL/min. His serum albumin was 2.2 g/dL. The urine sediment showed 0-2 red blood cells/high-power field and hyaline casts. Serum protein electrophoresis and urine protein electrophoresis did not reveal paraproteins. Serologic evaluation for other causes of renal dysfunction and proteinuria was negative. The purpose of the consultation was to recommend the optimal treatment strategy for treating the blood pressure and proteinuria and for inhibiting his progressive renal disease. DR. MATTHEW R. WEIR (Head, Division of Nephrology, and Director, Clinical Research Unit, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA): This case exemplifies the problem that clinicians face in the management of patients with hypertension and early renal insufficiency. What is the best strategy for preventing progression of both atherosclerotic cardiovascular disease and chronic renal failure? In my discussion, I will focus on the most relevant issues in the management of this patient. Among these, I will review the concept of renal autoregulation because it provides a rationale for optimal levels of blood pressure and for which medications might need to be prescribed. An understanding of renal autoregulation also provides a framework for understanding (1) the relationship between blood pressure and renal injury, (2) the option of intensive control of blood pressure, and (3) the particular role of drugs that block the renin-angiotensin-aldosterone system (RAAS). I will conclude with some comments about the importance of proteinuria as a prognostic and modifiable risk factor for cardiovascular and renal disease progression and why preventing renal failure is important for reducing the risk of cardiovascular events. These topics will provide a framework for an understanding of the optimal therapeutic strategies for delaying progression of renal and cardiovascular disease in the patient with incipient nephropathy. Multiple risk factors affect the development of cardiovascular disease and progression of renal disease in patients with early renal insufficiency. These include non-modifiable risk factors such as genetics, but more important, they include modifiable risk factors such as glycemic control, dietary protein and salt intake, blood pressure, dyslipidemia, hyperhomocystinemia, proteinuria, and cigarette smoking1UK Prospective Diabetes Study Group Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853https://doi.org/10.1016/S0140-6736(98)07019-6Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar, 2Vaccaro O. Ruth K.J. Stamler J. Relationship of postload plasma glucose to mortality with 19-yr follow-up. Comparison of one versus two plasma glucose measurements in the Chicago Peoples Gas Company Study.Diabetes Care. 1992; 15: 1328-1334Crossref PubMed Scopus (63) Google Scholar, 3The National High Blood Pressure Educator Program Working Group National High Blood Pressure Program. Working Group Report on Hypertension in Diabetics.Hypertension. 1994; 23: 145-158Crossref PubMed Scopus (325) Google Scholar. For the sake of clarity and brevity, I will focus here on factors related to blood pressure and proteinuria both as interdependent and independent modifiable risk factors for progression of renal insufficiency and ultimately cardiovascular disease. Renal autoregulation is the physiologic mechanism whereby glomerular capillary pressure varies by only about 5 mm Hg over a wide range (60 to 150 mm Hg) of alterations in the renal perfusion pressure. Increasing systemic blood pressure induces a myogenic reflex that stimulates smooth muscle cells in the afferent glomerular arterioles to initiate a reflex contraction that reduces renal blood flow4Navar L.G. Burke T.J. Robinson R.R. Clapp J.R. Distal tubular feedback in the autoregulation of single nephron glomerular filtration rate.J Clin Invest. 1974; 53: 516-525Crossref PubMed Scopus (57) Google Scholar. A second mechanism that facilitates preglomerular vasoconstriction is the increased delivery of sodium chloride to the distal nephron, which stimulates a tubuloglomerular feedback mechanism that causes afferent arteriolar vasoconstriction4Navar L.G. Burke T.J. Robinson R.R. Clapp J.R. Distal tubular feedback in the autoregulation of single nephron glomerular filtration rate.J Clin Invest. 1974; 53: 516-525Crossref PubMed Scopus (57) Google Scholar,5Walker III, M. Harrison-Bernard L.M. Cook A.K. Navar L.G. Dynamic interaction between myogenic and TGF mechanisms in afferent arteriolar blood flow autoregulation.Am J Physiol. 2000; 279: F858-F865PubMed Google Scholar. As a consequence of these two mechanisms, autoregulation of glomerular capillary pressure is carefully maintained within a tight range, thereby assuring stable glomerular filtration while simultaneously reducing the likelihood of mechanical injury to the delicate glomerular capillary vessels. Should glomerular capillary perfusion fall below the autoregulatory threshold of approximately 60 mm Hg because of systemic hypotension, then increasing activation of the RAAS enhances efferent glomerular arteriolar vasoconstriction and facilitates maintenance of glomerular capillary pressure in a range that is necessary for filtration6Just A. Ehmke H.T.L. Kirchheim H.R. Dynamic characteristics and underlying mechanisms of renal blood flow autoregulation in the conscious dog.Am J Physiol. 2001; 280: F1062-F1071PubMed Google Scholar. Adequacy of control of glomerular capillary pressure is likely one of the most important factors in reducing risk for progression of renal injury Figure 1. Control of glomerular capillary pressure works well within the normal autoregulatory range of the kidney (60-150 mm Hg)4Navar L.G. Burke T.J. Robinson R.R. Clapp J.R. Distal tubular feedback in the autoregulation of single nephron glomerular filtration rate.J Clin Invest. 1974; 53: 516-525Crossref PubMed Scopus (57) Google Scholar, 5Walker III, M. Harrison-Bernard L.M. Cook A.K. Navar L.G. Dynamic interaction between myogenic and TGF mechanisms in afferent arteriolar blood flow autoregulation.Am J Physiol. 2000; 279: F858-F865PubMed Google Scholar, 6Just A. Ehmke H.T.L. Kirchheim H.R. Dynamic characteristics and underlying mechanisms of renal blood flow autoregulation in the conscious dog.Am J Physiol. 2001; 280: F1062-F1071PubMed Google Scholar, 7Sorensen C.M. Leyssac P.P. Skott O. Holstein-Rathlou N.H. Role of the renin-angiotensin system in regulation and autoregulation of renal blood flow.Am J Physiol. 2000; 279: R1017-R1024PubMed Google Scholar. Patients with pressures exceeding 150 mm Hg, or patients with damage to the autoregulation capacity of the afferent glomerular arterioles (as can occur in a patient with diabetes and vascular disease or who ingests a high-protein diet) can be vulnerable to injury from levels of systemic blood pressure within the so-called “normotensive” range (125-140 mm Hg). This level of blood pressure exceeds the usual range of pressures in the glomeruli and therefore can cause glomerular capillary hypertension in patients with damaged autoregulatory capacity. These circumstances, coupled with the increased vasodilation of the afferent glomerular arteriole in diabetes mellitus8Komers R. Lindsley J.N. Oyama T.T. Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes.Am J Physiol. 2000; 279: F573-583PubMed Google Scholar, markedly increase glomerular capillary pressure and the risk for injury. The increasing pressure can result in mechanical stretch and strain within the delicate glomerular capillary vascular beds and mesangial cells; this stress in turn results in an injury and repair response largely mediated by fibrogenic cytokines and angiotensin II9Weir M.R. Dzau V.J. The renin-angiotensin-aldosterone system: A specific target for hypertension management.Am J Hypertens. 1999; 12: 205S-213Shttps://doi.org/10.1016/S0895-7061(99)00103-XCrossref PubMed Google Scholar. Repetitive injury results in scarring, inflammation, and glomerulosclerosis and ultimately leads to loss of renal function. Subsequent loss of nephrons results in the development of glomerular capillary hypertension in residual nephron units, consequently exposing them to further mechanical injury10Anderson S. Meyer T.W. Rennke H.G. Brenner B.M. Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.J Clin Invest. 1985; 76: 612-619Crossref PubMed Scopus (845) Google Scholar. This series of sequential events ultimately leads to progressive renal insufficiency. Consequently, patients with incipient nephropathy might require levels of systemic blood pressure below what we have traditionally targeted in order to reduce the risk for progressive renal injury. The kidney's ability to regulate glomerular pressure is important for prevention of renal injury. Rigorous control of both systemic and glomerular capillary blood pressure is needed, particularly in patients with certain diseases, such as diabetes, that can predispose to impaired renal autoregulation. Abundant clinical data indicate that the net level of blood pressure achieved with antihypertensive therapy is predictive of risk for losing renal function both in non-diabetic patients and diabetic patients with renal disease11Klahr S. Levey S. Levey A.S. Beck G.J. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884https://doi.org/10.1056/NEJM199403313301301Crossref PubMed Scopus (2051) Google Scholar, 12Weir M.R. Dworkin L.D. Antihypertensive drugs, dietary salt, and renal protection: How low should you go and with which therapy?.Am J Kidney Dis. 1998; 32: 1-22Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 13Parving H.H. Hovind P. Rossing K. Andersen S. Evolving strategies for renoprotection: Diabetic nephropathy.Curr Opin Nephrol Hypertens. 2001; 10: 515-522https://doi.org/10.1097/00041552-200107000-00006Crossref PubMed Scopus (74) Google Scholar, 14Kasiske B.L. Kalil R.S. Ma J.Z. Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis.Ann Intern Med. 1993; 118: 129-138Crossref PubMed Scopus (607) Google Scholar. The Modification of Diet in Renal Disease (MDRD) study demonstrated important benefits of rigorous control of blood pressure in patients with non-diabetic renal disease and proteinuria Figure 211Klahr S. Levey S. Levey A.S. Beck G.J. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group.N Engl J Med. 1994; 330: 877-884https://doi.org/10.1056/NEJM199403313301301Crossref PubMed Scopus (2051) Google Scholar,15Peterson J.C. Adler S. Burkart J.M. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar. The proteinuric patients (defined as patients with>1 g of proteinuria/day) demonstrated substantial benefits with better blood pressure control (125/75 mm Hg), perhaps because the proteinuria was a reflection, in part, of impaired renal autoregulation and glomerular capillary hypertension. Bakris demonstrated a nearly linear relationship between systolic blood pressure achieved with pharmacotherapy and rate of loss of renal function each year in an evaluation of non-diabetic patients and diabetic patients, both groups with renal disease16Bakris G.L. Maximizing cardio-renal benefits: Achieving blood pressure goals.J Clin Hypertens. 1999; 1: 141-148Google Scholar. Likewise, Jafar et al noted an increased risk for doubling of serum creatinine or reaching end-stage renal disease in a meta-analysis of patients with non-diabetic renal disease as a function of systolic blood pressure achieved with pharmacotherapy17Jafar T.H. Schmid C.H. Landa M. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Scopus (890) Google Scholar. These and other clinical observations have provided important insights for establishing goals for optimal levels of blood pressure in patients with renal disease. These analyses also have indicated that an average of 3 to 4 medications (or more) are needed to achieve lower, more intensive blood pressure control (125-130 mm Hg systolic) in patients with renal disease. However, these studies have not provided insight as to how early in the course of renal failure one should intensify treatment so as to optimally prevent progressive renal injury. As I will discuss in a moment, several clinical trials in diabetes indicate that the earlier the intervention, preferably in the so-called “pre-hypertensive stage” (blood pressure less than 130/80 mm Hg), the greater the likelihood of preventing progressive renal injury (as a reflection of preventing progression from microalbuminuria to clinical proteinuria). Needless to say, blood pressure is more easily controlled with less medication when the untreated systolic blood pressure is 130-140 mm Hg. Possibly, earlier treatment will prevent the need for more medication in subsequent years. This hypothesis is an important consideration that needs to be tested in clinical trials. Evidence from clinical trials indicates that proteinuria is an independent predictor of progression of renal disease15Peterson J.C. Adler S. Burkart J.M. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar, 18The GISEN Group Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1744) Google Scholar, 19Jafar T.H. Stark P.C. Schmid C.H. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.Kidney Int. 2001; 60: 1131-1140https://doi.org/10.1046/j.1523-1755.2001.0600031131.xAbstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar. The severity of baseline proteinuria is an important predictor, not only of the rate, but also of the likelihood, of loss of renal function15Peterson J.C. Adler S. Burkart J.M. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.Ann Intern Med. 1995; 123: 754-762Crossref PubMed Scopus (1228) Google Scholar,17Jafar T.H. Schmid C.H. Landa M. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Scopus (890) Google Scholar. Clinical trials also have demonstrated that the reduction in protein excretion with antihypertensive agents or dietary protein restriction correlates directly with the reduction of the rate of loss of renal function20El Nahas A.M. Masters-Thomas A. Brady S.A. Selective effect of low protein diets in chronic renal diseases.Br Med J (Clin Res Ed). 1984; 289: 1337-1341Crossref PubMed Scopus (95) Google Scholar,21Apperloo A.J. de Zeeuw D. de Jong P.E. Short-term antiproteinuric response to antihypertensive therapy predicts long-term GFR decline in patients with non-diabetic renal disease.Kidney Int. 1994; 45: S174-S178Google Scholar. Newer clinical trials indicate that the net reduction in proteinuria achieved with antihypertensive therapy ultimately predicts the rate of loss of renal function over time; the initial severity of baseline proteinuria does not19Jafar T.H. Stark P.C. Schmid C.H. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.Kidney Int. 2001; 60: 1131-1140https://doi.org/10.1046/j.1523-1755.2001.0600031131.xAbstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar,22Rossing P. Hommel E. Smidt U.M. Parving H.H. Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment.Diabetologia. 1994; 37: 511-516https://doi.org/10.1007/s001250050140Crossref PubMed Scopus (173) Google Scholar. These observations indicate that proteinuria is a modifiable risk factor of progressive renal disease. However, in clinical practice, attempting to reduce or abolish proteinuria is not common, as more emphasis has been placed on reducing blood pressure. Microalbuminuria is an important predictor of subsequent risk for nephropathy in both type 1 and type 2 diabetes23Mogensen C.E. Keane W.F. Bennett P.H. Prevention of diabetic renal disease with special reference to microalbuminuria.Lancet. 1995; 346: 1080-1084https://doi.org/10.1016/S0140-6736(95)91747-0Abstract PubMed Scopus (511) Google Scholar, 24Mogensen C.E. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes.N Engl J Med. 1984; 310: 356-360Crossref PubMed Scopus (1765) Google Scholar, 25Keane W.F. Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation.Am J Kidney Dis. 1999; 33: 1004-1010Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar. Its presence also is predictive of cardiovascular mortality in diabetic and non-diabetic patients23Mogensen C.E. Keane W.F. Bennett P.H. Prevention of diabetic renal disease with special reference to microalbuminuria.Lancet. 1995; 346: 1080-1084https://doi.org/10.1016/S0140-6736(95)91747-0Abstract PubMed Scopus (511) Google Scholar, 24Mogensen C.E. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes.N Engl J Med. 1984; 310: 356-360Crossref PubMed Scopus (1765) Google Scholar, 25Keane W.F. Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation.Am J Kidney Dis. 1999; 33: 1004-1010Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar. Microalbuminuria likely reflects evidence of a systemic vasculopathy, with damage to the glomerular vascular bed being one of the first areas of damage that is clinically evident. Microalbuminuria also can represent evidence of glomerular capillary hypertension and hyperfiltration, perhaps due to loss of afferent glomerular arteriolar vasoconstriction and dysfunctional autoregulation of glomerular capillary blood pressure. Thus, the presence of microalbuminuria, like proteinuria, indicates the patient with a greater risk of developing both progression of renal disease and cardiovascular events. Excessive proteins filtered by the glomerulus lead to an increase in both renal tubular cell reabsorption of proteins and overall protein catabolism. Remuzzi and Bertani have suggested that excessive renal tubular cell reabsorption of proteins activates vasoactive and inflammatory genes, thereby resulting in the synthesis and elaboration of several substances within the interstitium. These substances in turn result in fibrogenesis, collagen production, and scarring Figure 326Remuzzi G. Bertani T. Pathophysiology of progressive nephropathies.N Engl J Med. 1998; 339: 1448-1456https://doi.org/10.1056/NEJM199811123392007Crossref PubMed Scopus (1150) Google Scholar. Glomerular capillary hypertension would likely accelerate this process, as it results in increased glomerular permeability to proteins and, at the same time, greater mechanical stretch and strain within the glomeruli and surrounding mesangial cells. This process results in greater production of angiotensin II, transforming growth factor-β1, and a subsequent increase in collagen synthesis9Weir M.R. Dzau V.J. The renin-angiotensin-aldosterone system: A specific target for hypertension management.Am J Hypertens. 1999; 12: 205S-213Shttps://doi.org/10.1016/S0895-7061(99)00103-XCrossref PubMed Google Scholar,26Remuzzi G. Bertani T. Pathophysiology of progressive nephropathies.N Engl J Med. 1998; 339: 1448-1456https://doi.org/10.1056/NEJM199811123392007Crossref PubMed Scopus (1150) Google Scholar. Consequently, both glomerular hyperfiltration and excessive tubular reabsorption of proteins are likely additional causes of renal injury. The reduction of proteinuria is important in patients both with non-diabetic and diabetic renal disease. The Ramipril Efficacy in Nephropathy (REIN) study was in part designed to assess the relationship between proteinuria and progression of renal disease in non-diabetic patients. Investigators noted that the mean rate in decline in GFR of the patients whose urinary protein excretion was between 1 and 3 g/day was one-third that of the patients whose urinary protein excretion was greater than 3 g/day18The GISEN Group Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1744) Google Scholar. Moreover, this study also noted that the use of the ACE inhibitor ramipril was the only time-dependent variable that predicted the slower rate in decline of GFR. The report thus concluded that renal protection was linked to a reduction in urinary protein excretion and not blood pressure. Jafar et al conducted a meta-analysis of 1860 patients enrolled in 11 randomized controlled trials comparing the effects of multidrug antihypertensive regimens, including or not including ACE inhibitors, on the progression of non-diabetic renal disease17Jafar T.H. Schmid C.H. Landa M. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Scopus (890) Google Scholar. They demonstrated that the level of proteinuria achieved with pharmacotherapy was predictive of the rate of loss of renal function. This finding indicated that urinary protein excretion was a modifiable risk factor for the progression of renal disease. It is interesting that they also noted that the beneficial effect of ACE inhibitors in retarding progression of renal disease remained significant, even after they controlled for the level of urinary protein excretion achieved. The Collaborative Study Group demonstrated that only patients with type 1 diabetes who achieved at least a 50% reduction in urinary protein excretion derived benefit, defined as subsequent stabilization of renal function27Lewis E.J. Hunsicker L.G. Bain R.P. Rohde R.D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.N Engl J Med. 1993; 329: 1456-1462https://doi.org/10.1056/NEJM199311113292004Crossref PubMed Scopus (5018) Google Scholar. This study indicated that intensive antiproteinuric strategy, concurrent with an optimal blood pressure strategy, is important in reducing the likelihood of progressive nephropathy in type 1 diabetics. Information regarding the importance of reducing proteinuria on the rate of progression of renal disease in patients with type-2 diabetes is inconsistent, in large part because of the small size and short duration of the studies to date (abstract; Walker et al, J Am Soc Nephrol 3:339, 1992)28Lebovitz H.E. Wiegmann T.B. Renal protective effects of enalapril in hypertensive NIDDM: Role of baseline albuminuria.Kidney Int. 1994; 45: S150-S155PubMed Google Scholar, 29Bakris G.L. Copley J.B. Vicknair N. et al.Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy.Kidney Int. 1996; 50: 1641-1650Abstract Full Text PDF PubMed Scopus (381) Google Scholar, 30Nielsen F.S. Rossing P. Gall M.A. et al.Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.Diabetes. 1997; 46: 1182-1188Crossref PubMed Google Scholar, 31Fogari R. Zoppi A. Corradi L. et al.Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function.J Hum Hypertens. 1999; 13: 47-53https://doi.org/10.1038/sj.jhh.1000732Crossref PubMed Scopus (84) Google Scholar, 32Estacio R.O. Jeffers B.W. Gifford N. Schrier R.W. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes.Diabetes Care. 2000; 23: B54-B64PubMed Google Scholar. With the completion of the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with the Angiotensin II type-1 Antagonist Losartan (RENAAL) trial33LEWIS E.J. HUNSICKER L.G. CLARKE W.R. for The Collaborative Study Group 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: 851-860Crossref PubMed Scopus (5040) Google Scholar,34Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes and mortality in patients with type 2 diabetes and nephropathy: Results of the reduction of end points in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6147) Google Scholar, more information is now available to correlate the importance of reduction in proteinuria on renal outcomes in patients with type-2 diabetes and incipient nephropathy. Although not completely analyzed yet, both studies likely will show a direct correlation between the antiproteinuric effects of the angiotensin II receptor blocker and protection of renal function. Lower blood pressure goals in the presence of microalbuminuria or proteinuria are important considerations for treatment. Reaching the desired systolic blood pressure goal frequently requires one drug for every 10 mm Hg of systolic blood pressure reduction. The presence of microalbuminuria or proteinuria requires specific therapy including drugs that block the renin-angiotensin system, non-dihydropyridine calcium channel blockers, and restriction of dietary sodium and protein. Proteinuria and hypertension are separate and independent yet intertwined modifiable risk factors for progression of renal insufficiency. Angiotensin-converting-enzyme (ACE) inhibitors attenuate the rate of progression of renal disease both in type 1 diabetics13Parving H.H. Hovind P. Rossing K. Andersen S. Evolving strategies for renoprotection: Diabetic nephropathy.Curr Opin Nephrol Hypertens. 2001; 10: 515-522https://doi.org/10.1097/00041552-200107000-00006Crossref PubMed Scopus (74) Google Scholar,26Remuzzi G. Bertani T. Pathophysiology of progressive nephropathies.N Engl J Med. 1998; 339: 1448-1456https://doi.org/10.1056/NEJM199811123392007Crossref PubMed Scopus (1150) Google Scholar and patients with non-diabetic renal disease17Jafar T.H. Schmid C.H. Landa M. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Scopus (890) Google Scholar. The benefit of ACE inhibitors likely is derived from antihypertensive/antiproteinuric properties and the anti-mitogenic/anti-fibrogenic effects of angiotensin II antagonism9Weir M.R. Dzau V.J. The renin-angiotensin-aldosterone system: A specific target for hypertension management.Am J Hypertens. 1999; 12: 205S-213Shttps://doi.org/10.1016/S0895-7061(99)00103-XCrossref PubMed Google Scholar. The meta-analysis by Jafar et al demonstrated the important benefit of ACE inhibitors in patients with non-diabetic renal disease17Jafar T.H. Schmid C.H. Landa M. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Sc