Progression Of Nondiabetic Renal Disease Research Articles

Dual blockade of the renin‐angiotensin system with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)

The renin-angiotensin-aldosterone system can be blocked at one of several points (Figure 1). Simultaneous blockade at more than one point can be therapeutically beneficial, as in the addition of an aldosterone antagonist to an angiotensin converting enzyme (ACE) inhibitor in patients with severe heart failure [1] or with left ventricular dysfunction following myocardial infarction [2]. This makes good pharmacological sense, since angiotensin II is not the only stimulus to aldosterone secretion and when the synthesis or action of angiotensin II is blocked the concentration of circulating aldosterone falls initially but then climbs back toward pre-treatment values in some patients (‘aldosterone breakthrough’– see [3]). Figure 1 Renin-angiotensin-aldosterone pathway and its inhibition by angiotensin converting enzyme (ACE) inhibitors, AT1 receptor antagonists (ARBs) and other drugs. Note the potential for increased effects of combinations of ACE inhibitors and ARBs via ARB antagonism ... Monotherapy with an ACE inhibitor increases the concentration of circulating angiotensin I because of the loss of feedback inhibition of angiotensin II on renin secretion (Fig 1). Increased substrate (angiotensin I) may partially mitigate inhibition of ACE by a reversible competitive ACE inhibitor, restoring the concentration of active angiotensin II toward pretreatment levels [4,5], This might be termed ‘angiotensin breakthrough’ by analogy with ‘aldosterone breakthrough’, and is one reason why combined blockade by an AT1 receptor antagonist (an angiotensin receptor blocker or ARB) together with an ACE inhibitor might confer added benefit. Additionally, other enzymes distinct from ACE and not blocked by ACE inhibitors can form angiotensin II – for example mast cell-derived chymase [6]. Furthermore, ACE inhibition has pharmacological effects distinct from reducing angiotensin II, notably potentiation of bradykinin in vivo (for example in human resistance forearm vasculature [7]) and possibly also other ACE-inactivated vasodilator peptides (ACE is not substrate-specific for angiotensin I). There are thus several distinct mechanisms by which the combination of an ACE inhibitor (which potentiates vasodilator mechanisms as well as reducing circulating angiotensin II) and an ARB (which blocks AT1 receptor-mediated actions of angiotensin II, whether derived from ACE, chymase or other mechanism) could be qualitatively superior to increasing the dose of either such drug administered as a single agent. Combined ACE inhibition with AT1 receptor antagonism has a greater effect than monotherapy on blood pressure and on left ventricular hypertrophy (assessed by measurements of heart weight) in spontaneously hypertensive rats [8]. This supported the notion that these drug classes are at least additive and possibly synergistic, which is the basis for a concept of ‘dual blockade’ that is combining ACE inhibition with AT1 receptor antagonism. This strategy has been enthusiastically embraced by prescribers (academics as well as service providers) perhaps because of the seductiveness of the pharmacological rationale outlined above [9, and see below]. However, unlike the addition of aldosterone antagonists to ACE inhibitors [1,2], hard clinical evidence of improved outcomes with of dual blockade with ARBs and ACE inhibitors is weak. A systematic review and meta-analysis demonstrated an additional effect on blood pressure of around 4/3 mm Hg of the combination versus monotherapy [10]. This begs the question whether an increased dose of monotherapy might have had a similar effect and is modest compared with effects of adding a diuretic or a calcium channel blocker to an ACE inhibitor [see for example 11]. A meta-analysis of effects of combination therapy on albumin excretion (a surrogate marker of glomerular injury) in patients with renal disease did show that dual blockade reduced protein excretion by 20–25% more than monotherapy [12], which was interpreted by many as encouraging evidence in favor of combination treatment. However, while the ONTARGET trial of the combination of telmisartan (ARB) with ramipril (ACE inhibitor) versus monotherapy showed that combined therapy achieved a mean blood pressure reduction 2.4/1.4 mm Hg greater in the combination group than in the group treated with ramipril alone and a greater effect on urinary albumin excretion, the combination showed no benefits in terms of the primary study endpoint (a composite of cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure), caused more symptoms attributable to hypotension, and increased the decline in renal function and need for dialysis compared with ACE inhibitor monotherapy[13]. In a trial in patients with myocardial infarction and heart failure there was an increase in adverse events and no survival benefit in patients randomised to combination therapy with valsartan plus captopril [14]. Thus clinical endpoint evidence does not support combined use of ACE inhibitor with ARB, and incidentally also undermines the usefulness of albumin excretion rate as a surrogate marker of renal injury. Messerli concluded that ‘unless data emerge to the contrary, dual blockade should no longer be used in clinical practice’[9]. How has this slow-burning story influenced prescribing of ACE inhibitors and ARBs? In this issue of the Journal [15] Wan and colleagues describe trends in the co-prescription of ACE inhibitors and ARBs in Ireland between January 2000 and April 2009 (> a quarter of a million prescriptions): there has been a significant positive linear trend in co-prescription taking off in 2000–2001 and increasing thirty five-fold (from 0.16 to 5.72 per 1000 eligible population) in the past decade. There was no abrupt discontinuity noticeable following publication of the endpoint trials including COOPERATE (a trial reported in the Lancet in 2003 which purported to show clinical benefit of combination therapy on progression of non-diabetic renal disease but was subsequently retracted by the Lancet editors in 2009), VALIANT and ONTARGET, although a suggestion of a reduction in the rate of increase in co-prescription following publication of ONTARGET in 2008 (see Figure 1 in reference 15). The ‘dual-blockade strategy’ appears to be a juggernaut with considerable momentum, but without a clinical evidence base! What is the cause of these rather striking findings, and what is to be done to improve prescribing in this regard? In this editorial, which supports skeptical criticism of hypotheses (however ingenious and plausible) based on animal models, and increased reliance on clinical rather than surrogate endpoints, we hesitate to speculate as to the cause underlying these prescribing trends but we suspect our readers may be attracted to certain rather obvious possibilities! As regards what is to be done, the answer must surely be through better education in clinical pharmacology and prescribing skills, as we have argued previously [16].

Retraction—Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial

After a letter of concern, 1 Kunz R Wolbers M Glass T Mann JFE The COOPERATE trial: a letter of concern. Lancet. 2008; 371: 1575-1656 Summary Full Text Full Text PDF PubMed Scopus (87) Google Scholar which arose when Regina Kunz and colleagues attempted to include the data from COOPERATE into a meta-analysis, we have now received the conclusions of an institutional investigation into the COOPERATE trial. 2 Nakao N Yoshimura A Morita H Takada M Kayano T Ideura T Combination treatment of angiotensin II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003; 361: 117-124 Summary Full Text Full Text PDF PubMed Scopus (954) Google Scholar The investigation committee led by Yutuka Sanada, the President of Showa University Fujigaoka Hospital, met seven times, questioned the lead author, Naoyuki Nakao, directly, and examined the original medical records of his patients at Gen Gen-Do Kimitsu Hospital, where the trial was conducted. They concluded that contrary to statements in the paper, the trial had not been approved by the ethics committee of Gen Gen-Do Kimitsu Hospital. Also, contrary to the statement on patients' consent, Dr Nakao reposted that he had received verbal consent from patients shortly after the start of the study and written consent only during the study. The involvement of a statistician could not be verified. The committee concluded that the trial was not a double-blind study, because Dr Nakao knew the treatment allocation. In the attempt to assess the validity of the data, a sample of medical records was compared with the data provided by Dr Nakao. The committee concluded that it was unable to prove the authenticity of the data. RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trialCombination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched. Full-Text PDF The COOPERATE trial: a letter of concernIn the context of a meta-analysis,1 we had reason to take an in-depth look at a study by Naoyuki Nakao and colleagues2 published in The Lancet in 2003. We detected implausibilities of serious concern. Full-Text PDF

Sex, diabetes and the kidney

The incidence and the rate of progression of nondiabetic renal disease is generally greater in men compared with age-matched women, suggesting that the female sex is protective and/or that the male sex is a risk factor for the development and progression of nondiabetic renal disease. In diabetes, even though the male sex still appears to be a risk factor, this relationship is not as strong as it is in nondiabetic renal disease. Experimental evidence suggests that both estrogens and androgens play an important role in the pathophysiology of renal disease. Thus one of the potential mechanisms for the absence of a clear sex difference in the setting of diabetes may be alterations in sex hormone levels. Indeed, studies suggest that diabetes is a state of an imbalance in sex hormone levels; however, whether these changes correlate with the decline in renal function associated with diabetes is unclear. Furthermore, diabetic renal disease rarely develops before puberty, and the onset of puberty accelerates microalbuminuria, supporting the idea of the involvement of sex hormones in the development and progression of the disease. However, other than a handful of experimental studies indicating that treatment with or removal of sex hormones alters the course of diabetic renal disease, very few studies have actually directly examined the correlation between sex hormones and the disease development and progression. Further studies are necessary to determine the precise contribution of sex hormones in the pathophysiology of diabetic renal disease to develop novel and potentially sex-specific therapeutic treatments.

Clinical Research Methods in CJASN

Epidemiology and biostatistics have played an increasingly important role in the study of renal disease and, therefore, the nephrology literature. As a result, many nephrologists seek opportunities to improve their ability to read this literature critically. Responding to this need, we begin a series of articles in this issue of the Clinical Journal of the American Society of Nephrology (CJASN) that will highlight major clinical research methods that many of CJASN’s contributors use in their studies of renal diseases. Although this series will cover only a portion of the large set of methods and issues that are relevant to the conduct of clinical research in nephrology, it will be extended periodically to expand opportunities for CJASN readers to be exposed to the full array of clinical research tools. The number of published clinical research studies has increased greatly in the past decade. Since 2000 alone, Medline contains nearly 24,000 citations that both address kidney disease and are identified as using epidemiologic study methods. Clinical epidemiologic studies can be categorized according to broad areas of inquiry listed in Figure 1. Although questions in these areas can be informed by a variety of study methods, each is addressed most commonly by specific study designs. For example, studies of cause and prognosis often utilize cohort designs, whereas studies of therapy frequently utilize the clinical trial designs. Study designs also can be classified according to whether their focus is to describe patterns of disease (descriptive studies) or examine hypotheses about exposure–disease relationships (analytical studies). The latter can be divided further into those in which the investigator examines exposure–disease relationships as they naturally occur (observational studies) and those in which there is modification or creation of the study conditions (experimental studies). Figure 2 lists some of the most common clinical research study designs. The initial four papers of this series derive from the ASN′s Post-Graduate Education course delivered at the 2005 Annual Meeting in Philadelphia: “Critically Approaching the Literature: Applying the Principles of Epidemiology and Biostatistics.” Thadhani and Tonelli’s article in this issue on cohort research will be followed by contributions that address case-control methods, clinical trials, and meta-analysis, also provided by speakers from the ASN course. In addition to covering fundamental epidemiologic study designs, this series will review related concepts such as bias, confounding, and biostatistical tools such as confidence intervals and multivariate regression. All of our contributors will exemplify these topics through discussion of published studies in renal medicine. Thadhani and Tonelli’s article in this issue discusses cohort studies, a powerful method of observational research that tracks people forward in time from exposure to outcome. Cohort studies can be exceedingly potent designs, especially when using large data sets that record clinical attributes and outcomes over time, such as the US Renal Data System data set, and data sets from large health maintenance organizations and dialysis chains. Increasingly, prospective research that explores multiple scientific questions that are not addressed feasibly through randomized, clinical trials use the cohort method, such as the National Institute of Diabetes and Digestive and Kidney Diseases’ Chronic Renal Insufficiency Cohort Study (1), CKiD: A Prospective Cohort Study of Kidney Disease in Children (http://www.statepi.jhsph.edu/ckid/), and the African American Study of Kidney Disease and Hypertension (AASK) cohort study (2). The second contribution will cover case-control studies, another observational study design that efficiently works in reverse by tracing back from outcome to exposure. Case-control research increasingly has played a role in the nephrology literature, providing efficiencies over cohort study designs when the outcomes of interest are rare. Case-control studies also often provide opportunity to supplement exposure data beyond those that are available in preexisting clinical or administrative data sets by virtue of the relatively small number of patients who are required compared with cohort research. The third contribution will provide an overview of randomized, controlled trials, which are the gold standard method for providing the most unbiased estimate regarding the effect of a treatment. Clinical trials have provided unique opportunities to address questions of dialysis dose (3), progression of chronic kidney disease (4), and anemia management (5), among many others. Despite their clear advantage with respect to the control of confounding, clinical trialists must overcome substantial logistical challenges, including their high cost. As well, the generalizability of findings from clinical trials often is limited by the selected nature of both recruitment and clinical care that is provided during the study. The fourth contribution will cover systematic reviews and meta-analyses, which traditionally have been used to synthesize the findings of a series of clinical trials, each without a definitive conclusion. More recently, meta-analyses of observational research (e.g., cohort or case-control studies) have been performed, drawing on the strengths of techniques such as meta-regression to assist in the control of confounding. Meta-analyses already have provided important insights into important topics in medicine, such as the influence of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease (6). The past two decades have seen enormous growth in the use of epidemiologic methods as a central part of the research armamentarium that is used to address critical questions and problems in renal medicine. Large, early, and highly influential initiatives such as the US Renal Data System have greatly catalyzed the growth of high-quality clinical research that is common today throughout the published nephrology literature. By acquiring and refining their understanding of these research methods, practicing nephrologists will improve their ability to appraise critically and to interpret the clinical studies that appear on a regular basis in CJASN. This research methods series will provide readers a solid understanding of the key clinical research designs and their strengths, weaknesses, and most important uses, all critical to the ability to digest the vast array of clinical research findings.Figure 1: Key areas of inquiry in clinical epidemiology.Figure 2: Common clinical research study designs.

Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial

Summary Background Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximumdose, in patients with non-diabetic renal disease. Methods 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat. Findings Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·018) and 20 (23%) of 86 on losartan alone (0·40, 0·17–0·69, p=0·016). Covariates affecting renal survival were combination treatment (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·011), age (1·30, 1·03–2·29, p=0·009), baseline renal function (1·80, 1·02–2·99, p=0·021), change in daily urinary protein excretion rate (0·58, 0·24–0·88, p=0·022), use of diuretics (0·80, 0·30–0·94, p=0·043), and antiproteinuric response to trandolapril (0·81, 0·21–0·91, p=0·039). Frequency of side-effects with combination treatment was the same as with trandolapril alone. Interpretation Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched.

RETRACTED: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial

Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximum dose, in patients with non-diabetic renal disease. 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat. Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.018) and 20 (23%) of 86 on losartan alone (0.40, 0.17-0.69, p=0.016). Covariates affecting renal survival were combination treatment (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.011), age (1.30, 1.03-2.29, p=0.009), baseline renal function (1.80, 1.02-2.99, p=0.021), change in daily urinary protein excretion rate (0.58, 0.24-0.88, p=0.022), use of diuretics (0.80, 0.30-0.94, p=0.043), and antiproteinuric response to trandolapril (0.81, 0.21-0.91, p=0.039). Frequency of side-effects with combination treatment was the same as with trandolapril alone. Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive non-diabetic renal disease need to be researched.

Progressive renal and cardiovascular disease: Optimal treatment strategies

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

Evaluation and Treatment of Patients With Systemic Hypertension

HomeCirculationVol. 105, No. 21Evaluation and Treatment of Patients With Systemic Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBEvaluation and Treatment of Patients With Systemic Hypertension Jay Garg, Adrian W. Messerli and George L. Bakris Jay GargJay Garg From Rush University Hypertension Center, Department of Preventive Medicine, Rush Presbyterian/St Luke’s Medical Center, Chicago, Ill (J.G., G.L.B.); and Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Cleveland, Ohio (A.W.M.). Search for more papers by this author , Adrian W. MesserliAdrian W. Messerli From Rush University Hypertension Center, Department of Preventive Medicine, Rush Presbyterian/St Luke’s Medical Center, Chicago, Ill (J.G., G.L.B.); and Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Cleveland, Ohio (A.W.M.). Search for more papers by this author and George L. BakrisGeorge L. Bakris From Rush University Hypertension Center, Department of Preventive Medicine, Rush Presbyterian/St Luke’s Medical Center, Chicago, Ill (J.G., G.L.B.); and Cleveland Clinic Foundation, Department of Cardiovascular Medicine, Cleveland, Ohio (A.W.M.). Search for more papers by this author Originally published28 May 2002https://doi.org/10.1161/01.CIR.0000017143.59204.AACirculation. 2002;105:2458–2461A 65-year-old man presented for evaluation of high blood pressure found on screening at a local health fair. History and physical examination did not show any signs or symptoms suggestive of a secondary cause, nor was there evidence of target end-organ damage except for grade 1 Keith-Wagener-Barker retinopathy. The patient denied taking any prescription or over-the-counter medications.Hypertension is the most common disease-specific reason Americans visit a physician. Despite the risks associated with an elevated blood pressure (BP), there is still woefully low achievement of recommended BP goals. From 1991 to 1994, only 27.4% of hypertensive Americans aged 18 to 74 years had a BP <140/90 mm Hg, the current stated goal for most people with hypertension, and in those with diabetes, less than half that number (11%) were controlled to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI (JNC VI) recommended goal of <130/85 mm Hg.1 The present update will provide an overview of the evaluation and management of essential hypertension and help to guide clinicians in developing a management plan for a patient like the one described above.EvaluationTaking a proper BP is an important first step in the diagnosis of hypertension.2 Using the proper cuff size with patients resting quietly and comfortably (with back support if seated) for at least 5 minutes before measurement, 2 or more readings separated by 2 minutes should be taken and averaged. Initial elevated BP readings should be confirmed on at least 2 subsequent visits over a period of 1 week or more. A value that is consistently ≥140/90 mm Hg is diagnostic in healthy patients; a value >130/80 mm Hg should be used for those with diabetes or kidney disease and proteinuria.Initial evaluation of the hypertensive patient focuses on the presence or absence of target organ damage (TOD) and includes a physical examination, blood urea nitrogen/creatinine evaluation, measurement of electrolytes, urinalysis, and an ECG. Further, an assessment of cardiovascular (CV) risk factors with a thorough history and chemistry panel (glucose, cholesterol, and triglycerides) is routinely administered.1 Although the patient in our case study did not exhibit signs or symptoms of a secondary cause of hypertension, this possibility must be entertained in every hypertensive patient.3ManagementGoal BP management is determined by the presence or absence of TOD, diabetes and other CV risk factors, and other comorbidities. BP goal recommendations are based on results from randomized, controlled trials and recommendations from guidelines committees (Table 1). All patients with hypertension, except those with diabetes or evidence of TOD, should reduce their BP to <140/90 mm Hg.1 Those with diabetes mellitus or kidney disease with proteinuria (<1 g/d) should have a target BP of ≤130/80 mm Hg, and those with proteinuria >1 g/d should have a target BP of <125/75 mm Hg.1,4,5 Achieving these BP goals requires a combination of lifestyle modifications and pharmacological treatment. Patients with JNC VI stage 2 or 3 hypertension (systolic blood pressure [SBP] ≥160 mm Hg or diastolic blood pressure [DBP] ≥100 mm Hg) and those considered to be in a high-risk group (diabetics or subjects with clinical CV disease) should be prescribed antihypertensive drug therapy.1Recommended Target BP GoalsGuidelineUncomplicated HypertensionNo TOD or Clinical CV Disease; at Least 1 CV Risk Factor Excluding DiabetesDiabetes*NKF indicates National Kidney Foundation; ADA, American Diabetes Association.*JNC VI BP goal also recommended for those with TOD or clinical CV disease.JNC VI<140/90 mm Hg<140/90 mm Hg<130/85 mm HgNKF≤130/80 mm HgADA≤130/80 mm HgInitial lifestyle modifications include weight loss for obese hypertensive patients, modification of alcohol intake to no more than 2 drinks per day, and limiting Na+ intake to ≤100 mmol/d. A number of trials, such as the first Trial of Hypertension Prevention (TOHP-1),6 the follow-up Trial of Hypertension Prevention (TOHP-2),7 the Treatment of Mild Hypertension Study (TOHMS),8 and the Dietary Approaches to Stop Hypertension (DASH) study,9 demonstrate that lifestyle modifications, especially weight loss and a reduction in Na+ intake, have salutary effects on BP. In the studies with a longer follow-up, there were significantly fewer CV events in the group with both pharmacological treatment and lifestyle modification.8 High rates of recidivism were seen in the long-term studies, and drug therapy had to be resumed.10 Thus, although lifestyle modifications can help reduce BP, it is clear that pharmacological therapy is needed to maintain the goal BP.The primary goal of BP reduction is to reach optimal BP by the least intrusive means possible.1 The choice of antihypertensive agent should be based on the ability of that agent to reduce morbidity and mortality, especially in the areas of cardiovascular and kidney disease. Three classes of drugs (thiazide diuretics, β-blockers, and angiotensin-converting enzyme [ACE] inhibitors) reduce CV events and mortality when used as the initial therapy for hypertension in appropriately designed and implemented clinical trials, and calcium antagonists reduce stroke mortality and morbidity in the elderly in the absence of proteinuria.11 Thus, calcium antagonists are very useful adjuncts to help achieve BP goals because it takes an average of 3 different antihypertensive medications to achieve BP goals in high-risk individuals.12Cardiovascular DiseaseThe process of atherosclerosis is accelerated by hypertension, increasing an individual’s lifetime risk for adverse CV events ≈2- to 3-fold.13 The optimal therapy for a hypertensive patient with known coronary artery disease should do more than simply lower blood pressure. Ideally, the drug will help prevent development of ischemia and occurrence of future cardiovascular events. For patients with angina, an additional goal is reduction of symptoms. It is important to avoid antihypertensive agents that could potentiate myocardial ischemia. Vasodilators, specifically first- and second-generation dihydropyridine calcium-channel blockers (DHCCBs) and hydralazine, cause significant vasodilation, with compensatory increases in heart rate and myocardial contractility. Once coronary blood flow supply is unable to match myocardial oxygen demand, ischemia, often manifested as angina, may result.β-Blockersβ-Blockers without intrinsic sympathomimetic activity remain the most effective class of drugs for primary and secondary cardioprotection and are the mainstay of therapy for hypertensive patients with ischemic heart disease. They decrease heart rate and inotropy, thereby reducing myocardial oxygen demand. As primary preventive therapy, β-blockers reduce CVD and all-cause mortality in hypertensive patients.14 In the post–myocardial infarction setting, β-blockers limit infarct size, suppress ventricular arrhythmias, reduce the incidence of angina, reinfarction and sudden cardiac death, and improve survival.15 Importantly, β-blockers have proven benefit regardless of the severity of left ventricular dysfunction, but they are typically withheld from heart failure patients until ACE inhibitors have been initiated and titrated.16ACE InhibitorsInitially, ACE inhibitors were recommended as standard therapy for all patients who suffered a myocardial infarction with resultant left ventricular dysfunction.17 Given the results of the Heart Outcomes Prevention Evaluation (HOPE) study,18 in which ramipril reduced the risk of CV events by 22% compared with placebo, however, ACE inhibitors should be considered for both primary and secondary prevention in all high-risk patients and may be considered as first-line therapy in those patients not able to tolerate β-blockers.Calcium AntagonistsCertain calcium-channel blockers (CCBs) can be used if anginal symptoms or hypertension are not controlled with β-blockers and ACE inhibitors or if patients cannot tolerate β-blockers. Verapamil is an approved alternative if β-blockers cannot be tolerated. Caution should be exercised whenever a non-dihydropyridine CCB is combined with a β-blocker. Significant side effects, including profound hypotension, symptomatic bradycardia, and heart block, may occur in 10% to 15% of patients, predominantly those over 65 years of age or with a preexisting heart block. Long-acting DHCCBs could be used to lower BP in this setting, but they do not reduce mortality from ischemic causes of heart failure.19,20Kidney Disease/DiabetesThe National Kidney Foundation and the American Diabetes Association guidelines suggest that the target BP should be ≤130/80 mm Hg.4,5 These recommendations were based on trials and epidemiological data that, taken together, suggested that the risk for both kidney and CV diseases starts to increase at a DBP as low as 83 mm Hg and a SBP as low as 127 mm Hg.There is now strong evidence that drugs that inhibit the renin-angiotensin system should be a prominent part of the antihypertensive regimen for those with diabetes and/or kidney disease. In a meta-analysis using individual subject data of those with nondiabetic kidney disease, not only did ACE inhibitors reduce the risk of attaining the primary outcomes of end-stage renal disease (ESRD) or doubling of serum creatinine, they also dramatically reduced the amount of proteinuria.21 Increased urinary albumin excretion or albuminuria is an independent risk factor for both CV and kidney disease, especially in high-risk individuals such as diabetics.22 Because of this, it is important to evaluate all diabetics, whether hypertensive or not, for albuminuria (Figure 1). We now can use “evidence-based” medicine to decide which class of antihypertensive agent to use. In type 2 diabetics with gross proteinuria, only the use of an angiotensin receptor blocker (ARB) has been proven to reduce the risk of developing ESRD or doubling of serum creatinine.23,24 Conversely, ACE inhibitors or ARBs have been shown to blunt increases in microalbuminuria and, in some cases, normalize it25; however, only ACE inhibitors have been shown to reduce the risk of CV events in diabetics, irrespective of whether microalbuminuria was present.18 An algorithm to achieve BP goal in diabetics is presented in Figure 2. Download figureDownload PowerPointFigure 1. Recommended algorithm in screening for microalbuminuria.Download figureDownload PowerPointFigure 2. Algorithm for an approach to controlling hypertension in patients with type 2 diabetes mellitus.It is important to note that DHCCBs should not be used in the absence of an ACE inhibitor or ARB in the treatment of hypertension in those with type 2 diabetes or kidney disease. In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, there were fewer fatal and nonfatal myocardial infarctions with enalapril versus nisoldipine (P=0.001).26 In both the Irbesartan in Diabetic Nephropathy Trial (IDNT) and the African-American Study of Kidney Disease (AASK), both trials of participants with renal insufficiency and proteinuria, the amlodipine group had worse renal outcomes than the ACE inhibitor or angiotensin receptor blocker group.23,27Elderly PatientsIn a meta-analysis, it was found that in untreated subjects who were ≥60 years of age, the SBP was a more accurate predictor of mortality and CV events than DBP. This result may be due to the increased arterial stiffness that occurs with aging, leading to a higher SBP and lower DBP, and suggests that antihypertensive therapy in the elderly should focus on SBP rather than DBP, or even concentrate on the difference between the two, ie, pulse pressure.28 This meta-analysis also confirmed earlier results showing that treatment of hypertension in the elderly significantly reduced the incidence of strokes and coronary heart disease, irrespective of the medication used.28,29 JNC VI recommends that diuretics be the first-line therapy in the elderly, and there has been no evidence since its publication that has shown newer agents to be more effective. Of note, a meta-analysis published in 1998 questioned the use of β-blockers in the elderly, citing evidence that, except in subjects with coronary artery disease, they did not reduce CV morbidity or mortality.30ConclusionWe presented an elderly man with probable essential hypertension. Assuming that his diagnosis of hypertension is confirmed, the benefits of controlling his BP to reduce both CV and renal disease risk are clear. It is important to identify other comorbidities that he may have, such as diabetes, renal disease, or evidence of TOD, because these will impact what his goal BP should be (Table 1), as well as which antihypertensive agents should be used (Table 2). For patients with coronary heart disease, β-blockers and ACE inhibitors are the first-line therapy, with the option of using a non-dihydropyridine CCB. For patients with nondiabetic renal disease, ACE inhibitors are the initial agent of choice. For patients with type 2 diabetes mellitus, ACE inhibitors reduce cardiovascular risk and ARBs reduce the risk of progression of renal disease in those with overt nephropathy. DHCCBs should not be used in these patients without the concomitant administration of either an ACE inhibitor or an ARB. Update and Modification of JNC VI List of Co-Morbid Conditions and Drugs That May Have Favorable Effects on Comorbid ConditionsConditionAgentCAD indicates coronary artery disease.Anginaβ-blocker, calcium antagonistType 1 diabetes with or without proteinuriaACE inhibitorType 2 diabetes with microalbuminuriaACE inhibitor or ARB, not dihydropyridine calcium antagonist aloneType 2 diabetes without proteinuriaACE inhibitor or ARB, not dihydropyridine calcium antagonist aloneType 2 diabetes with proteinuriaARB, not dihydropyridine calcium antagonists aloneHeart failureACE inhibitor, ARB, β-blocker, potassium-sparing diuretic (spironolactone)PregnancyLabetolol, methyldopa, calcium antagonistsPrior myocardial infarction or CADβ-blocker and ACE inhibitorsProstatismα-blocker (not used alone)Kidney insufficiency (nondiabetic)ACE inhibitor (ARB if ACEI not tolerated)FootnotesCorrespondence to George Bakris, MD, Rush Medical Center, 1700 W Van Buren St, Suite 470, Chicago, IL 60612. E-mail [email protected] References 1 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997; 157: 2413–2446.CrossrefMedlineGoogle Scholar2 Perloff D, Grim C, Flack J, et al. Human blood pressure determination by sphygmomanometry. Circulation. 1993; 88: 2460–2470.CrossrefMedlineGoogle Scholar3 Black H, Bakris G, Elliott W. Hypertension: epidemiology, pathophysiology, diagnosis, and treatment. In: Fuster V, Alexander R, O’Rourke R, eds. Hurst’s the Heart. New York, NY: McGraw-Hill; 2001:1553–1606.Google Scholar4 American Diabetes Association: clinical practice recommendations 2002. Diabetes Care. 2002; 25 (suppl 1): S1–S147.CrossrefMedlineGoogle Scholar5 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. 2000; 36: 646–661.CrossrefMedlineGoogle Scholar6 The Trials of Hypertension Prevention Collaborative Research Group. The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, phase I. JAMA. 1992; 267: 1213–1220.CrossrefMedlineGoogle Scholar7 The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: results of the Trials of Hypertension Prevention, phase II. Arch Intern Med. 1997; 157: 657–667.CrossrefMedlineGoogle Scholar8 Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study: final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993; 270: 713–724.CrossrefMedlineGoogle Scholar9 Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001; 344: 3–10.CrossrefMedlineGoogle Scholar10 Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA. 1998; 279: 839–846.CrossrefMedlineGoogle Scholar11 Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001; 358: 1305–1315.CrossrefMedlineGoogle Scholar12 Bakris GL. Maximizing cardiorenal benefit in the management of hypertension: achieve blood pressure goals. J Clin Hypertens (Greenwich). 1999; 1: 141–147.MedlineGoogle Scholar13 Multiple risk factor intervention trial: multiple risk factors changes and mortality results. 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Am J Cardiol. 1998; 82: 881–887.CrossrefMedlineGoogle Scholar21 Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data. Ann Intern Med. 2001; 135: 73–87.CrossrefMedlineGoogle Scholar22 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.CrossrefMedlineGoogle Scholar23 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. 2001; 345: 851–860.CrossrefMedlineGoogle Scholar24 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. 2001; 345: 861–869.CrossrefMedlineGoogle Scholar25 Bakris GL. Microalbuminuria. what is it? Why is it important? What should be done about it? J Clin Hypertens (Greenwich). 2001; 3: 99–102.CrossrefMedlineGoogle Scholar26 Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998; 338: 645–652.CrossrefMedlineGoogle Scholar27 Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001; 285: 2719–2728.CrossrefMedlineGoogle Scholar28 Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000; 355: 865–872.CrossrefMedlineGoogle Scholar29 Insua JT, Sacks HS, Lau TS, et al. Drug treatment of hypertension in the elderly: a meta-analysis. Ann Intern Med. 1994; 121: 355–362.CrossrefMedlineGoogle Scholar30 Messerli F, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? JAMA. 1998; 279: 1903–1907.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By SRILATHA L and KUMAR N (2022) A COMPLICATION OF THE TEMPORARY PACEMAKER AND ANTIHYPERTENSIVE MEDICATIONS MAY CAUSE HEART BLOCK IN TERTIARY CARE HOSPITAL, International Journal of Current Pharmaceutical Research, 10.22159/ijcpr.2022v14i1.44117, (87-89) Hutchinson B, Keane D and Dodd J (2013) Renal Sympathetic Denervation: MDCT Evaluation of the Renal Arteries, American Journal of Roentgenology, 10.2214/AJR.12.8560, 201:2, (W342-W346), Online publication date: 1-Aug-2013. Fusi F, Durante M, Sgaragli G, Cuong N, Dung P and Nam N (2013) 2-Aryl- and 2-amido-benzothiazoles as multifunctional vasodilators on rat artery preparations, European Journal of Pharmacology, 10.1016/j.ejphar.2013.05.034, 714:1-3, (178-187), Online publication date: 1-Aug-2013. Agarwal R, Porter M and Obeid G (2013) Common Medical Illnesses that Affect Anesthesia and Their Anesthetic Management, Oral and Maxillofacial Surgery Clinics of North America, 10.1016/j.coms.2013.03.001, 25:3, (407-438), Online publication date: 1-Aug-2013. Erbel R, Möhlenkamp S, Moebus S, Lehmann N and Jöckel K (2011) Reply, Journal of the American College of Cardiology, 10.1016/j.jacc.2011.02.076, 58:10, (1081-1083), Online publication date: 1-Aug-2011. Correia L and Rassi A (2011) Is Reclassification of Intermediate-Risk Subjects by Coronary Artery Calcium Scoring Clinically Useful?, Journal of the American College of Cardiology, 10.1016/j.jacc.2010.11.085, 58:10, (1081), Online publication date: 1-Aug-2011. Pramanik T, Sharma H, Mishra S, Mishra A, Prajapati R and Singh S (2009) Immediate Effect of Slow Pace Bhastrika Pranayama on Blood Pressure and Heart Rate , The Journal of Alternative and Complementary Medicine, 10.1089/acm.2008.0440, 15:3, (293-295), Online publication date: 1-Mar-2009. Ker J (2014) Hypertension and the kidney, South African Family Practice, 10.1080/20786204.2004.10873156, 46:10, (45-46), Online publication date: 1-Nov-2004. Zeltser D, Justo D, Halkin A, Rosso R, Ish-Shalom M, Hochenberg M and Viskin S (2004) Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug, Journal of the American College of Cardiology, 10.1016/j.jacc.2004.03.057, 44:1, (105-108), Online publication date: 1-Jul-2004. Dornbrook-Lavender K, Pieper J and Roth M (2016) Primary Prevention of Coronary Heart Disease in the Elderly, Annals of Pharmacotherapy, 10.1345/aph.1D025, 37:11, (1654-1663), Online publication date: 1-Nov-2003. Waybill M and Waybill P (2003) A Practical Approach to Hypertension in the 21st Century, Journal of Vascular and Interventional Radiology, 10.1097/01.RVI.0000083253.29749.2F, 14:8, (961-975), Online publication date: 1-Aug-2003. Pappadis S and Somers M (2003) Hypertension in adolescents: a review of diagnosis and management, Current Opinion in Pediatrics, 10.1097/00008480-200308000-00003, 15:4, (370-378), Online publication date: 1-Aug-2003. May 28, 2002Vol 105, Issue 21 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000017143.59204.AAPMID: 12034648 Originally publishedMay 28, 2002 Keywordsagingkidneydiabetes mellitusdrugscoronary diseasePDF download Advertisement

Review: Angiotensin-converting enzyme inhibitors reduce the progression of nondiabetic renal disease

Source Citation Jafar TH, Schmid CH, Landa M, et al., for the ACE Inhibition in Progressive Renal Disease Study Group. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001 Jul 17;135:73-87. 11453706 (All 2002 articles were reviewed for relevance, and abstracts were last revised in 2008.)

Review: angiotensin-converting enzyme inhibitors reduce the progression of non-diabetic renal disease

(2001) Ann Intern Med 135, 73. Jafar TH, Schmid CH, Landa M . , et al, for the ACE Inhibition in Progressive Renal Disease Study Group. . Angiotensin-converting enzyme inhibitors...

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease

Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

Summaries for patients. Using a type of blood pressure medicine, angiotensin-converting enzyme inhibitors, to prevent worsening of kidney disease unrelated to diabetes.

Summaries for Patients17 July 2001Using a Type of Blood Pressure Medicine, Angiotensin-Converting Enzyme Inhibitors, To Prevent Worsening of Kidney Disease Unrelated to DiabetesSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-135-2-200107170-00003 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Angiotensin-converting enzyme (ACE) inhibitors are a type of medication used to treat high blood pressure. The ACE inhibitors have clearly been shown to prevent worsening of kidney disease caused by diabetes. Some studies suggest that ACE inhibitors benefit nondiabetic people with kidney disease, while other studies do not. More than 350,000 people in the United States have end-stage kidney disease and require either dialysis, a procedure that filters the blood through an artificial kidney machine, several times a week, or a kidney transplant to stay alive. It is ... Author, Article, and Disclosure InformationAffiliations: The summary below is from the full report titled “Angiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease. A Meta-Analysis of Patient-Level Data.” It is in the 17 July 2001 issue of Annals of Internal Medicine (volume 135, pages 73-87). The authors are TH Jafar, CH Schmid, M Landa, I Giatras, R Toto, G Remuzzi, G Maschio, BM Brenner, A Kamper, P Zucchelli, G Becker, A Himmelmann, K Bannister, P Landais, S Shahinfar, PE de Jong, D de Zeeuw, J Lau, and AS Levey, for the ACE Inhibition in Progressive Renal Disease Study Group.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAngiotensin-Converting Enzyme Inhibitors and Progression of Nondiabetic Renal Disease Tazeen H. Jafar , Christopher H. Schmid , Marcia Landa , Ioannis Giatras , Robert Toto , Giuseppe Remuzzi , Giuseppe Maschio , Barry M. Brenner , Annelise Kamper , Pietro Zucchelli , Gavin Becker , Andres Himmelmann , Kym Bannister , Paul Landais , Shahnaz Shahinfar , Paul E. de Jong , Dick de Zeeuw , Joseph Lau , Andrew S. Levey , and Metrics Cited byDevelopment and Analyses of Evaluation Criteria for Meta-analysis-Relationship between Renin-Angiotensin System Inhibitor and Diabetes Mellitus-Pharmacological strategies for kidney function preservation: are there differences by ethnicity? 17 July 2001Volume 135, Issue 2Page: I-21KeywordsACE inhibitorsAngiotensin converting enzyme inhibitorBlood pressureKidneysMedical dialysisProteinsRenal diseasesRenal failureRenal transplantationUrine ePublished: 17 July 2001 Issue Published: 17 July 2001 Copyright & PermissionsCopyright © 2001 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.

To examine the efficacy of ACE inhibitors for treatment of nondiabetic renal disease. 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens including ACE inhibitors to the efficacy of regimens without ACE inhibitors in predominantly nondiabetic renal disease. Studies were identified by searching the MEDLINE database for English-language studies evaluating the effects of ACE inhibitors on renal disease in humans between May 1977 (when ACE inhibitors were approved for trials in humans) and September 1997. Data on 1860 nondiabetic patients were analyzed. Mean duration of follow-up was 2.2 years. Patients in the ACE inhibitor group had a greater mean decrease in systolic and diastolic blood pressure (4.5 mm Hg [95% CI, 3.0 to 6.1 mm Hg]) and 2.3 mm Hg [CI, 1.4 to 3.2 mm Hg], respectively) and urinary protein excretion (0.46 g/d [CI, 0.33 to 0.59 g/d]). After adjustment for patient and study characteristics at baseline and changes in systolic blood pressure and urinary protein excretion during follow-up, relative risks in the ACE inhibitor group were 0.69 (CI, 0.51 to 0.94) for end-stage renal disease and 0.70 (CI, 0.55 to 0.88) for the combined outcome of doubling of the baseline serum creatinine concentration or end-stage renal disease. Patients with greater urinary protein excretion at baseline benefited more from ACE inhibitor therapy (P = 0.03 and P = 0.001, respectively), but the data were inconclusive as to whether the benefit extended to patients with baseline urinary protein excretion less than 0.5 g/d. Antihypertensive regimens that include ACE inhibitors are more effective than regimens without ACE inhibitors in slowing the progression of nondiabetic renal disease. The beneficial effect of ACE inhibitors is mediated by factors in addition to decreasing blood pressure and urinary protein excretion and is greater in patients with proteinuria. Angiotensin-converting inhibitors are indicated for treatment of nondiabetic patients with chronic renal disease and proteinuria and, possibly, those without proteinuria.

The role of systemic hypertension in the progression of nondiabetic renal disease

A role for hypertension in the progression of renal disease has been convincingly shown in experimental animals only. In human studies, the relation between hypertension and progression is difficult to demonstrate due to several confounding factors: age, gender, race; the difficult choice of blood pressure (BP) parameters that correlate with progression; the abnormal circadian BP pattern; and the many non-hemodynamic factors of progression. An important role for hypertension in progressive nondiabetic renal disease has been suggested by observational studies and clinical trials originally intended to evaluate the effect of dietary protein restriction on progression. In addition, several studies, summarized by a recent meta-analysis, have shown that pharmacological agents which lower both BP and proteinuria, mainly the angiotensin-converting enzyme inhibitors (ACEI), significantly slow the rate of progression in these diseases. In this article we review the effect of lowering BP on the progression of nondiabetic chronic renal disease, the patient characteristics that are associated with a greater or lesser benefit of blood pressure reduction, and the choice of antihypertensive regimens associated with better outcomes in patients with renal disease. Lower levels of achieved BP are associated with a slower decline in renal function, both in patients with and without proteinuria. ACEI are effective BP lowering agents and are associated with better preservation of renal function as opposed to antihypertensive regimens without ACEI. This protective effect of ACEI is in addition to their BP and urine protein lowering effects. The protective effect of ACEI on renal function is more pronounced in patients with proteinuria. In patients with nondiabetic renal disease and proteinuria, the risk of progression can be minimized by lowering both BP and proteinuria. ACEI have an additional beneficial effect.

The role of systemic hypertension in the progression of nondiabetic renal disease

The role of systemic hypertension in the progression of nondiabetic renal disease

Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.

There is previously published evidence that male gender is associated with a more rapid rate of progression of nondiabetic chronic renal disease. However, some investigators have concluded that no such association exists. To help resolve this issue, a meta-analysis was performed using 68 studies that met defined criteria and contained a total of 11,345 patients to evaluate the effect of gender on the progression of nondiabetic chronic renal disease. The results indicate that men with chronic renal disease of various etiologies show a more rapid decline in renal function with time than do women.

Advances in hypertension management: update 1998.

This article briefly reviews some important issues in the management of hypertension recently published or presented in medical congresses. The main results of several large outcome clinical trials, such as the Systolic Hypertension in Europe (Syst-Eur) trial, Hypertension Optimal Treatment (HOT) study and the Captopril Prevention Project (CAPPP) study, are summarized. The results of several retrospective studies dealing with the risk of cancer associated with antihypertensive treatments are presented. Finally, the nephroprotective effects of angiotensin-converting enzyme inhibitors in the progression of nondiabetic renal disease and the controversy surrounding the cardiovascular risk associated with dihydropyridine calcium antagonists are discussed.

Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group.

The effect of angiotensin-converting enzyme (ACE) inhibitors in slowing the decline in renal function in nondiabetic renal disease varies among studies. To use meta-analysis to assess the effect of ACE inhibitors on the development of end-stage renal disease caused by factors other than diabetes. The English-language medical literature, identified by a MEDLINE search and unpublished studies. All randomized studies that compared ACE inhibitors with other antihypertensive agents and had at least 1 year of planned follow-up were selected. Studies of diabetic renal disease and renal transplants were excluded. A total of 1594 patients in 10 studies was included. Data on end-stage renal disease, death, drop out, and blood pressure were extracted. Study investigators confirmed results and provided additional data. Among 806 patients receiving ACE inhibitors, 52 (6.4%) developed end-stage renal disease and 17 (2.1%) died; in the 788 controls, the respective values were 72 (9.1%) and 12 (1.5%). The pooled relative risks were 0.70 (95% CI, 0.51 to 0.97) for end-stage renal disease and 1.24 (CI, 0.55 to 2.83) for death; the studies were not significantly heterogeneous. The decreases in weighted mean systolic and diastolic blood pressures during follow-up were 4.9 and 1.2 mm Hg greater, respectively, in the patients who received ACE inhibitors. Angiotensin-converting enzyme inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage nondiabetic renal disease, and they do not increase mortality. It could not be determined whether this beneficial effect is due to the greater decline in blood pressure or to other effects of ACE inhibition.

Enalapril slowed the progression of chronic renal failure in patients with progressive chronic nephropathy

TherapeuticsJanuary 1, 1993Enalapril slowed the progression of chronic renal failure in patients with progressive chronic nephropathyJeffrey S. Berns, MDJeffrey S. Berns, MDThe Graduate Hospital, Philadelphia, Pennsylvania, USA (J.S.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-1993-118-1-007 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail Source CitationKamper AL, Strandgaard S, Leyssac PP. Effect of enalapril on the progression of chronic renal failure. A randomized controlled trial. Am J Hypertens. 1992 Jul;5:423-30.References1 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, and the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Eng J Med. 1993;329:1456-62. Google Scholar2 Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal diseases: theory and practice. J Am Soc Nephrol. 1996;7:2025-43. Google Scholar3 Giatras I, Lau J, Levey AS, and the Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med. 1997;127:337-45. Google Scholar4 Masachio G, Alberti D, Janin G, et al., and the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of the antiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996;334:939-45. Google Scholar5 The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349:1857-63. Google Scholar6 Ichikawa I. Will angiotensin II receptor antagonists be renoprotective in humans? Kidney Int. 1996;50:684-92. Google Scholar Author, Article, and Disclosure InformationAffiliations: The Graduate Hospital, Philadelphia, Pennsylvania, USA (J.S.B.) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails January 1, 1993Volume 118, Issue 1Page: 7KeywordsACE inhibitorsBlood plasmaBlood pressureCreatinineDiabetes mellitusDrug therapyDrugsEnzymesEpidermal growth factorImmunosuppressivesMedical dialysisNephrologyOutpatient clinicsProteinuriaRenal arteriesRenal diseasesRenal failureStenosisUrinary tract infections ePublished: 9 March 2020 Issue Published: January 1, 1993 Copyright & PermissionsCopyright © 1993 by American College of Physicians. All Rights Reserved.Loading ...