Modifiable Risk Factor For Progression Research Articles

Multimodal Migraine Management and the Pursuit of Migraine Freedom: A Narrative Review.

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associated symptoms and others accepting the occasional migraine attack if it does not impact functioning. Therefore, migraine management should be optimized so that patients can have the best opportunity to achieve their optimal treatment goals. With migraine freedom as a goal and, given the complex pathophysiology of migraine and the high incidence of comorbidities among individuals with migraine, treatment with a single modality may be insufficient, as it may not achieve migraine freedom in those with more frequent or disabling attacks. In this clinical perspective article, we have identified four key, partially overlapping principles of multimodal migraine treatment: (1) manage common comorbidities; (2) control modifiable risk factors for progression by addressing medication and caffeine overuse; (3) diagnose and treat secondary causes of headache, if present; and (4) individualize acute and preventive treatments to minimize pain, functional disability, and allodynia. There are many barriers to pursuing migraine freedom, and strategies to overcome them should be optimized. Migraine freedom should be an aspirational goal both at the individual attack level and for the disease overall. We believe that a comprehensive and multimodal approach that addresses all barriers people with migraine face could move patients closer to migraine freedom.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Treatment of Hypertension, Resistant to Conventional Antihypertensives, in Patients on Maintenance Hemodialysis

Background: Hypertension (HTN) is present in up to 90% of end stage kidney disease (ESRD) patients irrespective of the etiology of their kidney disease. Moreover, it is an important modifiable risk factor for progression to ESRD and its overall cardiovascular morbidity and mortality. Objective: to evaluate, prospectively, the role of Renin-Angiotensin-Aldosterone System blockade (RAAS) in HTN, resistant to 3 conventional antihypertensives, in patients on maintenance hemodialysis (MHD). Patients and methods: A total of 52 such patients were treated with Ramipril and 5 with Losartan after intolerable cough/shortness of breath following Ramipril-use. None of the patients had fluid depletion, renal artery stenosis and primary endocrinopathy. The study group was compared to a matched control group of MHD patients with normal blood pressure following 3 drugs-combination therapies. Results: All patients, with resistant HTN, had significant activation of RAAS system prior to treatment compared to inactive one in the control group. In those with resistant HTN, control of HTN, was established within 2 weeks of therapy and was associated with suppression of the RAAS. Such therapy was associated with minor side effects. Conclusion: Our study has shown that RAAS blockade is safe and effective in controlling such resistant HTN in MHD patients.

Quantifying varus thrust in knee osteoarthritis using wearable inertial sensors: A proof of concept

BackgroundVarus thrust during walking, visualized as excessive frontal plane knee motion during weight acceptance, is a modifiable risk factor for progression of knee osteoarthritis. However, visual assessment does not capture thrust severity and quantification with optical motion capture is often not feasible. Inertial sensors may provide a convenient alternative to optical motion capture. This proof-of-concept study sought to compare wearable inertial sensors to optical motion capture for the quantification of varus thrust. MethodsTwenty-six participants with medial knee osteoarthritis underwent gait analysis at self-selected and fast speeds. Linear regression with generalized estimating equations assessed associations between peak knee adduction velocity or knee adduction excursion from optical motion capture and peak thigh or shank adduction velocity from two inertial sensors on the lower limb. Relationships between inertial measures and peak external knee adduction moment were assessed as a secondary aim. FindingsBoth thigh and shank inertial sensor measures were associated with the optical motion capture measures for both speeds (P < 0.001 to P = 0.020), with the thigh measures having less variability than the shank. After accounting for age, sex, body mass index, radiographic severity, and limb alignment, thigh adduction velocity was also associated with knee adduction moment at both speeds (both P < 0.001). InterpretationAn inertial sensor placed on the mid-thigh can quantify varus thrust in people with medial knee osteoarthritis without the need for optical motion capture. This single sensor may be useful for risk screening or evaluating the effects of interventions in large samples.

Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study.

Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease.

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.

Increased Blood Pressure and Body Mass Index as Potential Modifiable Factors in The Progression of Myocardial Dysfunction in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by progressive cardiomyopathy. Left ventricular (LV) function may worsen by factors increasing LV afterload such as hypertension and obesity. To identify potential modifiable risk factors for progression of cardiomyopathy in Duchenne muscular dystrophy (DMD). We retrospectively analysed systolic blood pressures (SBP) and body-mass indexes (BMI) from 273 visits of 65 DMD patients aged 4-18 years between 2003 and 2016, divided in 14 age groups. Values were normalized using Z-scores (Z-SBP and Z-BMI). A linear mixed model was used to analyse correlations between Z-SBP and BMI, steroid use, age, ambulatory status and cardiac medication (CM) use. To study the relationship between SBP and BMI and myocardial deformation prior to the onset of clinical cardiomyopathy, LV deformation, defined by global longitudinal strain (GLS), was quantified in a subset of 36 patients <11 years. Multiple linear regression was used to study the relation between GLS and clinical parameters. Median follow-up was 5 years. SBP was significantly elevated in all age groups under 14 years (p≤0.04) and 15-16 years (p = 0.033) and correlated positively with BMI (p = 0.001) and negatively with CM use over time (p = 0.018). Z-BMI followed a bell-shaped distribution and plotted approximately one standard deviation above the mean in patients between 7 and 15 years. In the subset of younger patients, reduced GLS was associated with higher BMI (β= 0.348, p = 0.004). SBP and BMI may be potentially modifiable factors to retard deterioration of LV function in DMD.

Anti-Atherogenic Properties of Cannabis Sativa

Hypertension is an established risk factor for subsequent cardiovascular and renal disease in children as well as adults. Sickle cell disease (SCD) is a genetic disorder associated with chronic hemolytic anemia with the major manifestation of vaso-occlusive crises. Although this disease entity involves most organ systems causing vascular and pulmonary injury, little is known about blood pressure (BP) levels or prevalence of hypertension in children with SCD. A cross-sectional study was conducted on 56 children with SCD (54 with hemoglobin SS disease; 2 with hemoglobin Sβ0 thalassemia; 29 females). Study participants underwent 24-hour ambulatory BP monitoring (ABPM). Serum creatinine and cystatin C were obtained to assess estimated glomerular filtration rate with age-based formulas. A random urine sample was obtained to estimate urine osmolality and urine albumin to creatinine ratio. Mean age range was 11.9 (±4.5) years. Seventeen participants (30%) met criteria for hypertension based on ABPM. Of the 17 participants classified with hypertension, three had office hypertension with ambulatory hypertension, and 14 had masked hypertension detected on ABPM. Another 28 participants (50%) had some abnormal ABPM parameters in the form of either prehypertension and/or lack of normal nocturnal dipping status. The prevalence of confirmed hypertension, largely manifest by masked hypertension, is high in children, as young as 6 years of age with SCD. Early identification of hypertension in SCD children can confer benefit as it is an important modifiable risk factor for progression of cardiovascular and renal disease.

Ambulatory hypertension in a pediatric cohort of sickle cell disease

Hypertension is an established risk factor for subsequent cardiovascular and renal disease in children as well as adults. Sickle cell disease (SCD) is a genetic disorder associated with chronic hemolytic anemia with the major manifestation of vaso-occlusive crises. Although this disease entity involves most organ systems causing vascular and pulmonary injury, little is known about blood pressure (BP) levels or prevalence of hypertension in children with SCD. A cross-sectional study was conducted on 56 children with SCD (54 with hemoglobin SS disease; 2 with hemoglobin Sβ0 thalassemia; 29 females). Study participants underwent 24-hour ambulatory BP monitoring (ABPM). Serum creatinine and cystatin C were obtained to assess estimated glomerular filtration rate with age-based formulas. A random urine sample was obtained to estimate urine osmolality and urine albumin to creatinine ratio. Mean age range was 11.9 (±4.5) years. Seventeen participants (30%) met criteria for hypertension based on ABPM. Of the 17 participants classified with hypertension, three had office hypertension with ambulatory hypertension, and 14 had masked hypertension detected on ABPM. Another 28 participants (50%) had some abnormal ABPM parameters in the form of either prehypertension and/or lack of normal nocturnal dipping status. The prevalence of confirmed hypertension, largely manifest by masked hypertension, is high in children, as young as 6 years of age with SCD. Early identification of hypertension in SCD children can confer benefit as it is an important modifiable risk factor for progression of cardiovascular and renal disease.

Ambulatory Hypertension in a Pediatric Cohort of Sickle Cell Disease

▪Background and Objectives: Hypertension is an established risk factor for subsequent cardiovascular and renal disease in children as well as adults. Sickle Cell Disease (SCD) is a genetic disorder associated with anemia with the major manifestation of vaso-occlusive crises. While this disease entity involves most organ systems causing vascular and pulmonary injury, little is known about blood pressure (BP) levels or prevalence of hypertension in children and adolescents with SCD.Methods: We enrolled 41 children with severe genotypes of SCD (39 with Hb SS disease and 2 with Hb Sβ0 thalassemia). Study participants underwent 24-hour ambulatory blood pressure monitoring (ABPM). Clinical information regarding duration of SCD, SCD-related complications, requirement for chronic blood transfusion and chronic hydroxyurea therapy were obtained. Baseline characteristics obtained on each participant included age, gender, weight, height, body mass index (BMI) percentile, BMI-Z score and clinic BP. Serum creatinine and cystatin C were obtained to assess estimated glomerular filtration rate (eGFR) with age-based formulas. A random urine sample was obtained for standard urinalysis, albumin and creatinine estimation, to calculate urine albumin to creatinine ratio.Results: Based on ABPM study results participants were categorized into three groups as normal ABPM, abnormal ABPM, or hypertension ABPM (ambulatory hypertension, masked hypertension or severe ambulatory hypertension). The term abnormal ABPM designated participants who did not have normal ABPM or hypertension, but had other abnormal parameters on ABPM (presence of pre-hypertension and/or lack of normal nocturnal dipping). SCD children in the three groups were similar with respect to distribution of age, BMI z-scores, renal function, urine albumin excretion, urine osmolality, hemoglobin, history of chronic blood transfusion, and hydroxyurea therapy. Twelve participants (29.3%) met criteria for hypertension based on ABPM. Of the 12 hypertensive participants, three had clinic hypertension with ambulatory hypertension; and nine had masked hypertension detected on ABPM. Youngest child with ABPM confirmed hypertension was six years of age. Another 18 participants (43.9%) had some abnormal ABPM parameters that were largely present in the sleep period of ABPM.Conclusions: Findings from our study indicate that BP abnormalities are not uncommon in SCD children. Overall, the distribution of confirmed hypertension, largely manifested by masked hypertension, is high in pediatric participants with SCD; as young as 6 years of age. The underlying cause for the relatively high prevalence of masked hypertension and abnormal ABPM parameters including absence of nocturnal BP dip in children with SCD is unclear. Based on our findings more attention should be given to monitoring and management of BP in children with SCD. Early identification of hypertension in SCD children can confer benefit because hypertension is an important modifiable risk factor for progression of cardiovascular and renal disease.Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Recognizing CADASIL: a Secondary Cause of Migraine with Aura.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities. Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4-11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038-47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016). CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development.

Glaucoma

The term, glaucoma, describes a group of conditions that are characterised by progressive optic nerve damage. Untreated glaucoma causes progressive visual field loss and eventually blindness. There are four main types: primary open angle glaucoma, acute angle closure glaucoma, secondary glaucoma, and congenital glaucoma. Primary open angle glaucoma is a common condition; it affects 2.1% of the UK population and is the second-most-common cause of blindness in the UK. Incidence and prevalence increase with age. Intraocular pressure is the only modifiable risk factor for progression of glaucoma; treatment to reduce intraocular pressure can prevent progression of optic nerve damage and preserve vision. Acute angle closure glaucoma is an ophthalmic emergency and prompt recognition and treatment of the condition is sight-saving. This article will discuss the aetiology, diagnosis and management of primary open angle and acute angle closure glaucoma, the role of GPs in supporting patients with glaucoma, and summarise the Driver and Vehicle Licensing Agency guidance relevant to these patients.

Is Body Mass Index Related to the Progression of Monoclonal Gammopathy of Unknown Significance to Multiple Myeloma?

Introduction: Multiple Myeloma (MM) is a hematologic malignancy that is universally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS). Obesity is the only known modifiable risk factor for the development of MM, though it is unclear if this is due to increased MGUS incidence or transition of MGUS to MM. In an effort to better understand how obesity may influence the progression of MGUS to MM, we analyzed patient data from the U.S. Veterans Health Administration (VHA).Methods: The VHA database was used to identify patients diagnosed with MGUS between October 1, 1999 and December 31, 2009 using ICD-9 code 273.1. Data was obtained on patient demographics, myeloma direct treatments, weight, height, and other clinical characteristics. Transition to MM was identified using two occurrences of ICD-9 code 203.0 or use of myeloma directed therapy within six months of a single use of ICD-9 code 203.0. Additionally, two investigators reviewed patient records to confirm the diagnosis and verify the diagnosis date. The World Health Organization (WHO) Body Mass Index (BMI) classification (normal-weight: 18.5≤BMI<25, overweight: 25≤BMI<30, and obese: BMI>30) was utilized to categorize BMI. Weight recorded closest to the MGUS diagnosis date was used for BMI calculations. Multivariate survival analysis (controlling for sex, race, BMI, marital status, estimated household income level, modified Charlson co-morbidity score, and creatinine level) was conducted by parametric accelerated failure time left-censored analysis with Weibull-modeled survival time.Results: There were 9,430 unique MGUS patients identified in the VHA database. Progression to MM was noted in 501 (5.3%) patients overall, with a frequency of 98/2139 (4.6%), 236/3932 (6.0%), and 167/3359 (5.0%) of the normal weight, overweight and obese BMI groups, respectively. Survival analysis revealed a statistically significant difference in progression from MGUS to MM in overweight and obese patients compared to normal-weight patients. After controlling for other variables, multivariate analysis demonstrated that obese (HR: 1.53; 95% CI 1.19-1.98) and overweight (HR: 1.45; 95% CI 1.14-1.84) patients were at increased risk of progression from MGUS to MM. Black patients (HR: 1.78; 95% CI 1.46-2.17) were also at increased risk of progression to MM.Conclusions: Patients with Monoclonal Gammopathy of Unknown Significance who are overweight or obese at the time of MGUS diagnosis are at increased risk of progression to Multiple Myeloma compared to normal weight counterparts. Also the data is suggestive that an obese BMI is associated with a higher risk of progression to MM compared to being overweight. Elevated BMI is a modifiable risk factor for progression of MGUS to MM and weight loss is a potential strategy to decrease the risk of progression. DisclosuresCarson:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding.

Epidemiological issues in diabetic retinopathy.

There is currently an epidemic of diabetes in the world, principally type 2 diabetes that is linked to changing lifestyle, obesity, and increasing age of the population. Latest estimates from the International Diabetes Federation (IDF) forecasts a rise from 366 million people worldwide to 552 million by 2030. Type 1 diabetes is more common in the Northern hemisphere with the highest rates in Finland and there is evidence of a rise in some central European countries, particularly in the younger children under 5 years of age. Modifiable risk factors for progression of diabetic retinopathy (DR) are blood glucose, blood pressure, serum lipids, and smoking. Nonmodifiable risk factors are duration, age, genetic predisposition, and ethnicity. Other risk factors are pregnancy, microaneurysm count in an eye, microaneurysm formation rate, and the presence of any DR in the second eye. DR, macular edema (ME), and proliferative DR (PDR) develop with increased duration of diabetes and the rates are dependent on the above risk factors. In one study of type 1 diabetes, the median individual risk for the development of early retinal changes was 9.1 years of diabetes duration. Another study reported the 25 year incidence of proliferative retinopathy among population-based cohort of type 1 patients with diabetes was 42.9%. In recent years, people with diabetes have lower rates of progression than historically to PDR and severe visual loss, which may reflect better control of glucose, blood pressure, and serum lipids, and earlier diagnosis.

Dietary Salt, Blood Pressure, and Microalbuminuria

The relationship between dietary salt, blood pressure, and risk for cardiovascular disease has been debated for decades. Microalbuminuria is a biomarker for both cardiovascular and kidney disease. The presence of microalbuminuria correlates directly with the risk for myocardial infarction and stroke and indicates individuals at risk for the development of progressive kidney disease. Since patients with the metabolic syndrome, diabetes, or chronic kidney disease often are blood pressure salt sensitive, and it is well known that increasing dietary salt may offset both the antihypertensive and antiproteinuric effects of renin-angiotensin system blocking drugs, physicians must consider increased salt intake as a potential modifiable risk factor for progression of chronic kidney disease and possibly even cardiovascular disease.

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