Epidemiology/Population Studies

Prevalence of Resistant Hypertension in the United States, 20032008

Stephen D. Persell
From the Division of General Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL. Correspondence to Stephen D. Persell, Division of General Internal Medicine, Northwestern University, 750 N Lake Shore Dr, 10th Floor, Chicago, IL 60611. E-mail spersell@nmff.org

The prevalence of resistant hypertension is unknown. Much previous knowledge comes from referral populations or clinical trial participants. Using data from the National Health and Nutrition Examination Survey from 2003 through 2008, nonpregnant adults with hypertension were classified as resistant if their blood pressure was 140/90 mm Hg and they reported using antihypertensive medications from 3 different drug classes or drugs from 4 antihypertensive drug classes regardless of blood pressure. Among US adults with hypertension, 8.9% (SE: 0.6%) met criteria for resistant hypertension. This represented 12.8% (SE: 0.9%) of the antihypertensive drugtreated population. Of all drug-treated adults whose hypertension was uncontrolled, 72.4% (SE: 1.6%) were taking drugs from <3 classes. Compared with those with controlled hypertension using 1 to 3 medication classes, adults with resistant hypertension were more likely to be older, to be non-Hispanic black, and to have higher body mass index (all P<0.001). They were more likely to have albuminuria, reduced renal function, and self-reported medical histories of coronary heart disease, heart failure, stroke, and diabetes mellitus (P<0.001). Most (85.6% [SE: 2.4%]) individuals with resistant hypertension used a diuretic. Of this group, 64.4% (SE: 3.2%) used the relatively weak thiazide diuretic hydrochlorothiazide. Although not rare, resistant hypertension is currently found in only a modest proportion of the hypertensive population. Among those classified here as resistant, inadequate diuretic therapy may be a modifiable therapeutic target. Cardiovascular diseases, diabetes mellitus, obesity, and renal dysfunction were all common in this population.
http://hyper.ahajournals.org/cgi/content/abstract/57/6/1076

Serum Fetuin-A Levels Are Associated with Vascular Calcifications and Predict Cardiovascular Events in Renal Transplant Recipients
1. Cline Marchal*,

2. 3. 4. 5. 6. 7. 8. 9. 10.

Georg Schlieper, Pauline Nguyen*, Thilo Krger, Emmanuel Coche, Annie Robert, Jorgen Floege, Eric Goffin*, Michel Jadoul*, Olivier Devuyst*

+ Author Affiliations 1. 2. Division of Nephrology and Department of Radiology, Cliniques Universitaires Saint-Luc, Universit catholique de Louvain Medical School, Brussels, Belgium; 3. Division of Nephrology, RWTH University Hospital Aachen, Aachen, Germany; and 4. Department of Epidemiology and biostatistics, Ecole de Sant Publique, Universit catholique de Louvain, Brussels, Belgium
*

1. Correspondence: Dr. O. Devuyst, Division of Nephrology, Cliniques Universitaires Saint-Luc, UCL Medical School, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: 32-2-764-5450; Fax: 32-2-764-5455; Email: olivier.devuyst@uclouvain.be

Abstract
Background and objectives Vascular calcifications predict cardiovascular disease, the major cause of death in renal transplant recipients (RTRs). We studied the determinants of fetuin-A, a potent circulating calcification inhibitor encoded by the AHSG gene, and tested its association with vascular calcifications and long-term survival and cardiovascular events (CVEs) in RTRs. Design, setting, participants, & measurements Two hundred seventy-seven prevalent RTRs from a single center were included. CVEs and deaths were prospectively recorded during a 5year follow-up. Results Independent determinants of lower serum fetuin-A levels were lower plasma cholesterol, the AHSG rs4918 G allele, and history of smoking. Low serum fetuin-A level was a determinant of aortic calcifications (assessed using spiral CT). Low fetuin-A levels (0.47 g/L, first quintile) were independently associated with CVEs and deaths (hazard ratio = 1.83; 95% confidence interval, 1.07 to 3.04). The association was confirmed for all-cause mortality, and the major adverse cardiovascular endpoints were analyzed separately. Patients with low fetuin-A and high high-sensitivity C-reactive protein (>4.36 mg/L, fourth quintile) levels had a 3.5-fold increased risk of all-cause mortality and CVEs. In the presence of inflammation, CVE-free survival was influenced by common variants in the AHSG gene.

Conclusions These data show that low fetuin-A levels are independently associated with aortic calcifications and a higher risk of CVEs and mortality. They support fetuin-A as a circulating biomarker able to identify RTRs at risk for vascular calcifications and CVEs.

Received July 18, 2010. Accepted December 13, 2010. Copyright 2011 by the American Society of Nephrology

Sleep-Disordered Breathing and Excessive Daytime Sleepiness in Chronic Kidney Disease and Hemodialysis
1. 2. 3. 4. 5. 6. Maria-Eleni Roumelioti*, Daniel J. Buysse, Mark H. Sanders, Patrick Strollo, Anne B. Newman, Mark L. Unruh*

+ Author Affiliations 1. Renal-Electrolyte Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and 2. Department of Psychiatry, 3. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and 4. Department of Epidemiology and Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
1. Correspondence: Dr. Maria-Eleni Roumelioti, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, 200 Lothrop Street, PUH C-1111, Pittsburgh, PA 15213. Phone: 412-647-2571; Fax: 412-647-4787; E-mail: meroumeliotou@gmail.com
*

Abstract
Background and objectives Sleep-disordered breathing (SDB) and excessive daytime sleepiness (EDS) are highly prevalent among hemodialysis (HD) patients. It is unclear to what extent SDB is associated with advanced chronic kidney disease (CKD; stages 4 to 5). This paper describes and compares the prevalence, severity, and patterns of SDB and EDS among patients with advanced CKD, HD-dependent patients, and community individuals without known renal disease. Design (model), setting, participants (peserta), & measurements (ukuran) Eighty-nine CKD and 75 HD patients were compared with 224 participants from the Sleep-Strategies

Concentrating on Risk Evaluation Sleep-SCORE study of sleep and cardiovascular risk. Participants had in-home unattended polysomnography for quantifying SDB. EDS was defined by a score 10 on the Epworth Sleepiness Scale. Results The sample had a median age 58.1 years, was predominantly male (57.4%) and white (62.5%), and had a median body mass index of 28.1 kg/m2. Controls and Sleep-SCORE Study CKD patients had significantly higher median total sleep time and sleep efficiency compared with HD patients. The adjusted odds of severe SDB were higher for CKD and HD groups compared with the controls. Nocturnal hypoxemia was significantly elevated in the HD group compared with the CKD group. There were similar proportions of participants with EDS between the controls (33%), the CKD patients (29.3%), and the HD patients (40.6%). Conclusions Severe SDB (predominantly obstructive) and EDS are common among advanced CKD and HD patients. EDS correlated modestly with severe SDB and its obstructive and mixed patterns in the HD group.

Original Articles

Control of Hypertension in Adults With Chronic Kidney Disease in the United States
Carmen A. Peralta; Leroi S. Hicks; Glenn M. Chertow; John Z. Ayanian; Eric Vittinghoff; Feng Lin; Michael G. Shlipak
From the General Internal Medicine Section (C.A.P., M.G.S.), San Francisco Veterans Affairs Medical Center, California; Division of Nephrology (C.A.P., G.M.C., M.G.S.), Department of Medicine, University of California San Francisco; Department of Epidemiology and Biostatistics (G.M.C., E.V., F.L., M.G.S.), University of California San Francisco; Division of General Internal Medicine (L.S.H., J.Z.A.), Brigham and Womens Hospital, Boston, Mass; and Department of Health Care Policy (L.S.H., J.Z.A.), Harvard Medical School, Boston, Mass. Correspondence to Carmen A. Peralta, MD, General Internal Medicine, Department of Veterans Affairs, Box 111A1, 4150 Clement St, San Francisco, CA 94121. E-mail Carmen.Peralta@med.va.gov

Although improved control of hypertension is known to attenuate progression of chronic kidney disease (CKD), little is known about the adequacy of hypertension treatment in adults with CKD in the United States. Using data from the Fourth National Health and Nutrition Survey, we assessed adherence to national hypertension guideline targets for patients with CKD (blood pressure <130/80 mm Hg), we assessed control of systolic (<130 mm Hg) and diastolic (<80 mm Hg) blood pressure, and we evaluated determinants of adequate blood pressure control. Presence of CKD was defined as glomerular filtration rate <60 mL/min per 1.73 m2 or presence of albuminuria (albumin:creatinine ratio >30 g/mg). Multivariable logistic regression with appropriate weights was used to determine predictors of inadequate hypertension control and related outcomes. Among 3213 participants with CKD, 37% had blood pressure <130/80 mm Hg (95% confidence interval [CI], 34.5% to 41.8%). Of those with inadequate blood pressure control, 59% (95% CI, 54% to 64%) had systolic >130 mm Hg, with diastolic 80 mm Hg, whereas only 7% (95% CI, 3.9 to 9.8%) had a diastolic pressure >80 mm Hg, with systolic blood

pressure 130 mm Hg. Non-Hispanic black race (odds ratio [OR], 2.4; 95% CI, 1.5 to 3.9), age >75 years (OR, 4.7; 95% CI, 2.7 to 8.2), and albuminuria (OR, 2.4; 95% CI, 1.4 to 4.1) were independently associated with inadequate blood pressure control. We conclude that control of hypertension is poor in participants with CKD and that lack of control is primarily attributable to systolic hypertension. Future guidelines and antihypertensive therapies for patients with CKD should target isolated systolic hypertension.

Correlates of Systolic Hypertension in Patients With Chronic Kidney Disease

Rajiv Agarwal; Martin J. Andersen
From the Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Ind. Correspondence to Rajiv Agarwal MD, Associate Professor of Medicine, Indiana University and VAMC, 1481 Wt 10th St, Indianapolis, IN 46202. E-mail ragarwal@iupui.edu

Hypertension in patients with chronic kidney disease (CKD) is predominantly systolic. The contribution of risk factors for hypertension to the overall systolic blood pressure (BP) is unknown. To study the relationship between risk factors for hypertension and systolic BP in patients with CKD, 232 veterans (mean age 67 years; 96% men; 20% black; 39% with diabetes mellitus; estimated glomerular filtration rate [GFR] 48 mL/min per 1.73 m2) had clinic (routine and standardized measurements) and out-of-clinic (home and 24-hour ambulatory) BPs recorded. In multivariate analysis, using 17 risk factors, the log of the urine protein/creatinine ratio was the strongest predictor of systolic BP regardless of the BP measurement technique. The strength of the relationship between proteinuria and systolic BP was in the order ambulatory > home > standardized clinic > routine clinic BP measurement. Other independent predictors were age, race, and number of antihypertensive drugs used, and the model fit was better for out-of-clinic than clinic BP recordings. Estimated GFR was not an independent predictor of systolic BP by any technique. Nocturnal dipping was associated with higher estimated GFR, higher serum albumin, younger age, and less proteinuria. Proteinuria is the most important correlate of systolic BP in older men, the strongest relationship of which was with ambulatory and home systolic BP. Outof-clinic BP recordings correlate better with target organ damage, as measured by proteinuria, and may be of greater clinical value than clinic BP recordings in predicting hypertension-related outcomes such as end-stage renal disease and death. High blood pressure (hypertension) can be related to chronic kidney disease (CKD) in a number of ways. Hypertension can independently cause CKD, contribute to its development in the setting of other potential causes or even be the result of CKD, as is the case in patients with polycystic kidney disease. Regardless of the circumstances, hypertension is present in approximately 80 percent of patients with CKD. Studies show that as kidney function worsens the likelihood that a patient will have hypertension increases. Furthermore, as in patients without kidney disease, the risk of having hypertension in CKD patients is increased with advancing age, higher body weight and in African Americans.

The relationship between CKD and hypertension can be explained by several factors. CKD can lead to salt retention and subsequent volume overload. This may or may not be accompanied by swelling (edema) along with increased blood pressure. In addition, failing kidneys appear to trigger increased activity of the sympathetic nervous system, causing something like an adrenaline surge. More advanced CKD can also lead to low blood count or anemia. The treatment may help to produce hypertension, depending on the resultant rise in the blood count. Hormonal mechanisms also play an important role in the link between CKD and hypertension, primarily via the renin-angiotensin system. These hormones can be released in response to chronic damage and scarring of the kidneys, and can contribute to a patients hypertension by stimulating both salt retention, as well as constriction of blood vessels. Fortunately, medications known as angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) now exist to help us try to control these undesirable actions. Another hormone that may raise blood pressure and has increased quantities with advancing CKD is the parathyroid hormone (PTH). The PTH raises calcium in the blood, which can also cause tightening of the blood vessels, resulting in hypertension. Again, this effect can be at least partly regulated by medication, such as vitamin D, that lowers the PTH level. A condition that can lead to CKD and hypertension is renal artery stenosis (tightening of the blood vessels supporting the kidneys). When narrowing becomes severe enough, the lack of blood flow can cause a loss of kidney function. If the blood supply to both kidneys is affected, or blood flow to a single functioning kidney, such as following the removal of a kidney due to cancer, is compromised, a patient will develop CKD. This reduction in blood flow triggers the renin-angiotensin system, causing hypertension. In cases of progressive kidney failure and/or uncontrollable hypertension, it may be worthwhile to consider a procedure to open the diseased blood vessel. However, these procedures can carry some risk and may not always achieve their goals. Therefore, they should be undertaken with caution and only after thorough discussion of risks and benefits with a kidney specialist. Why is it important to control blood pressure once a patient has CKD? The answer is two-fold. First, study after study has shown better blood pressure control slows progression of CKD, thereby making it less likely a patient will require dialysis. Second, patients with CKD are more likely to die of cardiovascular disease than they are to require dialysis. In other words, lowering blood pressure will reduce the risk of heart disease, which for most patients with CKD, is more of an immediate threat than end-stage renal disease (ESRD). Blood pressure goals for patients with CKD have been debated for years and are constantly in flux. One of the determining factors is the amount of protein a patient loses in his/her urine. Patients that lose a significant amount of protein in the urine are at somewhat higher risk, both for progressive kidney disease and heart disease. Currently, guidelines support a goal blood pressure less than 130/80 for all patients with CKD and less than 125/75 for those patients losing more than one gram of protein in the urine per day. Treatment for hypertension in CKD patients can be divided into two categories: nonpharmacological and pharmacological. Neither is more important than the other. Medications

are certainly essential in the treatment of hypertension, especially in CKD, but there are lifestyle changes patients can make that may have a just as profound impact on their blood pressure and general health. Weight loss of as little as eight to 10 pounds can have a dramatic impact on blood pressure. Exercise must be an integral part of any successful weight loss program. Excessive alcohol intake is a clear risk factor for hypertension, and blood pressure can often be lowered without medication merely by reducing consumption of alcohol. The role of elevated salt intake as a risk for hypertension has been controversial, but it is likely that certain populations, such as the elderly, African Americans and patients with CKD, benefit from sodium restriction. Pharmacological therapy of hypertension is a subject that occupies entire textbooks. As new studies are released each year, the recommendations change to use the most desirable drug or combination of drugs. One now indisputable finding is most patients with CKD require more than one medication to achieve adequate control of blood pressure. Two classes of medications have now emerged as leaders in hypertension treatment of CKD patients. They are the ACE inhibitors and ARBs. These medications counteract effects of the renin-angiotensin system. They have been shown to slow the progression of kidney disease in patients with and without diabetes. While especially effective in reducing protein loss in the urine, they will preserve kidney function even in patients that do not lose protein. They can even reduce the risk of death of patients already on dialysis, independent of their effects on blood pressure. Other classes of medications are also very useful. Diuretics can eliminate salt excess and reduce volume overload, which can be a key component of hypertension in CKD. Beta-blockers work by stifling the adrenaline surge in CKD patients, helping reduce the risk of progressive kidney and heart disease. Calcium channel blockers are effective in patients with volume overload and can reduce protein loss in some patients. Regardless of the medications or nonpharmacological methods used, evidence provides hope and motivation in showing that by achieving the recommended blood pressure goals, CKD patients can reduce their risk of needing dialysis or experiencing an adverse cardiovascular event, such as a heart attack or stroke.

Hypertension and chronic kidney disease: the role of lifestyle modification and medication management.
Publication: Nephrology Nursing Journal Publication Date: 01-JAN-10 Format: Online Delivery: Immediate Online Access

Full Article Title: Hypertension and chronic kidney disease: the role of lifestyle modification and medication management.(Disease/Disorder overview)

Article Excerpt According to recent estimates by the American Heart Association, one in three U.S. adults has high blood pressure (Appel et al., 2006). Approximately 50 million individuals in the U.S. and

one billion individuals worldwide have hypertension (Appel et al., 2006). Incidence rates are a direct result of missed diagnosis due to hypertension having few accompanying symptoms. Despite the high incidence, only one-third of patients are actually treated to a goal blood pressure (Alexander, 2006). Reasons for this may vary but can include ineffective patient teaching, lack of understanding, poor lifestyle modifications, sub-optimal treatment adherence, limited access to health care, or failure of healthcare providers to treat hypertension aggressively. The specific physiologic cause of an individual's high blood pressure can also be unknown. Potential factors can include race (higher incidence in African Americans), age (hypertension increases with age), obesity, lack of exercise, excessive alcohol use, high dietary salt intake, oral contraceptives, gender, family history, and other diseases, such as chronic kidney disease (CKD) (Alexander, 2006). An estimated 26 million Americans (one of every six adults) live with CKD. (Burrows & Muller, 2007). High-risk groups include those with diabetes mellitus, hypertension, and family history of kidney disease. The prevalence of CKD is particularly high in older adults, and these patients are often at an increased risk for cardiovascular disease (CVD) (Schiffrin, Lipman, & Mann, 2007). The relationship between CKD, cardiovascular disease, and hypertension suggests a need for enhanced understanding of hypertension, the relationship between hypertension and CKD, as well as modifiable lifestyle behaviors. The American Heart Association recognizes patients with CKD as having the highest risk for developing cardiovascular disease. The majority of patients with CKD progress slowly to end stage renal disease (ESRD), and hypertension often plays a role in this pathogenesis (Kalra, 2007). To reduce the increasing medical and economic burden of CKD, therapeutic strategies that slow or prevent the onset and progression of renal disease must be implemented in patients at high risk for renal disease and those already displaying symptoms of early disease (Wenzel, 2005). Hypertension and CKD To clearly understand the effects of hypertension associated with CKD and examine ways to address these effects, it is essential to first understand the pathophysiology. The following discussion presents the types of hypertension, pathophysiology of hypertensive renal damage, diagnostic testing, and adverse effects of CKD. Hypertension Defined The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) describes the relationship between blood pressure and CVD as continuous, consistent, and independent of other risk factors (Chobanian et al., 2003). The authors of the JNC 7 also clearly identify a relationship between increasing blood pressure elevations and greater risk for myocardial infarct, heart failure, stroke, and kidney disease. JNC 7 identifies individuals with a systolic blood pressure of 120 to 139 mmHg or a diastolic blood pressure of 80 to 89 as pre-hypertensive requiring health-promoting lifestyle modifications (Chobanian et al., 2003). Persons older than 50 years of age with a systolic blood pressure greater than 140 mmHg have an increased risk for CVD regardless of diastolic blood pressure (Chobanian et al., 2003). Most patients with hypertension will require two or more antihypertensive medications to achieve a goal blood pressure (less than 120/80 mmHg or less

than 130/80 mmHg for patients with diabetes or CKD (Thomas & Atkins, 2006). Types of Hypertension Two forms of high blood pressure have been identified, including essential (or primary) hypertension and secondary hypertension. Essential hypertension is more commonly diagnosed, accounting for 95% of hypertension cases, and is often multifactorial (Chobanian et al, 2003). Secondary hypertension accounts for 5% of hypertension and is the result of a secondary abnormality in an organ or system of the body, such as the kidneys (Chobanian et al, 2003). Patients with CKD can have essential (primary) hypertension, secondary hypertension, or both. Researchers have shown that essential hypertension can cause or mediate kidney damage (essential hypertension) (Hagberg, Montain, Martin, & Ehsani, 1989), but inversely, kidney disease caused by another factor, such as diabetes mellitus, can also lead to secondary hypertension. In most cases, there is a clear relationship between the incidence of hypertension and the degree of renal impairment. When patients reach ESRD, about 80% to 90% are hypertensive (Kalra, 2007). Risk of CKD increases with the extent and duration of continuous high blood pressure. Pathophysiology of Hypertensive Renal Damage Renal damage involves mediators from extracellular systems, including activation of the reninangiotensin system (RAS) (Wenzel, 2005). Damage is further mediated through the activation of the sympathetic nervous system (SNS). This can occur when renal function is only slightly impaired. Hypertension associated with renal failure can be related to an increase in plasma volume and increased peripheral vascular resistance. Researchers have suggested that the increase in peripheral vascular resistance is due to anatomical changes, transport defects, and altered baroreceptor or hormonal responses (St. Peter, Clark, & Levos, 1998). The progression of renal damage is measured by a decrease in the glomerular filtration rate (GFR) or an increase in the serum creatinine level. Systemic hypertension can be transmitted to the glomerulus, causing hyper-perfusion, increased glomerular capillary pressure, and damage to endothelial cells with activation of platelets and interglomerular coagulation (Burke, 1994). The effects of systemic hypertension on the glomerulus causes altered glomerular stability, leading to an even higher blood pressure in the gomerulus, which can eventually lead to irreversible kidney damage. Diagnostic Testing Hypertension is common among patients with CKD, and prevalence has been shown to increase as a patient's GFR decreases (Burrows & Muller, 2007). The Modification of Diet in Renal Disease (MDRD) Study showed that the prevalence of hypertension rose from 65% to 95% as the GFR declined from 85 to 15 ml/min/1.73[m.sup.2] (Buckalew et al., 1996). The authors of this study showed that patients who did not have diabetes mellitus but who had proteinuria had greater renal protection with a blood pressure of 125/75, as compared to previously targeted blood pressures less than 140/90 (Buckalew et al., 1996). A decline in GFR can be delayed when proteinuria is decreased through the use of antihypertensive therapy. Protection of renal function

has been shown to be dependent on the extent of initial proteinuria (Wenzel, 2005). It is important to note that GFR decreases with age. This has led some practitioners to believe that equations used to calculate GFR result in over-diagnosing CKD (Dukkipati, Adler, & Mehrotra, 2008). In the U.S., most commercial and hospital laboratories routinely use the four-variable MDRD Study equation to report estimated GFR, including age, sex, serum creatinine, and race. There are five stages used to identify CKD as shown in Table 1. Adverse Effects of CKD The two main outcomes that can adversely affect a patient with CKD are loss of kidney function (requiring renal replacement therapy) and cardiovascular disease. CVD is the most common mediator of death in patients with ESRD resulting from CKD (Burrows & Muller, 2007). Both the loss of kidney function and CVD can further be complicated by the presence of hypertension. CKD promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Hypertension, dyslipidemia, and diabetes mellitus are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis (Schiffrin et al., 2007). Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in CKD (Schifffin et al., 2007). Promoters of calcification are increased, and inhibitors of calcification are reduced, leading to the development of metastatic vascular calcification, an important participant in vascular injury. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease (Schiffrin et al., 2007). Management of Hypertension Associated with CKD As discussed previously, hypertension is closely linked to CKD. Studies focusing on hypertension and CKD have shown that optimal blood pressure control can slow the progression of renal function impairment, regardless of the underlying kidney disease (Kalra, 2007). Data from the National Health and Nutrition Examination Survey (2000) showed that 58% of patients were receiving treatment, and 29% of individuals with a diagnosis of hypertension were within goal limits (Centers for Disease Control and Prevention [CDC], 2002). This means that of the 58% receiving treatment, 19% were not at a goal blood pressure and were at risk for renal function impairment. Reasons for poor blood pressure control vary, but potentiating causes include failure of practitioners to treat aggressively, the medical community's acceptance of blood pressures above goal limits, and lack of patient awareness (Alexander, 2006). Hypertension treatment that promotes renal protection should focus on an individual's age, race, socioeconomic situation, and any interrelated conditions or familial history. Patient understanding, lack of adequate education, and poor adherence may also play a role in blood pressure management. For these reasons, an examination of lifestyle modifications, medication management, and the role of healthcare providers will be included. Lifestyle Modifications Blood pressure and CKD management rely heavily upon the patient's ability to self-manage and willingness to change or maintain health-promoting behaviors. Weight loss, sodium restriction, fluid restriction, exercise, and limitation of alcohol intake appear to offer the greatest benefit in

reducing the incidence of hypertension (Miller, 2003). As previously discussed, decreasing the incidence of hypertension can slow the progression of renal function impairment. In addition, obesity accounts for three times greater risk for developing hypertension (Grubbs & Sica, 2007). Research has shown that a decrease in weight by 10 pounds can decrease blood pressure in normal and hypertensive individuals (Grubbs & Sica, 2007; Hagberg et al., 1989). The Intersalt Cooperative Research Study, which measured urinary sodium in over 10,000 individuals from 32 countries, found that consumption of greater than 100 mmol/day of sodium was associated with significantly higher blood pressures (Miller, 2003). Sodium restriction is also a crucial component to dietary intake for patents with CKD. The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to produce the most benefit in blood pressure reduction through sodium restriction and weight loss, and can also decrease LDL cholesterol. The DASH diet is a result of a feeding study of 459 adults (49% women, 60% African American) with high normal or elevated blood pressure. Alcohol intake contributes to high blood pressure by increasing both systolic and diastolic blood pressure (Thomas & Atkins, 2006). Elevations in either can directly affect the kidneys and renal arteries, which may produce acute or chronic renal failure. Evidence suggests that a reduction in alcohol intake by individuals with normal blood pressure or high normal blood pressure may help prevent hypertension (Miller, 2003). Recommendations suggest no more than one drink per day in women and two drinks per day in men to reduce overall cardiovascular risk (Miller, 2003). Recommendations also call for moderate intensity exercise for at least 30 minutes most days of the week. Hagberg and colleagues (1989) found that walking produces positive effects on CVD risks and blood pressure, both of which have been identified as mortality risks with CKD. Their research showed that men and women with a mean age of 64 years who were involved in a home walking program three times per week for at least one hour each walk had a decrease in blood pressure by 20/11 mmHg. Medication Management Multiple antihypertensive drug classes have been shown to reduce blood pressure as well as provide renal protection by decreasing systemic blood pressure and reducing the effects of intrarenal damage (Wenzel, 2005). The JNC 7 recommends initiating treatment with two antihypertensive agents if systolic blood pressure is greater than 20 mmHg or diastolic blood pressure is greater than 10 mmHg above goal (or greater than 150 mmHg systolic and greater than 90 mmHg diastolic) (Chobanian et al., 2003). Most patients with uncomplicated hypertension require treatment with at least two antihypertensive medications to achieve blood pressure goal, as demonstrated by the Hypertension Optimal Treatment (HOT) trial, the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial. A fixed dose antihypertensive therapy is acceptable for patients who qualify for two-drug therapy at the start of treatment (Andrews & Gibbs, 2002). Fixed-dose combinations medications have been proven safe and cost effective for the management of hypertension (Andrews & Gibbs, 2002). Current guidelines, such as those from the JNC-7, recommend achieving adequate blood pressure control by inhibiting the renin-angiotensin axis (Rahman et al., 2006). Some studies have shown agents targeted at decreasing efferent arteriolar tone, such as those that block the renin-

angiotensin system, may be more useful in preventing renal injury, when compared with blood pressure reduction without changes in glomerular capillary pressure (Thomas & Atkins, 2006). The hypertensive guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI) recommend ACE inhibitors or angiotensin-receptor blockers as the preferred agents in diabetic kidney disease and in patients with kidney disease who do not have diabetes mellitus and who have a urine spot total protein to creatinine ratio greater than 200 mg/g (National Kidney Foundation [NKF], 2002). Ironically, the most important adverse effect of ACE inhibitors and angiotensin-receptor blockers in patients with ESRD is an increase in serum creatinine. Patients with a baseline serum creatinine greater than 3 mg/dL should be administered ACE inhibitors with extreme caution (Andrews & Gibbs, 2002). The effectiveness of ACE inhibitors appears to be higher than that of other agents with a similar decrease in blood pressure reduction, although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction regardless of drug choice (Thomas & Atkins, 2006). The study by Lewis, Hunsicker, Bain, and Rohde (1993) examined treatment with captopril (an ACE inhibitor)...

From the viewpoint of hemorheology, it states that patients with chronic kidney disease (hereinafter called CKD) have an elevation in plasma viscosity, blood viscosity, and the content of fibrin and the aggregation of thrombocyte get revved up. These phenomena are the main reason to trigger ischemia and necrosis. 1.Infections are one of the main inductions to CKD, such as Pharyngitis and Tonsillitis etc. Meanwhile, cold is the most prevalent infection to trigger and aggravate chronic kidney disease. 2. Severe surroundings such as wind and dampness can decrease human bodys immunity and disease-resistant ability. 3. Excessive fatigue result in the decline of human immunity, which can develop into CKD over time. 4. Long-term suppressing urine not only damages bladder, but urine retention in bladder can facilitate bacteria reproduction. Once these bacteria go backward to ureter or kidney, these toxic substances can infect kidney so that urinary infection, kidney disease and even uremia emerge. 5. There are numerous CKD cases which are caused by taking medicine blindly. Many medicines for treating cold and defeating inflammation, pain-killer, diet pill and Chinese herbal medicine belongs to nephrotoxic medicines. They are very common and widely used. Patients are readily to be in danger if they have no medical knowledge about these medicines. 6. Kidney is more likely to happen if excessive salt are absorbed. The main content of salt is Nacl. As we know, Na+ is an essential mineral for human body, and Cl- is necessary to produce

gastric acid and sustain blood osmotic pressure of human body. However, excessive Na+ can make water retention in human body so that edema takes place. Moreover it can increase blood volume and small arteries tension so that elevated blood pressure occurs in patients. Therefore, people who takes more salt is more likely to have a high incidence of hypertension. Hypertension is readily to cause Nephropathy.

Molecular Mechanism for Elevation of Asymmetric Dimethylarginine and Its Role for Hypertension in Chronic Kidney Disease
Kyoko Matsuguma*, Seiji Ueda*, Sho-ichi Yamagishi, Yuriko Matsumoto*, Utako Kaneyuki*, Ryo Shibata*, Toshiko Fujimura*, Hidehiro Matsuoka, Masumi Kimoto, Seiya Kato, Tsutomu Imaizumi and Seiya Okuda*
*

Division of Nephrology; Division of Cardiovascular Medicine, Department of Medicine; Department of Pathology, Kurume University, School of Medicine, Kurume, Japan; and Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Japan

Address correspondence to: Dr. Seiji Ueda, Division of Nephrology, Department of Medicine, Kurume University, School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. Phone: +81-942-31-7002; Fax: +81-942-31-7763; E-mail: ueda@med.kurume-u.ac.jp

Received for publication December 29, 2005. Accepted for publication May 17, 2006. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcriptionPCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.
http://jasn.asnjournals.org/content/17/8/2176.short JASN journal of the American Society of Nephrology Detecting kidney disease

Chronic Kidney Disease appears in five stages, ranging from an early stage with little obvious effect to a final stage where the patient is on life-saving dialysis or awaiting a transplant. Each stage has certain characteristics and means of detection. The more that people know the various signs and effects of being in each stage, the sooner they may get a proper diagnosis from their doctor. Early detection is the best key to effective treatment. Stage One leaves the patient with 90% kidney function. The person can survive at this level, but its still necessary to detect the problem so causes and treatments can be addressed. If they dont take steps at this point, the disease is very likely to progress to the next level. Stage Two leaves only 60-89% kidney function, as the damage to these organs has increased.

The difficulty is that there are no obvious symptoms of kidney dysfunction at either stage. This may lead to a lack of detection at a crucial time when the disease could have been nipped in the bud, or curtailed before it got much worse. So its essential that the person have their regular yearly physical checkups, including urine tests and extensive blood work. Even with no other physical symptoms, these tests can detect: 1. elevated creatinine levels (which indicate how well the kidneys are filtering out wastes) 2. elevated protein levels (another indication of inefficiency in filtering wastes) 3. elevated blood urea nitrogen levels (kidneys take urea from the blood and expel it in the urine, but if the blood levels are high, this is another hint of failing kidneys) In addition to the potential for early detection with blood and urine tests, high blood pressure is a well known hint of problems with kidney function. The most often mentioned symptom is high blood pressure, which can either cause kidney disease, or be caused by it. So if a persons blood pressure rises, this can be a spur to doing the urine and blood tests, either to detect kidney disease or rule it out. And all steps (medication, exercise, alterations in diet) must be taken to bring the blood pressure down. If blood and urine tests indicate a possible problem, doctors can go further and take a kidney biopsy, do a CT scan, or perform an MRI. So even at these early stages, while its more difficult, its still possible to detect incipient kidney disease. What it takes is vigilance, and thorough, regular checkups. This entry was posted in Detecting Kidney Disease, Kidney Disease Symptoms. Bookmark the permalink. II. Weve discussed Stages One and Two of kidney disease, and what to look for, to get ones condition diagnosed as quickly as possible. But as many people learn to their distress, the first two stages of this disease are not easily detected unless one looks and watches very carefully. The first clearly noticeable symptoms finally reveal themselves as the disease reaches Stage Three, when already the person has less than 60% kidney function remaining, and may have as little as 30%. Yet even then, the symptoms can often be mistaken for something else. People can go on for a long time with such reduced kidney function, because some of the initial symptoms tiredness and changes of appetite are so vague that they could be caused by many other things. But when they are combined with other symptoms like itching, water

retention, and anemia, this is when the pieces slowly fall into place. As the kidneys become less able to filter fluids and remove them from the body, more fluids are retained, and the person may experience swelling and puffiness. Even their urine may become more clear, because fewer impurities are being excreted. Naturally this contributes to higher blood pressure. But the blood itself becomes more anemic, because its when the kidney releases the hormone erythropoietin (EPO) that red blood cells can be created. When the kidney cant release as much EPO as its supposed to, the blood cell count goes lower and the patient becomes more anemic. In turn, the blood carries less oxygen and the body has to work harder in order to function. As a result, the person experiences greater and greater fatigue. At this stage, the patient absolutely must take steps to reduce sodium in the diet and bring the blood pressure down. The higher the pressure, the more damage to vein walls, and the more damage to veins in the kidneys, the worse kidney function becomes. Adjustments must also be made to other elements of diet: protein will need to be reduced, though the patient cant live completely without it. Patients may also need to take a phosphorus binder and vitamins that help boost kidney function. Working on these things with a knowledgeable dietitian is essential. Even if earlier stages have been missed and the person has advanced well into Stage Three, its vital to get diagnosed as early as possible, to preserve what kidney function is left and prevent the disease from progressing any further. This entry was posted in Detecting Kidney Disease, Kidney Disease Symptoms and tagged kidney disease, stage three. Bookmark the permalink.
III. which stimulates blood cell production, so anemia is another problem.

At Stage Four, a cascade of effects may produce other effects, all of which contribute to an increasing weakness and a worsening of symptoms. As the kidneys become less able to filter phosphate, the levels of that electrolyte increase. In turn, this makes it more difficult for the body to absorb calcium. And since its the proper interaction of phosphorous and calcium that strengthens bones, bone density itself may gradually decrease. This may produce aching in the bones, but it also leaves the person more prone to fractures, which take longer than usual to heal.

Treatments at this stage are many. Blood pressure is often treated with diuretics, though some of these can play havoc with potassium levels. Anemia can usually be successfully counteracted with drugs resembling erythopoietin. Medications may prevent bone disease, and much of the phosphorous/calcium imbalance can be reduced with diet. But these are generally stop-gap measures. This is the stage where the patient begins heading in the direction of dialysis, and starts receiving consideration for a possible transplant. While the effects of Stage Four can be mitigated to some extent, the fact remains that the kidneys are so seriously diseased that the body cant go on forever like this. Again, it is extremely important to take good, thorough stock of ones complete health every few months. The symptoms of kidney disease are easy to miss, in the stages when a person might do something about it. This entry was posted in Detecting Kidney Disease, Kidney Disease Symptoms and tagged kidney disease, stage four, symptoms, treatments. Bookmark the permalink.

Potassium and Sodium form another electrolyte pair that relate to each other and face connected problems when affected by kidney disease. First of all, these two chemicals form a specific balance of fluids inside and outside of the cells of the body. Potassium is highly concentrated inside cells, while sodium is more highly concentrated outside. While sodium regulates fluid levels throughout the body itself, the sodium-potassium insideoutside chemical balance of the cells is very important. This balance creates an electrically charged potential at the cell membrane. And its this electrical potential that is crucial to such things as heart function, muscle contraction, and the transmission of nerve impulses. If these

chemicals are thrown out of balance, its clear that people could suffer anything from heart problems to weak muscles or even nerve problems. The kidneys serve a vital function in keeping these electrolytes balanced, excreting excess amounts so the body stays regulated. But what happens if there is more of a particular chemical in the body than the kidney can possibly eliminate? We see this question coming more and more to the forefront as the North American diet, in particular, is increasingly swamped with sodium. Excess sodium can lead to fluid retention, high blood pressure, and kidneys that become so overworked that they start to falter or even fail.

The Cardio Renal Continuum

What is the cardio-renal continuum?

The concept of the cardiovascular continuum, a progressive chain of pathophysiological events from cardiovascular risk factors through to cardiovascular disease, was developed in the 1990s. It is now apparent that changes occurring in the cardiovascular system are intimately linked with changes in the renal system, with deteriorations in either system having an effect on the other. This is known as the cardio-renal continuum.

The concept of the cardio-renal continuum proposes that cardiovascular and renal disease reinforce each other, with deteriorations in either system having an effect on the other. As the early stages of the cardio-renal continuum are not associated with symptoms, the early assessment of respective risk factors (e.g. dyslipidaemia, hypertension, diabetes, visceral obesity, smoking) is important. One major risk factor contributing to the cardio-renal continuum is diabetes, which itself shares risk factors with both cardiovascular and renal disease. Diabetes is the leading cause of chronic kidney disease and end stage renal disease (ESRD). In patients with type 2 diabetes, cardiovascular disease is the most common cause of death, and is 10-20 times more common in people with diabetes than in the general population. The interrelated nature of the different elements of the cardio-renal continuum also has implications for treatment strategies. Intensified, multifactorial treatment targeted at hyperglycaemia, hypertension and dyslipidaemia can lower the risk of both cardiovascular and renal disease.1,21. Gaede P, et al. N Engl J Med. 2003; 30:383-93. 2. Gaede P, et al. N Engl J Med. 2008; 358(6):580-91.

What is the link between renal disease and cardiovascular disease?

Many patients with kidney disease also have cardiovascular disease (CVD), and a patient with kidney disease is more likely to die of cardiovascular disease than of renal disease itself.

Albuminuria is an early marker for both types of disease, as renal disease and cardiovascular disease frequently coexist.

Risk of CVD in patients with chronic kidney disease

Renal disease and cardiovascular disease frequently coexist. For example, among patients in the Framingham Heart Study, 19% of patients with mild renal insufficiency also frequently had cardiovascular disease.33. Culleton BF, et al. Kidney Int. 1999 Dec;56(6):2214-9. Even in individuals with very early-stage kidney disease whose glomerular filtration rate (GFR) is still within the normal range, the cardiovascular risk is already elevated. More patients with chronic kidney disease die from cardiovascular causes than progress to end-stage kidney disease. Conversely, the presence of comorbid chronic kidney disease worsens the prognosis of patients with primary cardiovascular disease 44. Hillege HL, et al. Circulation 2006; 113:671-8. and patients with cardiovascular disease experience accelerated loss of renal function.55. Hillege HL, van et al. Eur Heart J 2003; 24:412-20. An example of a major clinical trial that demonstrates the association is the Heart Outcomes and Prevention Evaluation (HOPE) study, which evaluated blockade of the renin-angiotensin system (RAS) with the angiotensin-converting enzyme (ACE) inhibitor ramipril in patients who had vascular disease or diabetes plus a cardiovascular risk factor. Patients who had mild renal insufficiency (serum creatinine <1.4 mg/dL) were compared with those who did not. Mild renal disease significantly increased the risk of cardiovascular events - cardiovascular death, myocardial infarction, or stroke.66. Mann JF, et al. Ann Intern Med. 2001 Apr 17;134(8):629-36.

6. Mann JF, et al. Ann Intern Med. 2001 Apr 17;134(8):629-36.

Recently, a meta-analysis undertaken by the Chronic Kidney Disease Prognosis Consortium confirmed the independent association between chronic kidney disease and mortality risk in the general population.55. Hillege HL, van et al. Eur Heart J 2003; 24:412-20. The risk of mortality was unrelated to eGFR between 75 and 105 mL/min/1.73 m2 and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m2, the adjusted HRs for all-cause mortality were 1.18, 1.57, and 3.14 for eGFRs of 60, 45, and 15 mL/min/1.73 m2.77. Matsushita K, et al. Lancet. 2010;375(9731):2073-81. Another recent study highlighted the importance of proteinuria in modulating the risks of adverse outcomes associated with chronic kidney disease. The study involved nearly 100,000 adults receiving routine clinical care in the Canadian province of Alberta. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria (whether determined by urine dipstick or ACR) and eGFR of 60 mL/min/1.73 m2 or greater) as compared with those with eGFR of 4559.9 mL/min/1.73 m2 and normal protein excretion.88. Hemmelgarn BR, et al. JAMA. 2010;303(5):423-9.

Albuminuria as a marker for both cardiovascular and chronic kidney disease

The HOPE study provided key evidence that microalbuminuria, previously thought of as a marker of kidney damage, is a marker for cardiovascular disease as well. In patients with and without diabetes, any level of microalbuminuria increased the risk of cardiovascular events.99. Gerstein HC, et al. JAMA. 2001;286(4):421-6.

9. Gerstein HC, et al. JAMA. 2001;286(4):421-6.

Other studies have confirmed this and it has become clear that microalbuminuria signals damage to the (micro)vasculature in general, not just in the kidney. In the general population, the level of albuminuria is a strong predictor of cardiovascular mortality. The Prevention of Renal and Vascular End Stage Disease (PREVEND) study of over 40,000 non-diabetic residents of the Dutch city of Groningen found that a twofold increase of albumin within the albuminuria range 30-300 mg/day was associated with a 29% increase in cardiovascular disease risk and a 12% increase in the risk of all-cause mortality.1010. Hillege HL, et al. Circulation. 2002 Oct 1;106(14):1777-82.

Furthermore, even when the albumin level was at the higher end of the conventional 'normal' range the risk of cardiovascular mortality was raised (overnight albumin 10-20 g/min, that is below the conventional cut-off for microalbuminuria). There is a linear relationship between increasing albuminuria and increasing cardiovascular risk, regardless of the threshold of normoalbuminuria or albuminuria.

What is the relationship between renal disease and hypertension?

Hypertension is both a cause and a complication of chronic kidney disease. Antihypertensive drugs reduce the risk of renal disease progression. Intriguingly, this effect is not wholly accounted for by lowering of the blood pressure, indicating the involvement of other mechanisms.

Hypertension is both a cause and a complication of chronic kidney disease. It is also the major risk factor for progression of kidney disease in diabetic and non-diabetic chronic kidney disease. Given that both kidney disease and hypertension are more prevalent in older age groups and the population is aging, they have recently been described as 'a marriage that should be prevented'.1111. Bakris GL, et al. J Hypertens 2009; 27:666-9.

Hypertension may increase pressure in the glomerular capillaries, unless the preglomerular arteriole vasoconstricts and prevents transmission of the arterial pressure to the glomerulus. The loss of vascular 'tone', that is the ability to vasoconstrict and vasodilate, leads to a loss of autoregulation of renal blood flow and GFR. The kidney's ability to control sodium excretion is thus impaired leading to chronic kidney disease, in parallel, the ability to maintain blood pressure within normal levels deteriorates. The result is that most patients with chronic kidney disease also have hypertension. Trials of antihypertensive angiotensin II receptor blockers (ARBs), which inhibit the reninangiotensin system (RAS) via blockade of angiotensin II AT1 receptors, have been shown to reduce the risk of progression to end-stage renal disease and diabetic nephropathy.12,1312. Brenner BM, et al. N Engl J Med. 2001;345(12):861-9. 13. Lewis EJ, et al. N Engl J Med 2001; 345:851-60. However, renal protection in patients receiving RAS-inhibiting drugs is not fully explained by lowering of the blood pressure, suggesting the involvement of mechanisms that are bloodpressure independent.

How are renal disease and diabetes related?

The link between diabetes and renal disease is very strong. A high proportion of patients with type 2 diabetes develop renal disease and the risk of renal disease increases over time. The link between diabetes and renal disease is very strong - a high proportion of patients with type 2 diabetes develop renal disease, and the risk is augmented by high blood pressure. The rate of end-stage renal disease (ESRD) in people with diabetes is far greater than that in matched non-diabetic individuals.

In patients with type 2 diabetes, the risk of renal disease increases over time. In the UK Prospective Diabetes Study (UKPDS) there was a steady progression from normal albumin levels through microalbuminuria to macroalbuminuria. Death rates were also correlated with albumin levels. Patients with macroalbuminuria were more likely to die of cardiovascular causes than to reach end-stage kidney disease.1414. Adler AI, et al. Kidney Int. 2003 Jan;63(1):225-32. Hyperglycaemia damages glomeruli. Typical changes - basement membrane thickening and mesangial expansion - are also seen in kidneys of nondiabetic donors transplanted into patients with type 1 diabetes.2,32. Mauer SM, et al. Diabetes 1989; 38:516-23. 3. Osterby R, et al. Diabetologia 1991; 34:668-74. In this respect, it is interesting that there is a 'legacy effect' for good control of glycaemia (bloodglucose level) early in the course of diabetes. In the UKPDS, among patients whose glycaemia was tightly controlled early on there was significantly less microvascular disease, myocardial infarction and all-cause mortality a decade later, irrespective of glycaemic control in the intervening period.

Does diabetes cause hypertension?

At the time of diagnosis, 80% of patients with type 2 diabetes already have hypertension. Blood pressure increases even further if the diabetic patients have proteinuria or renal failure. Pathophysiological mechanisms have now been identified that link diabetes and hypertension. Hypertension is a common feature of the pre-diabetic stage (metabolic syndrome). At the time of diagnosis 80% of patients with type 2 diabetes already have hypertension. Blood pressure increases even further if the diabetic patients have proteinuria or renal failure. A number of pathophysiological mechanisms in diabetic nephropathy link diabetes and hypertension:

High glucose concentrations activate the renal synthesis and release of renin by the juxtaglomerular apparatus and other renal structures Insulin and glucosuria cause sodium retention Hyperglycaemia causes renal structural damage in the glomerulus and blood vessels by several pathomechanisms, including oxidative stress

17. Ritz E, et al. In: Hypertension - Pathophysiology, Diagnosis and Management, Vol. 2. JH Laragh, BM Brenner (eds). New York: Raven Press, 1990;1705.

Hypertension also accelerates progression of diabetic nephropathy by increasing proteinuria and increasing the rate of GFR loss. There is evidence that in hypertensive type 2 diabetics, tight

control of blood pressure significantly reduces diabetes-related endpoints and diabetes-related death. In contrast to the 'glycaemic legacy', that is the persisting benefit from a history of tight glycaemic control during a limited period of time, continuous lowering of blood pressure is required to maintain the benefit from antihypertensive treatment.18 Chronic kidney disease (CKD) is a growing healthcare problem with a high risk for poor outcomes, including cardiovascular (CV) disease and progression to end-stage renal disease (ESRD). Accurate staging of CKD is critical to disease management because treatment recommendations are guided by stage. Once viewed as a life-threatening condition requiring lifelong specialty care for a small population of patients, CKD is now considered a prevalent condition that involves the collaboration of primary and specialty care for prevention, early detection, and treatment.[1] Driving this transition is a better understanding of the risk factors for ESRD and the potential for adverse outcomes. Beyond basic measures of kidney function such as glomerular filtration rate (GFR), factors such as albuminuria and the presence of comorbidities such as diabetes and hypertension substantially influence the natural history of CKD. In an effort to provide a more effective tool for risk stratification, a movement has emerged to incorporate these prognostic factors into the current CKD classification system.

KDOQI CKD Staging System

In 2002, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) published guidelines on the evaluation, classification, and risk stratification of patients with CKD.[2] These guidelines provide a conceptual framework that facilitates diagnosis of CKD independent of cause. The guidelines provide a staging scheme based on GFR, which is considered the best single measure of overall kidney function (Table 1).[2] The Kidney Disease Improving Global Outcomes (KDIGO) group endorsed the KDOQI classification system with only minor modifications.[3] At the 2006 KDIGO Controversies Conference, KDIGO added a method of documenting treatment by transplantation or dialysis, using the suffix "T" for all kidney transplant recipients at any level of GFR and "D" for patients with CKD stage 5 treated by dialysis.[3] Table 1. KDOQI Stages of CKD Stage 1 2 3 4 5 Description Kidney damagea with normal or GFR Kidney damagea with mild GFR Moderate GFR Severe GFR Kidney failure GFR (mL/min/1.73 m2) 90 6089 3059 1529 <15 (or dialysis)

GFR = glomerular filtration rate. a Evidence of kidney damage defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. National Kidney Foundation.[2] Strengths and Weaknesses of the Current Staging System The KDOQI staging system facilitates standardized research on CKD treatments and promotes stage-specific care.[2] Before these criteria were developed, healthcare providers described kidney disease with terms such as "chronic renal failure," "chronic renal insufficiency," and "predialysis," which lack precision on the severity of renal function.[4] The KDOQI guideline provides a convenient nomenclature for communicating the severity of renal dysfunction to other medical personnel and laypersons, and for conveying progression of CKD. The staging system complements a model of CKD management from screening of at-risk patients, through slowing CKD when present and management of its complications, through preparation for dialysis or transplant if required (Figure 1).[2] Current CKD stages correlate with increasing disease severity and the need for increasingly aggressive treatment.

Figure 1. Conceptual Model for CKD Progression and Treatment Complications refer to all complications of CKD and its treatment, including complications of decreased GFR (hypertension, anemia, malnutrition, bone disease, neuropathy, and decreased quality of life) and CV disease. Reprinted from National Kidney Foundation,[2] with permission from Elsevier. The KDOQI CKD staging system does have significant weaknesses that limit its clinical value.

Imprecise estimations of GFR: GFR cannot be measured easily in clinical practice and therefore is estimated from serum creatinine, age, race, sex, and body size. In the current KDOQI CKD staging system, GFR is calculated using a 4-component model of the Modification of Diet in Renal Disease (MDRD) study equation.[5] However, the MDRD equation was developed by studying patients with preexisting CKD. For this and other

reasons, the MDRD equation underestimates true GFR at higher values. As a result, the MDRD-based classification system results in overdiagnosis and misdiagnosis of CKD as well as overuse of specialty resources.[6] Discordance between CKD stage and prognosis: The KDOQI CKD staging system does not reflect clinical reality for many CKD patients in terms of prognosis, symptoms, or need for intervention.[5,7] For example, stage 12 CKD is not associated with adverse outcomes severe enough to require specific intervention. Stage 3 CKD (estimated GFR [eGFR] 3059 mg/min/1.73 m2) comprises a broad range of disease severity, allocating the same stage to patients with chronic renal insufficiency who require specialty care and patients with a clinically inconsequential reduction in kidney function.[7] No recognition of age-related changes in GFR: By defining normal GFR as 90 mL/min/1.73 m2 for patients of all ages, the KDOQI CKD staging system does not account for age-related changes in GFR.[7] After age 20 to 30 years, GFR measurements decline by 4.6 mL/min per decade in men and 7.1 mL/min per decade in women.[8] The steady decline in GFR is consistent across the elderly population and appears to be a feature of aging rather than a pathologic condition. Without adjusting for the effects of aging on GFR, the staging system may raise concerns about the presence of renal disease in patients whose only symptom is declining GFR, or overestimate the severity of renal failure in older patients with CKD.[7]

Prognostic Factors in CKD

A primary goal of treatment for patients with CKD is risk reduction of progression to ESRD. The KDOQI CKD staging system does not account for certain prognostic factors and comorbidities that strongly influence outcomes in patients with CKD. For example, albuminuria is common and has important diagnostic and prognostic implications. Higher levels of albuminuria suggest certain types of CKD, including diabetic kidney disease, nondiabetic glomerular disease, or glomerular disease in the transplanted kidney. As a prognostic finding, albuminuria is associated with more rapid progression of kidney disease and a higher risk of CV events (Figure 2).[9] The presence of higher levels of albuminuria also identifies patients more likely to benefit from antihypertensive therapy.[2] Although the KDOQI staging system incorporates albuminuria into the definition of stage 12 CKD, the definition of stage 35 disease relies solely on GFR.

Figure 2. Relationship Between GFR, Albuminuria, and CV Disease eFR = estimated filtration rate; UAE = urinary albumin excretion. Reproduced from Brantsma AH, et al.[9] by permission of Oxford University Press. Risk management requires accurate evaluation of kidney function as well as assessment of prognostic factors beyond GFR. Cardiovascular disease is the leading cause of mortality and a frequent contributor to morbidity in patients with CKD. Assessment of albuminuria and GFR may be sufficient to assess the patient's level of risk for progressing to ESRD but may be less valuable for determining risk of CV disease (Table 2).[10] For patients with CKD, the presence of major CV risk factors such as diabetes and dyslipidemia plays a significant role in CV and renal outcomes.[10] Comprehensive risk assessment of the patient with CKD should take into account a broad range of possible findings and comorbidities, including albuminuria, CV risk factors, and other prognostic indicators. Accordingly, healthcare providers should monitor risk factors directly related to CKD, such as GFR and albuminuria, as well as risk factors related to other potential complications. Table 2. 10-Year CKD Prognosis: Risk Factors and Outcomes 10-year prognosis eGFR Albuminuria Risk of CV disease or ++ ++ Risk Factors Other major risk factors History of CV disease

mortality Risk of kidney failure (ESRD or death) Rate of decline in GFR Acute kidney injury or drug toxicity

Major CV risk factors (blood pressure, cholesterol, diabetes, age, sex, race) +++ + ++++ ++ +++ +++? Type of kidney disease (diagnosis, diabetes, blood pressure, older age, "protective") Type of kidney disease (diagnosis, blood pressure, race) Older age, medication type

Number of + signs indicates the strength of association. Coresh J.[10]

Looking Ahead: Revised CKD Staging

Many experts support revision of the current CKD definition and classification system.[5,7,11,12] Several modifications have been proposed. Improving Estimates of GFR In 2010, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) validated an equation that improves the accuracy of GFR estimates, particularly at higher GFR levels.[13-15] Compared with the MDRD equation, the CKD-EPI formula incorporates recalibrated measures of serum creatinine as well as data on age, race, sex, and body mass index. In development and validation studies, the CKD-EPI equation was as accurate as the MDRD equation in patients with a low GFR (< 60 mL/min/1.73 m2) and substantially more accurate among patients with a GFR 60 mL/min/1.73 m2. The CKD-EPI formula performed well across all patient subgroups defined by age, sex, race, diabetes, transplant status, and BMI.[13] Compared with the MDRD equation for GFR, the CKD-EPI equation may enable more accurate risk prediction of adverse outcomes, including CV disease and mortality.[16] The greater accuracy of the CKD-EPI equation may influence clinical decision making in patients with decreased kidney function. The CKD-EPI equation also should reduce the risk of false-positive results and misdiagnosing persons with high GFRs as having poor kidney function. Current recommendations call for reducing the dose of drugs excreted by the kidney, avoiding certain imaging procedures that require use of contrast media, and setting lower targets for CV risk factors in patients with low GFR. Falsely low eGFR could lead to insufficient dosing, withholding diagnostic tests, and overly aggressive CV risk factor reduction in patients who do not need and could be harmed by these precautions. The CKD-EPI equation changes the apparent prevalence of CKD in the general population.[16] Analysis of data from the National Health and Nutrition Examination Survey database showed that the CKD-EPI equation provided a lower estimated prevalence of CKD than the MDRD equation (11.5% vs 13.1%). The shift was due primarily to a lower estimated prevalence of stage 3 CKD (6.3% vs 7.8%). Based on the CKD-EPI equation, the prevalence of CKD in the United States is 23.2 million, approximately 3 million fewer than estimated by the MDRD study equation.[16]

Rule and colleagues developed a quadratic equation based on healthy subjects and patients with chronic renal diseases.[17] This equation has similar diagnostic performance as the MDRD equation in diabetic patients, but it does not underestimate normal GFR in diabetic subjects. Redefining Stage 3 CKD Some investigators suggest subdividing stage 3 by GFR into stages 3A (45-59 mL/min) and 3B (30-44 mL/min).[18] These GFR ranges are associated with different clinical patterns and risks: patients with stage 3B CKD probably should be referred to specialized renal care, whereas those with stage 3A disease can be managed in the primary care setting.[18] This recommendation has gained acceptance in the nephrology community. In the United Kingdom, the National Institute for Clinical Excellence guidelines suggests subdividing stage 3 CKD into 4 subcategories based on the presence or absence of proteinuria and whether the eGFR is < or > 45 mL/min/m2. Classification of CKD by Comorbidity Recent research suggests that incorporating albuminuria into risk stratification models better predicts renal and CV outcomes in patients with CKD.[5] In the Prevention of Renal and Vascular End-stage Disease (PREVEND) trial, patients with stage 3 CKD and urinary albumin excretion (UAE) levels > 30 mg/24 hours had a 60% higher risk of CV morbidity and mortality than those with stage 3 CKD and UAE levels 30 mg/24 hours (Figure 2).[9] Incorporating information on the presence or absence of comorbidities such as diabetes and hypertension may enhance the current framework for CKD classification.[1] Redefining Risk Categories Early detection and risk factor reduction are critical steps in preventing the onset or slowing the progression of chronic disease. In the setting of CV disease, this concept has driven cholesterol targets lower and given rise to the term "prehypertension." For CKD, this strategy is more controversial. Some nephrologists advocate combining stages 1 and 2 CKD, which cannot be distinguished reliably by the MDRD equation for estimating GFR.[18] Many clinical laboratories calculate the MDRD eGFR and report the value only if it is < 60 mL/min/1.73 m2. Another proposed classification system eliminates the current stage 1 category and redefines the remaining stages to describe low, moderate, and high risk of progression to kidney failure based on 4 categories of eGFR ( 60, 45-59, 30-44, and 15-29 mL/min/1.73 m2) and 3 categories of albuminuria (normoalbuminuria, microalbuminuria, and macroalbuminuria) (Table 3).[19,20] In this system, patients at low risk of progression to kidney failure are treated in general practice, those at moderate risk are managed by collaboration between a primary care clinician and nephrologist, and patients at high risk are treated in a nephrology outpatient clinic.[20] Table 3. Proposed CKD Classification System

Risk for progression to kidney failure is categorized as low (green), moderate (yellow), or high (red). Hazard ratios (95% confidence interval) for progression to kidney failure are adjusted for age, sex, blood pressure, antihypertensive medication, diabetes, high-density lipoprotein cholesterol, and physical activity. ACR = albumin to creatinine ratio. Hallan SI, et al.[20]

Implications for the Multidisciplinary Care Team

Revising the current staging system may change the indications for treatment initiation and adjust referral rates from primary care to nephrology clinics. In the current system, most patients with stages 1 to 3 CKD are managed by primary care physicians, whereas more than 75% of patients with stages 4 and 5 disease are managed by nephrologists.[21] However, several studies show the benefits of multidisciplinary careearly and continued involvement of primary and specialty physicians, nurses, dietitians, social workers, and other healthcare professionalsin survival and other clinical outcomes in patients with CKD.[22,23] To encourage multidisciplinary collaboration between general practice and specialty care, the National Kidney Foundation has defined indications that should trigger referral to specialists in kidney disease, hypertension, or CV disease regardless of CKD stage (Table 4).[24] In the primary care and specialty settings, nurses should educate patients about the importance of controlling diabetes, hypertension, and other comorbidities to improve renal and CV outcomes.[25,26] Table 4. Recommendations for Comanagement of CKD Indication GFR < 30 mL/min/1.73 m
2

Specialist Referral Kidney disease specialist Kidney disease specialist Kidney disease specialist Kidney disease specialist Kidney disease specialist Kidney disease or hypertension specialist

Spot urine total protein-creatinine ratio > 5001000 mg/g Increased risk of progression of kidney disease GFR decrease > 30% within 4 mo without explanation Hyperkalemia (serum potassium > 5.5 mEq/L despite treatment) Resistant hypertension (> 130/80 mm Hg despite adherence to a 3drug antihypertensive regimen that includes a diuretic)

Difficult-to-manage drug complications Acute presentations of CV disease Complex or severe chronic CV disease conditions Age < 18 years National Kidney Foundation.[24]

Kidney disease or hypertension specialist CV disease specialist CV disease specialist Pediatric kidney disease specialist

Summary
Optimal care for patients with CKD begins with accurate evaluation of risk. Therefore, risk classification systems that incorporate multiple risk factors, including albuminuria and comorbidities such as diabetes and hypertension, may allow better assessment of prognosis. Furthermore, a revised CKD classification system may facilitate risk reduction strategies tailored to the spectrum of potential outcomes among patients with CKD. In the future, a revised system for CKD staging may empower primary care providers to manage low-risk patients, while focusing specialty care on patients who are most likely to benefit from treatment by nephrologists. We care for children with all forms of kidney disease and hypertension. We care for children at Children's Memorial Hermann Hospital (CMHH), Lyndon Baines Johnson General Hospital (LBJ), and M.D. Anderson Cancer Center (MDACC), as well as several clinics serving the metro Houston area and much of east Texas. We provide a multidisciplinary team approach to patient care. We use disease state management, where we care for the patient in the hospital, in the office, at school, and at home. We perform a multitude of diagnostic tests, including genetic analysis, urine sediment analysis, and renal biopsy. For patients with sudden loss of kidney function, we offer acute renal replacement therapy: hemodialysis, peritoneal dialysis, continuous venovenus hemofiltration (CVVH), and slow low efficiency dialysis (SLED). We work in close affiliation with pediatric urology, pediatric radiology, renal pathology, pediatric cardiology, vascular surgery, and transplant surgery divisions. Our nephrologists remain at the forefront of techniques for treatment through research in hypertension, immune mediated kidney diseases, dialysis, and transplantation. Ongoing research studies focus on managing chronic kidney disease (CKD) and high blood pressure. We collaborate with most national and some international pediatric research networks to better understand how to manage our patients and their disorders. We provide physician, nursing, and staff support for our patients each summer in Kidney Camp, held at Camp For All. The camp's medical team is equipped to provide care for children with a broad range of kidney disorders, including dialysis.

How the Kidneys Work

The kidneys are two bean-shaped organs located toward the back of the body on either side of the spine near the waistline. They are about the size of a fist and protected by other organs and two of the lower ribs. Normally functioning kidneys serve the body by:

Cleaning the blood and removing waste products Balancing water and salt to control fluid in the body Controlling blood pressure Helping to make red blood cells and build strong bones Controlling the amount of potassium, calcium, magnesium, and phosphorus in the blood

Nephrology is the study of kidney function and disease. Nephrons are the basic building blocks of the kidney, and each kidney has about one million nephrons. Nephrons include a glomerulus, the filter, and a tubule which drains the urine. Each nephron drains into a collecting duct that eventually becomes the renal pelvis. Ureters drain into the bladder, and the bladder empties via the urethra. The word renal is an adjective that indicates relationship to the kidney. For example, the renal artery delivers blood to the kidney, and the renal vein takes blood from the kidney back to the heart. A renal biopsy is a sampling of kidney tissue. Renal replacement therapy is a way of replacing kidney function artificially, also known as dialysis. To learn more, consider enrolling in Kidney School.

Children's Dialysis
Our Children's Dialysis Unit provides acute or chronic hemodialysis and/or peritoneal dialysis to inpatient and outpatient children from birth to 21 years of age. Many patients are referred to us from the Memorial Hermann Pediatric Nephrology Clinic and from physicians and other hospitals for specialized diagnostic care. The dialysis unit is equipped to care for children with any medical or surgical problem. Our nephrology nurses are specially trained to work with neonatal and pediatric patients, and they stay current through continuing education. Close collaboration between our nurses and physicians enhances the quality of care our patients receive. Dialysis is a procedure performed routinely on people with acute or chronic renal failure. It removes waste substances and fluid from the blood that are normally eliminated by the kidneys. Dialysis may also be used to prevent renal failure in children who have been exposed to or have eaten toxic substances. There are two types of dialysis that may be performed on your child: peritoneal or hemodialysis.
Peritoneal Dialysis

Peritoneal dialysis is performed by surgically placing a special soft, hollow tube into your child's lower abdomen near the navel. After the tube is placed, a special solution called dialysate is

administered into the peritoneal cavity. This cavity houses the organs of the abdomen and is lined by two membrane layers called the peritoneum. The dialysate is left in the abdomen for a designated period of time, which is determined by your child's physician. The dialysate fluid absorbs waste products and toxins through the peritoneum. The fluid is then drained from the abdomen, measured, and discarded. We perform two types of peritoneal dialysis: continuous ambulatory peritoneal dialysis (CAPD) and continuous cyclic peritoneal dialysis (CCPD). CAPD does not require a machine. Exchanges, often referred to as passes, can be done three to five times a day during waking hours. CCPD requires the use of a special home dialysis machine that performs dialysis automatically, even while your child is asleep.
Hemodialysis

Hemodialysis is performed in the dialysis center of the hospital by trained health care professionals. A special type of access, called an arteriovenous (AV) fistula, is implanted, usually under your child's arm. An external intravenous (IV) catheter may also be inserted, but this is less common for long-term dialysis. After access has been established, your child will be connected to a large hemodialysis machine that drains the blood, bathes it in a special dialysate solution to remove waste substances and fluids, then returns it to the bloodstream. Hemodialysis is usually done several times a week and lasts for four to five hours. Because of the length of time required, it may be helpful to bring games or reading material for your child.

Kidney Transplant
A number of diseases can directly damage the kidneys, seriously affecting their functioning. If damage is severe enough, transplantation may be necessary. A transplant provides a child with a kidney that can keep up with the demands of a full, active life. We make it a policy to continuously follow all kidney transplant recipients for the life of their kidney. This policy helps ensure the childs health, and it allows us to follow the long-term outcomes of our patients and better understand the effects of immunosuppressive therapy. The quality of our follow-up care has resulted in the distinguished recognition awarded to Memorial Hermanns Organ Transplantation Program. The United Network for Organ Sharing (UNOS) oversees organ distribution in the United States for liver, kidney, pancreas, heart, lung, and cornea transplantation. Criteria have been developed to ensure that all people on the waiting list are judged fairly as to the severity of their illness and the urgency of their need for a transplant. People waiting for a transplant are placed on a waiting

list and given a status code. Those placed highest on the waiting list are given first priority when a donor organ becomes available. Many of our patients have related family members who are interested in donating a kidney to the child with failing kidneys. Although it is not safe for all people to donate a kidney, those that fit specific criteria often do chose to donate, and their remaining kidney keeps them healthy. This is called a living related donor transplant, and the recipients often get their new kidney without ever needing to go on dialysis for their kidney failure. Memorial Hermann and Memorial Hermann Children's Hospital, where more than 2,500 kidney transplants have been performed, are nationally recognized leaders in dialysis and kidney transplantation. Our surgeons are specifically trained in pediatric transplantation. Because every child is unique, every transplant is different. In collaboration with LifeGift, our area's organ procurement organization, we have been able to provide kidney transplants for about one third of newly listed patients within a year of their registration as candidates for transplantation. The Kidney Transplant Clinic is located on the ground floor of Jones Pavilion in Memorial Hermann Hospital. The clinical team includes surgeons, nephrologists, nurse coordinators, pharmacists, dietitians, and social workers who make daily rounds using a multidisciplinary approach to patient care. At referral, children are immediately assigned to a coordinator when they select transplantation as a potential treatment option. Because children with chronic renal disease require comprehensive coordination, the care coordinator follows each child through the transplant work-up, during the transplant operation, and for the life of the transplanted kidney thereafter. Our one-coordinator-does-it-all concept ensures continuity of your childs care through each stage of the process. Our transplant care coordinators are on call 24 hours a day.

Location & Contact

6431 Fannin Street MSB 3.020 Houston, Texas 77030 713-500-5757 (Voice)
Other Locations

Children's Memorial Hermann Hospital LBJ General Hospital M. D. Anderson Cancer Center Clinics

Children's Learning Institute Center for Clinical Research and Evidence Based Medicine Shriners Hospital for Children

Nephrology

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Indian journal nephrology

Introduction

Chronic kidney disease (CKD) leads to many comorbidities that affect patients at all stages of the disease. The complications of CKD are due to the disease itself as well as the mode of renal replacement therapy (RRT). Kidney function can only be partly replaced by maintenance dialysis, which provides only 5-10% of excretory renal function. [1] At present, out of the three modalities of treatment-conservative management, hemodialysis (HD), and peritoneal dialysisabout 82% of patients are on HD. [1] Cardiovascular morbidity and mortality is highest in the dialysis population. Recently, an association has been found between RRT and the development of pulmonary hypertension. The normal pulmonary artery pressure in a person living at sea level has a peak systolic value of 18-25 mmHg. Definite pulmonary hypertension is present when pulmonary artery systolic and mean pressures exceed 30 and 20 mmHg, respectively. The normal pulmonary vascular bed offers less than one-tenth of the resistance to flow offered by the systemic bed. Pulmonary artery pressure and pulmonary vascular resistance increase with advancing age. Reduced compliance of the pulmonary vascular bed, secondary to intimal fibrosis or increased wall thickness in the muscular pulmonary arteries, is a possible cause for this. It is also possible that some of the

changes in the pulmonary arteries are related to the reduced compliance to left ventricular filling, which is passively reflected on the pulmonary vascular bed. [2] The majority of the patients with CKD have hypertension with diastolic dysfunction, arteriovenous fistulas (AV fistulas), anemia, uremic lung, volume overload with interstitial pulmonary edema, and a high cardiac output state, all of which can lead to increased pulmonary vascular pressures. [3],[4] The following study was done to find out the prevalence of pulmonary hypertension in a cohort of CKD patients at a tertiary care center. We also examined the correlation of pulmonary hypertension with the duration of renal failure, HD, continuous ambulatory peritoneal dialysis (CAPD), various biochemical parameters, hemoglobin, systemic hypertension, and diabetes mellitus. ~ Materials and Methods

We studied a total of 100 CKD patients in a tertiary care center after obtaining written consent. The group included 25 on conservative management (male 18, female 7), 65 on HD (male 44, female 21), and 10 on CAPD (male 7, female 3). The mean age of the patients on conservative management was 52 13 years, that in the HD group was 48 12 years, and in the CAPD group it was 57.5 12 years. Duration of renal failure, duration of dialysis [Table - 1], and the presence or absence of an arteriovenous fistula was noted. Known cases of coronary artery disease and pulmonary disease (including smokers) were excluded. The selected subjects underwent a detailed clinical examination and the relevant biochemical investigations were done. The two comorbid conditions which were taken into consideration were diabetes mellitus and hypertension, and their distribution in the study group is shown in [Table - 2]. All patients had a 2D-echocardiogram done by an experienced cardiologist and the findings were confirmed by a second blinded cardiologist. Pulmonary artery systolic pressure was recorded by tricuspid regurgitation jet method [Figure - 1]. In HD patients the echocardiogram was done on the day after dialysis; in CAPD patients there was no such specification. Once the data was collected, it was analyzed by the Chi-square test. The relationships of all the variables to pulmonary hypertension in CKD were assessed by multivariate regression analysis. ~ Results

Ninety six percent of the patients had a hemoglobin value below 10 gm/dl and 98% had a hematocrit <35. In 96% of the patients the BUN was >20 mg/dl and in 36% the creatinine was >5 mg/dl. Metabolic acidosis was present in 85% (serum HCO 3 < 20 mmol/l) at the time of study. Twenty-seven percent of patients had documented renal failure for 11-20 months. The duration of dialysis was <10 months in 29% of the patients. Forty-one patients had pulmonary hypertension, of whom 33% were on HD [Figure - 2]. The multivariate regression analysis gave the results shown in [Table - 3].

~ Discussion

In recent literature, there has been recognition of a novel cardiopulmonary complicationsecondary pulmonary hypertension in CKD and HD patients. [5],[6],[7],[8],[9],[10] At the ultrastructural level, these changes include swelling of the pulmonary capillary endothelial cells, thickening of the basal lamina, and wide separation of groups of connective tissue fibrils, all indicative of interstitial edema. With persistent edema, there is proliferation of the reticular and elastic fibrils leading to dense connective tissue infiltration in the alveolar capillaries. [11] Structural changes in the small pulmonary arteries, arterioles, and venules include medial hypertrophy and intimal fibrosis. Many patients with left ventricular diastolic dysfunction exhibit increased pulmonary vascular resistance and moderately severe pulmonary hypertension. In our study, we found that hemoglobin and hematocrit were negatively correlated with pulmonary hypertension. However, Nissenson et al . has recommended optimization of the hematocrit to maximize the blood oxygen carrying capacity and minimize the impact of arterial hypoxemia. [12] It has been found that repeated episodes of hypoxia during and/or after HD lead to the development of pulmonary hypertension and cause morphological changes in the lung.
[13],[14],[15]

We also found that as the duration of renal failure increased so did the chances of developing pulmonary hypertension. Braunwald has stated, 'Relieving the downstream obstruction results in the normalization of pulmonary artery pressure this has been believed to be related to the chronicity of the active pulmonary hypertension, leading to irreversible vascular changes.' [16] One of the recent observations as to why pulmonary hypertension occurs in CKD patients has to do with the role of the parathyroid hormone. A study found that in patients with hyperparathyroidism there is an increase in the intracellular calcium in the pulmonary vessels, causing increased pulmonary pressures. [17] However, the study failed to prove this theory and could not show any correlation between this variable and pulmonary hypertension. In our study, the prevalence of pulmonary hypertension was highest in the HD group, which is not surprizing, as these patients had AV fistulas; lower hemoglobin, hematocrit, and serum bicarbonate values and higher BUN and serum creatinine levels. CAPD patients had the least evidence of pulmonary hypertension. Hence, it seems that CAPD may be the better RRT if development of pulmonary hypertension is to be prevented. A recent report by Gueraoui et al . in 1994 showed that 48% of chronic HD patients had pulmonary hypertension. [7] Patients on dialysis, especially those on HD, need to be evaluated for cardiac function with 2-D echocardiography. Severe pulmonary hypertension in these patients can be ameliorated by banding of the fistula to reduce the high output state, thereby reducing left ventricular end diastolic pressure. Additional strategies include management of anemia with recombinant

erythropoietin and iron, correction of metabolic acidosis with sodium bicarbonate, and increasing the frequency of dialysis and renal transplantation.