Effect of Hypertension in Patiens with Chronic Kidney Disease

Contents : Abstract Contents Introduction Structure and Function of the Kidney Chronic Kidney Disease Phatogenesis of Chronic Kidney Disease Phatogenesis Hypertension in Patiens with CKD Clinical Feature of Chronic Kidney Disease and Hypertension Treatment Conclusion References

Abstract Background and Objectives 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 Design, Setting, Participants, & Measurements 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 hypertension. 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. 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 Results 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 130 mm Hg. Non-Hispanic black race

pressure >80 mm Hg, with systolic blood pressure

(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) 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.(5) Conclusions 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.

Introduction Chronic Kidney Disease in defined by the National Kidney Foundation as kidney damage or an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1,73 m2 of at least 3 months duration. It may manifest as abnormalities in urine analysis, imaging studies, or blood measurements of kidney function. Chronic kidney disease stages are based on estimade GFR (mL/min/1,73 m2) as follows : 1) normal or elevated (>90), with kidney damage; 2) mildly descreased (60-89), with kidney damage; 30 moderatly descreased (3059); 4) severely decreased (15-29); and 50 kidney failure (<15). Chronic kidney disease is often progressive and can lead to loss of kidney function and kidney failure; it is also strongly assosiated with cardiovascular disease. Hypertension is one of the most important determinants in the development end these of points. The prevalence of hypertension increases linearly as the GFR falls, and ultimately present in 80% to 85% of patients with chronic kidney disease. Patients hypertension and chronic kidney disease are at much greater risk for cardiovascular morbidity and mortality as compared with those without chronic kidney disease. Even after controling for the level of blood preasure, patients with kidney disease at higher risk for cardiovascular disease. This risk progressively increases as the loss of renal function become more severe. 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 isone of the major risk factors for development and progression of chronic kidney disease. The loss of renal function leads to impaired renal autoregulation and renders the kidney vulnerable to the damaging effects of uncontrolled hypertension. Mounting evidence indicates that angiotensin-converting enzyme inhibitor and angiotensin reseptor blockers slow the progression of chronic kidney disease through effect beyond lowering blood pressure. Studies are needed to determine whether high doses of the single agent or combination theraphy is most effective in providing renal protection. Urinary protein excretion is a useful tool fo monitoring and tritating Theraphy to maximize renal protection. Changes in the serum creatinine concentration and hyperkalemia are complications of antihypertensive theraphy in patients with chronic kidney disease that can be successfully managed to allow continued use of renin-angiotensis blockade.

Structure and function of the kidney Surgical relations of the kidney a. Posterior relations : The kidneys are well protected, tucked in on either side of the spine. Behind each kidney is the lung, constantly moving up and down, so the inferior border of the kidney may lie anywhere between the 2nd and 4th lumbae trans verse processes The other posterior relations of the kidney are 12th rib, diaphragm, quadratus lumborum ad psoas muscle The ilioinguinal and hypogastric nerves cross the quadratus lumborum muscle and are often injured in approaching the kidney from the loin. b. Anterior relations : Left The tail of the pancreas and the spleen lie in front of the left kidney and are easily injured at operation. The duodenojejunal flexure and descending colon also lie just front of the left kidney, so indigestion or bowel distension is common when there is inflammation or obstruction of the kidney, and cancer of the kidney easily invades the adjacent bowel. Right Ascending colon The second part of the duodenum Common bile duct:it is not surprising that indigestion often accompanies disorder of the right kidney(3) Structure of the kidney 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

a. Renal pyramid The basic unit of the mammalian kidney is the pyramid. In porpoises the pyramids remain separate so that the kidney looks like a bunch of grapes. In most other mammals (including man) the porpoise arrangement is still seen in the foetus. In the adult, the dozen pyramids are squeezed together. Each pyramid is like a bunch of flowers in a vase, the blooms are the glomeruli, the stems the collecting duct and the whole bunch, the papilla, sits in a vase, the calix. b. Renal papilla The collecting ducts open onto the papilla obliquely so that when pressure rises in the calix the ducts are closed as if by a valve. Children may be born with papillae that are fused together-compound papillae. These make the valve mechanism ineffective so that if the pressure in the pelvis rises, from obstruction of reflux, urin is forced into the renal parencyma where it my cause inflammation and scarring. The collecting ducts gather the glomerular filtrate from the nephrons which are arranged like corn on the cob. Each nephron has two parts: a filter, the glomerulus, and the processing plant, the renal tubules. c. Glomerulus

The glomerulus is made of an arteriole, coiled like a ball of wool, whichis invaginated into a hollow ballon-bowmans capsule-whose stem drains into the proximal tubule. The glomerular arteriol is very permeable, with an endothelium specially dimpled to increase its porosity. Its basement membrane is supported like filter paper on agrid formed by the foot processes of the ephitalial cells of the Bowmans capsule, wich interlock like a zip-fastener. The spaces between the zip are called slit-pores and their size has been measured using peroxidases of known molecular mass: those molecular mass less than 40,000 can slip through: those above 160,000 get stuck. Filtration is not merely a matter of the size of the molecule. The proteins of the basement membrane are negatively charged. They repel negatively charger molecules, albumin, but allow positively charged molecules of similiar size to to pass through. The pressure inside the glomerular arteriol is about 60 mmHg. The plasma oncotic pressure is about 35 mmHg. The pressure inside Bowmans capsule is about 10 mmHg. The arteriol of the glomeruli are 50 times more permeable than those of arterioles elsewhere, muscle, and they allow enormous volumes of fluid to leak out. The whole plasma water is filtered every 30 minutes and the entire body water processed fout times a day. The first task of the tubules is to recapture this huge amount of water. d. Renal tubules - Proximal tubule About 75% of the excess water is reabsorbed in the proximal tubule, which is lined with active cells whose surface area is enormously increased by their bush border of microvili. These metabolically busy cells also recover glucos, phosphate and amino acids from the glomerular filtrate. - Loop of henle The filtrate now pased through the loop of henle. Most of these are quite short, but those in the inner part of the pyramid dip down like hairpins into the papilla, where they run alongside collectihing tubules. The cells of the loops of Henle are thin, and allow osmosis to withdraw salt and water from the glomerular filtrateinto the concentrated tissue of the papilla. So called loop diuretics, frusemide, inhibit Cl transport, reduce hypertonicity in the papilla, and allow more water escape along potassium. - Distal tubule

The filtrate now rises up into the distal convoluted tubule whose cells are thick and metabolically active but have no brush border. The exchange Na for K and H ions to regulate the acid-base balance of the body. Disease of the distal convoluted tubules prevents the urine from forming an acid urine, the so-called renal tubular acidosis. - Collecting tubules Leaving the distal convoluted tubule the filtrate enters the collecting tubule, and once more runs the gauntlet of the hypertonic papilla. Here the last fine-tuning of the reabsorption of water takes place under rhe control of the pituitary antidiuretic hormone. (3)

Chronic Kidney Disease 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. At present, out of the three modalities of treatment-conservative management, hemodialysis (HD), and peritoneal dialysis-about 82% of patients are on HD.Cardiovascular morbidity and mortality is highest in the dialysis population. Recently, an association has been found between RRT and the development of pulmonary hypertension. Against this background it is critical to appreciate that the majority of cases of ESRD result from the slow progression of chronic kidney disease (CKD) over many months or years. There is therefore an opportunity to intervene in the course of CKD to slow the rate of decline in renal function and thereby reduce the number of patients requiring renal replacement therapy. We review the mechanisms that contribute to CKD progression as well as clinical aspects and interventions that are effective in slowing the rate of decline in renal function.(1)

Phatogenesis of Chronic Kidney Disease CKD should be viewed as a clinicopathologic syndrome that ensues after renal injury resulting from a wide range of kidney pathologies. This suggests that the progressive decline in renal function that is characteristic of CKD result from a common set of mechanisms that is largely independent of the initiating renal pathology.

a. Glomerular Hemodynamic Factors Studies in animal models of CKD reported that when the nephron number was severely reduced by surgical ablation, marked hemodynamic changes were observed in the remaining glomeruli, characterized by a substantial increase in the filtration rate of each glomerulus (single nephron glomerular filtration rate, SNGFR) that resulted in part from an increase in glomerular capillary hydraulic preassure (Pgc). Whereas these adaptations for nephron loss, further studies indicated that they were associated with structural injury to glomerular cells and subsequent glomerulosclerosis. In subsequent experiments, treatment with an angiotensin-converting enzyme inhibitor (ACEI) normalized Pgc without abrogating the adaptive increase in SNGFR and prevented glomerulosclerosis, suggesting that increased Pgc (also termed glomerular capillary hypertension) was the hemodynamic factor most likely responsible for glomerular injury. These observations suggested that adaptive hemodynamic changes in glomeruli after substantial nephron loss result in further glomerular damage and nephron loss, thereby estabilishing a vicious cycle of progressive renal injury b. Angiotensin II

Angiotensin II is a potent vasocontrictor peptide that has been identified as an important mediator of the glomerular hemodynamic adaptions observed after nephron loss. Whereas systemic levels of angiotensin II are normal or decreased in CKD, experimental studies have confirmed that intrarenal angiotensin II levels are elevated. Additionally, recent research has identified multiple nonhemodynamic effects of angiotensin II that may contribute to progressive renal injury. These include effects on glomerular permeability resulting in exacerbation of proteinuria, plasminogen activator inhibitor-1 production by endothelial and vascular smooth muscle cells, mesangial cell proliferation and transforming growth factor (TGF)-beta expression, macrophage activation, and adrenal production of aldosterone, recently identified as a mediator of renal fibrosis. Taken together, it is clear that angiotensin II plays a central role in the pathogenesis of progressive renal injury through multiple hemodynamic and non hemodynamic mechanism. Inhibition of the production or actions of angiotensin II therefore represent a single intervention that may abrogate many of these mechanisms and would be expected to be effective in slowing the progression of CKD. c. Proteinuria Proteinuria is usually a result of disordered permselectivity of the glomerular filtration barrier and therefore the hallmark of glomerulopathy as well as a marker of disease severity. In the normal kidney small amounts of low-molecular-weight proteins are present in the tubular fluid and are reabsorbed by proximal tubule cells. In vitro experiments have found that culturing renal tubule cells in the presence of high concentrations of plasma protein induces expression of a range proinflamatory cytokines. In therefore seems likely that these proinflammatory molecules are recreted into the peritubular interstitium where they contribute to the development of interstitial inflammation and fibrosis. Thus, proteinuria provides a mechanistic link between glomerular and tubulointerstitial pathology.

Phatogenesis Hypertension in Patiens with CKD 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.

Clinical Feature of Chronic Kidney Disease and Hypertension Chronic kidney disease is often asymptomatic until moderated to severe renal failure has developed. If severe protein-uria is present, peripheral edema may be the first symptom to develop. Patients with advanced renal failure may present with malaise, breathlessness, pruritus, loss of appetite, nausea, and vomiting. Similarly, abnormal clinical signs are often lacking in the patients with CKD. Hypertension is almost universally present and is often the first detectable sign. It is thus critical that all patients with newly diagnosed hypertension be screened for CKD. Peripheral edema may be present in patients with severe proteinuria or more advanced renal failure. Clinical pallor due to anemia may be observed in patients with CKD stage 3-5. Proteinuria is the hallmark of CKD and many be accompained by hematuria.(1) The two major goals of the evaluation of the hypertensive patients are to recognize clinical clues for secondary forms of hypertension and to identify evidence of target-organ damage from the hypertension. Chronic kidney disease should be suspected in patients presenting with severe hypertension, sudden-onset hypertension prior to 30 years of age or after 55 years of age. In such as patients, with all of their functioning kidney mass distal to a critical RAS, maintenance of the glomerular filtration rate (GFR) is dependent upon efferent arteriol vasocontriction mediated by angiotensin II. Once this preservation of function is lost after administration of an ACE or ARB, a decline in renal function seen.(2)

Treatment 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. a. Nonpharmacologica LifestyleModifications Blood pressure and CKD management rely heavily upon the patient's ability to selfmanage 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. 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. Research has shown that a decrease in weight by 10 pounds can decrease blood pressure in normal and hypertensive individuals. 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. Sodium restriction is also a crucial component to dietary intake for patents withCKD.

Alcohol intake contributes to high blood pressure by increasing both systolic and diastolic blood pressure. 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. Recommendations suggest no more than one drink per day in women and two drinks per day in men to reduce overall cardiovascular risk. Recommendations also call for moderate intensity exercise for at least 30 minutes most days of the week. 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

20/11mmHg.

b. Pharmacological 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. 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). 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. Fixed-dose combinations medications have been proven safe and cost effective for the management of hypertension.

Current guidelines, such as those from the JNC-7, recommend achieving adequate blood pressure control by inhibiting the renin-angiotensin axis. 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. 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.

Ironically, the most important adverse effect of ACE inhibitors and angiotensinreceptor 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. 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. Thiazide diuretics are classified according to their chemistry and spesific pharmacological effect of the kidney. Obviously, the recent increased interest in thiazide diuretics has been largely driven by lesson from yhe Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Estabilishing the benefits and risk of the thiazide diuretics requires a prospective study design with emphasis on meningful hard clinical outcomes. To settle the debate about first line drug therapy for hypertension, the National Institutes of Health (NIH) sponsored the ALLHAT, which the double-blind, randomized trial designed to compare the efficacy of a thiazide diuretic (chlortalidone), a calcium channel blcoker (reprenseted by lisinopril). In this landmark trial (without commercial influence) involving 33,357 individuals (age 55 or older) with hypertension and at least one other coronary risk factor. The most common symptoms of thiazide-induced hyponatremia are malaise and lethargy. Other symptoms included dizzy spells, vomiting, mental confusion or obtundation, and falls.(4)

Conclusion 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 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.

References

1. Lerma, Edgar V., Berns, Jeffrey S., Nissenson, Allen R. Nephrology & Hypertension: Slowing the Progression of Chronic Kidney Disease. United States of America: Mc Graw Hill; 2009; 201-203. 2. Lerma, Edgar V., Berns, Jeffrey S., Nissenson, Allen R. Nephrology & Hypertension: Secondary Hypertension. United States of America: Mc Graw Hill; 2009; 361 3. Blandy, John., Kaisary, Amir. Urology: Structure and Function. Singapore: WileyBlackwell; 2009; 24-31. 4. Chow, Kai-Ming. Thiazide Diuretics-Recent Controvesies and new Insight. Medical Progress. 2007; 423-427. 5. Hypertension. Available at: http://hyper.ahajournals.org/cgi/content/abstract/57/6/1076 Accessed on: Jun 5,2011 6.