D. TETA 400 other potential contributors such as uric acid, pseudou- ridine, advanced glycation end-pro ducts. Factors other than renal function modulate the hyperlep- tinemia and hyperadiponectinemia a ssociated with CKD and include: \200 fat mass; \200 in \202 ammation; \200 hyperinsu linemia; \200 acidosis. Signi \201 cance of insulin resistance in CKD Insulin resistance is associated with the de velopment of endothelial dysfunction, an early step in the pathogenesis of atherosclerosis. The presence of IR correlates with cardiovascular mortal- ity in nondiabetic dialysis pati ents. Insulin resistance contributes to muscle catabolism in dia- lysed patients. Insulin r esistance may also contribute to the progression of CKD via deleterious renal hemodynamic e ffects. The accumulation of adipokines in CKD may directly con- tribute to the development of CKD a nd associated compli- cations: \200 hyperleptinemia may contribute to protein-energy wast- ing observed in patients with ESRD; hyperleptinemia may worsen the sympathetic overactiv- ity seen in CKD and ESRD; hyperleptin emia promotes hypertension. Assessment of insulin resistance Insulin resistance is assessed by the HOMA-IR (homeosta- s is model assessment of insulin resistance). HOMA-IR calculation: insulin concentration ( U /ml) \227 fasting glucose (mmol/L) The role of hyperadiponectinemia in CKD and its compli- cations is unclear and is awaiting further investigation. Further reading Axelsson J, Stenvinkel P. Role of fat mass and adipokines in chronic 22.5 kidney disease. Curr Opin Nephrol Hypertens 2008; 17: 25 \200\22331. Impact of dialysis technique on insulin resistance Hemodialysis and peritoneal dialysis onl y partially correct the IR seen in patients with CKD. PD is associated with higher insuline mia than HD and a more severe IR due to the result of the glucose load absorbed from glucos e-based dialysis \202 uids. The use of icodextrin and aminoacids as glucose-free peri- to neal dialysis \202 uids reduces IR. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thy roid hormone levels (total and free forms) in euthyroid patients with chronic kidney diseas e. J Intern Med 2007; 262: 690 \200\223701. Feldt-Rasmussen B, Lange M, Sulowicz W, et al.; APCD Study Group. Growth hormone treatment during hemodialysis in a random- ized trial improves nutrition, quality of life, and cardio vascular risk. J Am Soc Nephrol 2007; 18: 2161 \200\2232171. Ritz E. Metabolic syndrome and kidney disease. Blood Purif 2008; 26: 59 \200\22362. Drugs known to improve insulin resistance \200 \200 \200 \200 Seikaly MG, Salhab N, Warady BA, Stablein D. Use of rhGH in chil- dren with chronic kidney disease: lessons from NAPRTCS. Pediatr Nephrol 2007; 22: 1195 \200\223204. ACEIs. ARBs. 25-(OH) vitamin D3. Thiazolidinediones. Internet resources Insulin Resistance and Pre-Diabetes: Adipokines Adipokines are a group of hormones and cytokines secreted by adipocytes. The mos t important adipokines identi \201 ed to date are lep- tin and adiponectin. The known biol ogical actions of leptin include: \200 \200 \200 \200 http://diabetes.niddk.nih.gov/dm/pubs/insulin- resistance/ International Committee for Insu lin Resistance (ICIR): http://www.insulinresistance.us/about.php Growth hormone for children with chronic kidney d isease (The Cochrane Collaboration): anorexia; increased energy expenditure; proin \202 ammatory effects; proatherogenic effect s. http://www.cochrane.org/reviews/en/ab003264. html Adipocytye.co.uk, a website devoted to th e adipocyte and adipokines: The known biological actions of adiponectin include: \200 \200 \200 http://adipocyte.co.uk/Adiposetissuepeptides. htm a potent insulin-sensitizing effect; antiatherogenic effects; anti-in \202 ammatory effect s. See also Sexual disorders in CKD, p. 402 Hypertension in CKD, p. 406 Cardiovascular risk factors in CKD, p. 412 CKD in diabetic patients, p. 472 Adipokines in CKD and ESRD There is marked hyperleptinemia (5 \200\2237 times normal in ESR D: PD > HD). There is moderate hyperadiponectinemia ( 2-fold increase in ESRD). This page intentionally left blank D. TETA 402 Sexual disorders in chronic kidney disease Introduction Sexual dysfunction is a common problem in patients with chronic kidney disease (CKD) both in males and in females. The pathophysiology of these disorders is primarily or ganic in origin. Many factors contribute including: \200 \200 \200 \200 \200 \200 In nonresponders, vacuum erector devices or penile implants may be used. Psychological inte rventions may also be useful. An approach to sexual dysfunction in the male patient is summ arized in Fig. 11.3.1. hormone abnormalities; peripheral vascular disease; peripheral neuropathy; autonomic dysfun ction; drug therapy; psychological factors associated with CKD and its treat- ment. Sexual dysfunction in females Clinical features include: \200 \200 \200 \200 \200 loss of libido; irregularity of menstrual cycle; amenorrhea; anovulation; sterility. Sexual dysfunction in males Clinical features include: \200 \200 \200 \200 \200 <10% of women with ESRD on dialysis have regular menses. loss of libido; impotence; testicular atrophy; gynecomastia; infertility. Hormone abnormalities Estradiol levels are normal to low. Estrone levels are normal to low. Progesterone levels are normal to low. Testosterone levels are normal to low. FSH is norma l. LH is mildly elevated. Increased LH:FSH ratio similar to that seen in prepuberty. Impair ed positive hypothalamic feedback in response to estrogens. No mid-cycle surge of LH and FS H, resulting in no ovulation. Hormonal abnormalities Testosterone is decreased, indicating peripheral testicular failure. Luteinizing hormone (LH) is increased. Follicle-stimulating hormone (FSH) is increased. Re sponse to LH-releasing hormone (LHRH) is unpredict- able (blunted, normal or exaggerated), indicating central hypothalamic abnormalities. Hyperprolactinemia and hyperparathyroidism m ay also contribute (see below). Treatment of sexual dysfunction Much less is known about the factors contributing to sex- u al dysfunction in women with CKD and therefore treat- ments are lacking. There is some evid ence in the non-CKD population that sildena \201 l may be useful for the treatment of fema le sexual dysfunction although there is no evidence in the CKD population. There may be a r ole for psychological interventions in some women. Factors involved in the pathogenesis of impotence Gonadal dysfunction: \200 \200 decreased production of testosterone; hypothalamic \200\223pituitary function; \200 \200 \200 \200 blunted increase in serum LH levels; decreased amplitude of LH secretory burst; variable in crease in serum FSH levels; increased prolactin levels. Psychological factors related to CK D. Zinc de \201 ciency. Medications. Anemia. Secondary hyperparathyroidism. Impaired arter ial in \202 ow and venous drainage of the penis. Autonomic neuropathy. Pregnancy in CKD Female patients with ESRD on dialysis may occasionally become pregnant. Re sidual renal function may improve the likelihood of preg- nancy. Daily dialysis may improve both the likelihood of pregnancy and the maternal and fetal outcomes once pregnancy has oc curred. Impact of renal transplantation Rapidly restores fertility in pre-menopausal women. Ovulati on usually starts within a month of transplantation. Stable graft function, adequate contro l of blood pressure and minimal immunosuppression are advised before con- ception is consid ered, i.e. a waiting time of 2 years after transplantation is usual. Data on the effective ness of contraceptive agents in this setting are lacking. An approach to sexual dysfunction in the female patient is summarized in Fig. 11.3.2. Treatment of impotence Stop B-blockers. Start sildena \201 l or analogs. Consider an eryth ropoesis-stimulating agent: reduces hyperprolactinemia and hyperparathyroidism, but has no effect on plasma testosterone. May alleviate the impact of lack of energy and fatigue on im potence. In some cases: cavernous injections may be tried; should be used with caution in h ypertensive patients (vasoconstric- tor effect). CHAPTER 11.3 Sexual disorders in chronic kidney disease 403 Fig. 11.3.1 Approach to sexual dysfunction in the male patient with CKD. (Reproduced with p ermission from Palmer, 1999.) Fig. 11.3.2 Approach to sexual dysfunction in women with CKD. (Reproduced with permission f rom Palmer, 1999.) D. TETA 404 Further reading Bellinghieri G, Santoro D, Lo Forti B, et al. Erectile dysfunction in uremi c dialysis patients: diagnostic evaluation in the sildena \201 l era. Am J Kidney Dis 2001 ; 38(4 Suppl 1): S115 \200\223117. http://kidney.niddk.nih.gov/kudiseases/pubs/impotence/ index.htm Sexuality and the renal pa tient: http://aakp.org/newsletters/KB-The-Magazine/ Feature-Story/Sexuality/ Sex problems with ren al failure: Bellinghieri G, Savica V, Santoro D. Vascular erectile dysfunction in chronic renal failure. Semin Nephrol 2006; 26: 42 \200\22345. Finkelstein FO, Shirani S, Wuerth D, Finkelstein SH. Therapy insight: sexual dysfunction in patients with chronic kidney disease. Nat Clin Pract Nephrol 2007; 3: 200 \200\223207. http://www.kidney.org.uk/Medical-Info/sex- problems/index.html Lai CF, Wang YT, Hung KY, et al. Sexual dysfunction in peritoneal dialysis patients. Am J Nephrol 2007; 27: 615 \200\223621. See also Endocrine disorders in CKD, p. 398 Psychological aspects of treatment for renal fa ilure, p. 538 Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol 1999; 10: 1381 \200\2231388. Internet resources Clinical trials website listing trials in sexual dysfunction: http://clinicaltrials.gov/ Erectile dysfunction: This page intentionally left blank C. TOMSON AND K. ANDERSON 406 Hypertension in chronic kidney disease Introduction Hypertension (HTN) is frequent in all types of primary kidney disease, and is nearly universally present in patients with advanced CKD. All types of HTN, even those due to \200\230nonrenal \200\231 causes such as endocrine HTN, involve altera- tions in the wa y the kidney handles salt and water. Hypertension is a major risk factor for progression of most types of CKD, so untreated HTN leads to a \200\230vicious cycle \200\231 resulting i n progressive worsening of excretory kidney function and rising blood pressure (BP). Howeve r, excre- tory kidney function is partly dependent on the pressure perfusing the glomeruli, so reduction of BP can also cause deterioration of kidney function. Clinicians treating pa tients with kidney disease and HTN therefore need some understanding of the pathophysiol- o gy of these conditions. and the kidney is therefore both \200\230villain and victim \200\231 in HTN. Whether \200 \230essential \200\231 HTN (de \201 ned as HTN in the absence of \200\230primary \200\231 kidney disease) can cause signi \201 cant kidney damage has been controversial, largely b ecause most large- scale long-term studies (with 20 year follow-up, at least, being necessa ry to answer this question) have not included exhaustive tests to exclude primary renal dis ease at base- line. The histological entity of \200\230hypertensive nephroangiosclero- sis \200\231 is well de \201 ned (having \201 rst been described in wedge biopsies of patie nts undergoing surgical lumbar sympathec- tomy as the only treatment then available for HTN ) and is distinct from other forms of renal injury such as glomeru- lonephritis \200\223 a lthough of course the two conditions can, and often do, coexist. It is also probable that c hronic atheromatous embolism (resulting from ulcerated atheromatous plaques in the renal ar teries or upstream aorta) contributes to the paren- chymal damage seen in patients with CKD and HTN. The association of HTN with a higher risk of progressive loss of GFR among indivi duals with CKD does not, how- ever, prove causality. It is possible, for instance, that bot h HTN and progression are determined by the nature of the underlying kidney dis- ease. Proo f that the association is causal comes from numerous studies demonstrating that antihyperte nsive treatment reduces the rate of progression of most types of kidney disease, with the p ossible exception of polycystic kidney disease. Autoregulation of renal blood \202 ow The kidneys have extensive capacity to autoregulate in response to changes in systemic arterial pressure. In healthy people GFR is independent of BP over a wide range. This autoregulatory range is reduced in CKD and in severe congest ive cardiac failure, so that GFR becomes pressure dependent (Fig. 11.4.1). Diagnosis The diagnosis of HTN depends on repeated, careful meas- urements of resting BP. B lood pressure should be measured according to British Hypertension Society standards: \200 patient seated for \211 5 min; \200 free from caffeine and nicotine for the preceding 30 min; \200 arm supported at heart level; \200 appropriate-sized cuff; \200 two meas urements a few minutes apart; \200 further measurements until two measurements within 5 m mHg of each other are obtained. Types of kidney disease causing hypertension Hypertension is a frequent feature of all type s of parenchy- mal kidney disease. Normal BP in the presence of reduced GFR suggests coin- cident heart failure, but can occur in salt-wasting types of kidney disease (e.g. after rel ief of bilateral urinary tract obstruction). Renal artery stenosis is an important treatabl e cause of HTN, and is not necessarily associated with a reduction of GFR. A so-called \200\230Page kidney \200\231 is caused by encasement of a kid- ney by scar tissue, for inst ance after trauma; release of the scar tissue can cure the HTN. Chronic high pressure reten tion of urine is also an impor- tant treatable cause of HTN. NICE recommends that HTN is diagnosed when: \200 clinic or surgery systolic BP (SBP) >140 mmHg or diasto- lic BP (DBP) >90 mmHg; con \201 r med on two further occasions. HTN should not be diagnosed on the basis of a single BP measurement. Epidemiology Hypertension is extremely common in patients with CKD. 83% of 1795 patients sc reened for the Modi \201 cation of Diet in Renal Disease study were hypertensive, and the fre- quency of HTN increased with reducing glomerular \201 ltra- tion rate (GFR). Hyperte nsion is very common among patients on dialysis and frequently persists after kidney transp lantation, partly due to the effects of calcineurin inhibitors on BP regula- tion. Etiology The major contributors to HTN in CKD are: \200 increased activity of the renin \200\223angiotensin system (RAS); increased peripheral symp athetic nervous system (SNS) activity; expansion of extracellular volume. RAS overactivity is seen in renal artery stenosis, but also in many types of parenchymal ki dney disease. SNS overactivity has been demonstrated in ESRD, and appears to be caused by a n afferent signal arising in Cause or effect? Although HTN is a common consequence of renal injury, it is also a major risk factor for pr ogressive kidney damage, CHAPTER 11.4 Hypertension in chronic kidney disease 407 Transplantation of kidneys from hypertension-prone strains of rat causes the recipient to h ave higher BP than transplantation of kidneys from normotensive strains. Similarly, transpl antation of kidneys from human donors with a history of HTN is associated with higher post- trans- plant BP in the recipient than transplantation of kidneys from normotensive donors. High Chronic hypertension with chronic renal disease e r u s s e r P r a l u r e m o l g a r t n Chronic hypertension with normal renal function Normal Hypertension complicating correction of anemia Rapid correction of longstanding renal anemi a can cause severe HTN (and hypertensive encephalopathy), particu- larly in patients with p re-existing HTN. This may be caused by: \200 \200 \200 \200 I Low 80 120 160 Mean Arterial Pressure (mm Hg) Fig. 11.4.1 Relationship between mean arterial pressure and intraglomerular pressure in hea lth and chronic kidney disease. increases in blood viscosity; extracellular volume expansion; persistence of raised cardiac output; direct effect of erythropoiesis-stimulating agents on peripheral vascular tone; diseased kidneys; no increased traf \201 c is seen in patients who have undergone bilatera l nephrectomy, and the activ- ity is reduced by ACEIs. Glomerular hyper \201 ltration in proteinuric CKD Intraglomerular pressure, and single nep hron GFR, are both increased in many types of kidney disease, including diabetic nephropath y. These changes, together with glomerular hypertrophy, are also seen after experimental re duction in nephron number, and are maladaptive, leading eventually to glomeruloscle- rosis and further loss of functioning nephrons. The increased glomerular pressure causes an incre ase in proteinuria, which causes tubular damage and further con- tributes to nephron loss. The degree of proteinuria is an accurate predictor of the risk of progression of CKD. Reduc tion of urine protein excretion is an important ther- apeutic target in CKD. Drugs that sel ectively decrease intraglomerular pressure, such as ACEIs and ARBs, also reduce proteinuria . These drugs may also have other bene \201 cial effects, for instance on glomerular hyper trophy and \201 brosis. Drugs that increase intraglomerular pressure, such as dihy- dropy ridine calcium channel antagonists, often increase proteinuria. Reduction of glomerular HTN also reduces glomerular hyper \201 ltration, and treatment with ACEIs and ARBs can be exp ected to cause a reduction in GFR of up to 30% in pro- teinuric patients. Short-term treatm ent-induced reduction of GFR has been shown to be associated with long-term stability of GF R among proteinuric patients. Other endocrine effects A number of changes in intrarenal and systemic vasoactive mediators have all been implicated in HTN in the presence of kidney disease: \200 \200 increased production of endothelin; reduced production of medullolipin (a vasodilator lipid produced in the renal medulla); reduced renal or systemic synthesis of nitric oxide (possi bly due to accumulation of asymmetric dimethyl- arginine, an inhibitor of nitric oxide synt hase); de \201 cient production of renalase, a circulating monoam- ine oxidase that catabo lizes circulating catecholamines. Secondary hyperparathyroidism and sleep apnea (common in advanced CKD) may also contribute. Salt sensitivity Humans and experimental animals vary in their response to altered salt int ake, with \200\230salt-sensitive \200\231 and \200\230salt-resistant \200\231 phenotypes. By de \201 nition, higher salt intake causes more of a rise in BP in salt-sensitive than in salt-resistant individuals. In general, salt-sensitive HTN is more common in people of B lack race and in older people, but is also common in CKD. Salt-sensitive HTN responds to re striction of dietary salt intake and to diuretic treatment, both of which are there- fore i mportant in the treatment of HTN in CKD. Salt sensitivity is associated with renal microvas cular changes causing local ischemic damage. Risk factors for the development of salt-sensi tive HTN include: \200 Arterial hypertension as a treatable risk factor for progressive kidney disease Patients wi th kidney disease have more to gain from ade- quate treatment of HTN, both because they are at increased risk of cardiovascular disease and because of the risk of progressive loss of GFR. Patients with proteinuria are more at risk of progression, and have more to gain (in terms of prevention of progres- sion) from BP reduction. low birth weight (associated with reduced nephron number); Black race; obesity; insulin res istance; hyperuricemia; low-level lead intoxication. \200 \200 \200 \200 Crosstransplantation experiments and observations Evidence that the kidneys themselves are major contribu- tors to HTN comes from a variety of sources. Treatment thresholds and targets Current UK guidelines state that the threshold for initia- tion of treatment, and the target BP, should be lower in the C. TOMSON AND K. ANDERSON 408 Renal artery stenosis Reduction in renal perfusion caused by stenosis of the renal artery r esults in increased renin release from the underperfused kidney, which causes systemic HTN. If the other kidney has a normal arterial supply, pressure- natriuresis occurs, causing vo lume contraction. This can occasionally cause the \200\230hyponatremic hyperten- sive synd rome \200\231, a type of hyponatremia caused by hypovo- lemia-induced secretion of antidiur etic hormone. If both kidneys are involved, volume expansion occurs, with a risk of recurre nt \200\230 \202 ash \200\231 pulmonary edema, a form of hypertensive heart failure that can occur despite normal left ventricular systolic function. presence of proteinuria (de \201 ned as a random urine PCR of \211 100 mg/mmol/L). No pro teinuria: \200 \200 threshold \211 140/90 mmHg target <130/80 mmHg. With proteinuria: \200 \200 threshold \211 130/80 mmHg target <125/75 mmHg. These guidelines (along with all other guidelines on BP) can be dif \201 cult to implement because current antihyper- tensive therapy does not allow the clinician to manipulate SBP and DBP separately. Pulse pressure (SBP minus DBP) rises as a consequence of reduced compli ance of conduit vessels, which is common in kidney disease and aging. For patients with hig h pulse pressures, it is reasonable to titrate treatment against mean arterial blood pressu re (MAP), as was done in the trials on which these recom- mendations were based. Types of renal artery stenosis Fibromuscular dysplasia (FMD) is a nonatherosclerotic, nonva sculitic, nonin \202 ammatory disease most commonly affecting the renal and cerebral arter ies. The main subtype, medial dysplasia, is characterized by variable thickness of the arte rial media, causing a \200\230string of beads \200\231 appearance on angiography. It may b e complicated by aneurysm formation or dissection. Intimal and adventi- tial \201 broplas ias are rarer. FMD is said to be a disease of young women, but can occur in both genders an d at any age. Atherosclerotic renal ar ter y stenosis (ARAS) is usually associated with wid espread atherosclerotic disease and most commonly affects the ostium of the renal artery. MAP = diastolic + 1/3 pulse pressure. For example, the MAP is 92 at 125/75 but also at 146/65, 156/60, 166/55, and 176/50. Importance of salt restriction Hypertension in the presence of established kidney disease i s nearly always salt-sensitive, and restriction of dietary intake of sodium chloride is the refore important. Sodium bicarbonate does not have the same effect on extracellular volume or BP as sodium chloride, and so can be used in the treatment of acidosis in CKD without co m- promising BP control. Restriction of salt intake is particularly important in the presen ce of proteinuria: a high salt intake completely abro- gates the antiproteinuric effect of ACEIs. Salt intake can be assessed by measurement of 24 h urinary sodium excretion. Intakes of >300 mmol/24 h are common in the UK but intakes of <100 mmol/24 h can be achieved by di etary modi \201 cation, although many \201 nd this very dif \201 - cult to accomplish. Kidney function in renal artery stenosis Even in severe bilateral FMD, the GFR is seldom re duced. Reduced GFR in ARAS is caused by parenchymal kidney disease, to which the diseased p laque may contribute by causing repeated showers of atheromatous ( \200\230cholesterol \200 \231) emboli into the renal circulation. Diagnosis of renal artery stenosis In skilled hands and with slender patients, duplex USS h as good diagnostic accuracy. Isotope renography has largely been supplanted by CT or MR ang iography. Direct angiography is usually only undertaken when it is proposed to proceed to t reatment by angioplasty. Choice of antihypertensive drug treatment The choice of which drug to use is far less impor tant than the BP reduction achieved. A combination of drugs is nearly always required to ac hieve perfect BP control. The effect of antihypertensive drugs on intraglomerular pressure (a measure of the extent to which systemic pres- sure is transmitted to the glomerulus) var ies. ACEIs and ARBs decrease intraglomerular pressure, whereas dihydropyridine calcium chan nel blockers increase it. Reduction of proteinuria, and prevention of progressive kid- ney damage, is associated with reduction in intraglomerular pressure, so ACEIs and ARBs are the drugs of \201 rst choice, particularly if the systemic BP remains above target. If compl iance with dietary salt restriction is poor, diuretic therapy can also augment the antiprot einuric effect of RAS inhibition. It is widely stated, without good evidence, that thiazide diu- retics are ineffective in advanced CKD. These drugs have the advantage of promoting p otassium excretion, which can be useful in advanced CKD, particularly when ACEIs or ARBs ar e used. Treatment of renal artery stenosis Percutaneous balloon angioplasty is the standard of care for FMD of the renal arteries. For treatment of ARAS, angioplasty is nearly always fol- lo wed by stent placement. Various surgical revascularization techniques including autotranspl antation are available for patients in whom per- cutaneous treatment is impossible for tech nical reasons. When to look for, and treat, renal artery stenosis Investigating patients for \200\230trea table \200\231 causes of HTN requires an analysis of the costs and complications of investi gation versus the likelihood of bene \201 t from treatment. Most guidelines suggest that i nvestigation for RAS should be reserved for patients with atypical presenting features: \200 \200 young age; recurrent pulmonary edema with normal systolic function; CHAPTER 11.4 Hypertension in chronic kidney disease 409 rise in serum creatinine >20% from baseline during ACEI or ARB treatment; resistance to sta ndard drug therapy. In patients with a high prior probability of ARAS, treat- ment-induced rise in serum creati nine probably indicates functionally signi \201 cant ARAS, with GFR being preserved by int ense angiotensin-II-mediated efferent arteriolar vaso- constriction; in patients with paren chymal kidney disease, the same phenomenon probably indicates a reduction in intraglomerula r hypertension by efferent arteriolar vasodilatation. Proteinuria is probably the best sing le discriminator between these two states. In addition to these recommendations, it is also good prac- tice to advise patients (and their GPs) that ACEIs and ARBs should be discontin ued temporarily in the face of intercur- rent illness, particularly if associated with hypo volemia or hypotension. The likelihood of \201 nding ARAS is greater in: \200 \200 \200 smokers; patients with known atherosclerotic disease; patients with abdominal bruits. The effect of correction of RAS on BP is greater in FMD than in ARAS. Whether treatment pre vents progressive loss of GFR in ARAS is uncertain. Two large clinical trials (ASTRAL, CORA L) are currently investigating the effect of angioplasty and stent placement on the outcome of ARAS. Hypertension in end-stage renal disease Hypertension is common, and is probably a major con - tributor to the high cardiovascular mortality in patients receiving dialysis. Short-term observational studies showing higher mortality with lower BP are a good example of \200 \230reverse causation \200\231: systolic failure causes low BP and is associated with a hig h risk of death. Systolic failure in dialysis patients may itself result from sustained poo rly controlled HTN, and this would be an argument for aggressive treatment of HTN in these patients. How to achieve this safely remains controversial. Adverse effects of renin \200\223angiotensin axis inhibition in the presence of reduced ren al perfusion Autoregulation of GFR is achieved, in part, by local activa- tion of the RAS i n response to decreased renal perfusion. Locally produced angiotensin II causes preferentia l vaso- constriction of efferent glomerular arterioles, with less effect on afferent arteri oles. This mechanism maintains glomerular pressure and \201 ltra- tion in a number of set tings, including: \200 \200 severe renal artery stenosis; severe hypovolemia (diarrhea, vomiting, or hemor- rhage); eff ective hypovolemia caused by heart failure. In these settings, use of ACEIs or ARBs can precipitate an acute fall in GFR. This is more likely to be noticed (if using serum creatinine as a \201 ltration marker), and the clini cal consequences likely to be more severe, if the GFR is already low \200\223 and may go u nrecognized if baseline renal function is near normal (e.g. in unilateral renal artery sten osis). Among patients referred because of a clinical suspicion of ARAS, a rise in serum cre atinine \211 20% is highly predictive of signi \201 cant RAS on angiography. The reductio n in GFR is reversible if the ACEI or ARB is withdrawn promptly, but irreversible renal atr ophy may be the consequence of continued use of ACEI or ARB in the presence of severe RAS. The risk of this complication has to be weighed against the bene \201 ts of ACEI or ARB tr eatment in heart failure and atherosclerotic vascular disease. Current recommendations for the use of ACEIs and ARBs require that serum creatinine is checked: \200 \200 \200 Treatment of hypertension in patients on dialysis An oversimpli \201 ed but useful clinica l approach is to regard all HTN in kidney failure as a combination of: \200 \200 volume overload and overactivity of the RAS, with different contributions from each in individual patients. It follows from this simpli \201 cation that BP can usually be controlled in patients receiving conventional thrice we ekly hemodialysis (HD) by the achievement of \200\230dry weight \200\231 combined with the use of ACEIs or ARBs. B-Blockers should be used in the presence of ischemic heart disease or systolic dysfunction. Vasodilator drugs increase the risk of intradialytic hypoten- sion , which itself may contribute to progressive myocardial injury, and should be avoided if po ssible. It is possible to obtain excellent drug-free BP control by volume control alone, us ing long slow dialysis, at the expense of frequent muscle cramps for the \201 rst 4 \200 \2236 weeks of treatment and loss of residual urine output. BP slowly normalizes during thi s 4 \200\2236 week period (the \200\230lag phase \200\231) and normotension is associated with a low systemic vascular resistance ( \200\230paradoxical vasodila- tation \200\231) de spite volume contraction, suggesting that salt depletion causes changes in resistance vesse ls during the \200\230lag \200\231 phase. Patients treated with daily HD also often achiev e drug-free normotension. The following pragmatic rules are useful in the manage- ment of H TN in dialysis patients: \200 prior to initiation; within 2 weeks after initiation; after each dose increase. Repeated measurements are required to con \201 rm a sus- pected deterioration of kidney fu nction. Referral is recommended if a rise in serum creatinine of >20% is detected. These re commendations may appear to con \202 ict with the recommendation that ACEIs or ARBs are us ed in parenchy- mal kidney diseases, and that a treatment-induced rise of serum creatinine of up to 30% is acceptable and may pre- dict future stabilization of kidney function. The r ecommendations are based on evidence collected in very different populations. In a dialysis patient with poor BP control, whose BP was previously well controlled on the same or less drug treatment, the patient has lost body weight, and the C. TOMSON AND K. ANDERSON 410 Internet resources British Hypertension Society: guidelines on measurement of blood pressur e and on treatment: HTN will respond to a progressive reduction in target weight. In patients with no kidneys ( bilateral nephrectomy, no transplant kidneys in situ), HTN is always caused by \202 uid o verload, and antihypertensive drug treatment is never necessary. Symptomatic hypotension du ring dialysis does not neces- sarily mean that the target weight is set too low; it might r esult from many other factors, including vasodilatation caused by drugs or heat transfer, t he rate of \202 uid removal, rapid reduction in plasma urea concentration, etc. A rise in BP during HD is nearly always due to \202 uid over- load, not \202 uid depletion; so-c alled \200\230paradoxical HTN \200\231 due to removal of too much \202 uid is very rare. Achieving sodium balance in PD patients can be dif \201 cult due to differential removal of sodium and water ( \200\230sodium sieving \200\231); dietary restriction of sodium intak e is impor- tant, particularly in those with low residual kidney function. http://www.bhsoc.org/ NICE guideline on hypertension: http://www.nice.org.uk/CG034 Fibromuscular Dysplasia Society of America: www.fmdsa.org ASTRAL trial website: www.astral.bham.ac.uk CORAL trial website: www.coralclinicaltrial.org UK CKD guidelines: www.renal.org/CKDguide/ckd.html KDOQI guidelines: www.kidney.org/professionals/kdoqi/guidelines_ bp/index.htm Useful site for calculating Mea n Arterial Pressure: Future prospects Both the ASTRAL trial and the CORAL trial may give further information on how to treat atherosclerotic renal artery stenosis. Preliminary reports from ASTRAL indicat e no bene \201 t from revascularisation over medical treatment, despite inclusion of many patients with bilateral stenoses. www.mdcalc.com/map See also Clinical approach to hypertension, p. 286 Renovascular disease, p. 292 Hypertensiv e children, p. 304 Hypertensive disorders in pregnancy, p. 310 Cardiovascular risk factors in CKD, p. 412 Further reading Guyton AC. Renal function curve \200\223 a key to understanding the pathogenesis of hypertension. Hypertension 1981; 10; 1 \200\2235. Johnson RJ. Subtle acquired renal injury as a mechanism of salt- sensitive hypertension. N Engl J Med 2002; 346: 913 \200\223923. Palmer BF. Renal dysfunction complicating the treatment of hyper- tension. N Engl J Med 2002; 347: 1256 \200\2231261. This page intentionally left blank K. ANDERSON AND C. TOMSON 412 Cardiovascular risk factors in chronic kidney disease Introduction Cardiovascular disease is the single leading cause of mor- bidity and mortalit y in patients with CKD at all stages. The risk of a cardiovascular event (de \201 ned as h ospitalization for coronary disease, heart failure, stroke, or peripheral arte- rial diseas e) increases inversely as the GFR falls (Fig. 11.5.1). It is increasingly recognized that e ven minor impairment of kidney function is a powerful risk factor for cardiovascular diseas e. Patients who reach ESRD are a minority who have survived. In all but young patients with CKD, the risk of death, primarily from cardiovascular causes, is higher than the risk of n eeding dialysis or transplantation. Arterial disease in CKD is a combination of: \200 For every 0.4 mg/mmol increase in the ACR, the adjusted hazard of major CV events increases by 5.9%. In the SAVE study cohort, albuminuria and reduced eGFR were independently and add itively associated with increased mortality. Whether these two risk factors in \202 uence outcomes by the same or separate mechanisms has not yet been established; endothelial dysfu nction would be a potential common pathway. Two large studies have demonstrated that reduct ion of albuminuria with an ARB in diabetic and nondiabetic sub- jects results in a reductio n in cardiovascular risk. Altered conduit artery function Endothelial dysfunction, arteriosclerosis and vascular calc i- \201 cation all interfere with the cushioning effects of large arteries, causing incre ased pulse wave velocity and earlier re \202 ection of the systolic pressure wave. This re sults in a widened pulse pressure which in the heart results in: \200 atherosclerosis (characterized by focal lipid-laden intimal plaques); arteriosclerosis (cha racterized by diffuse medial thicken- ing and reduplication of the internal elastic lamina) . Fundamental to each of these processes is endothelial dysfunction. Myocardial damage may be the result of: \200 \200 increased systolic pressures causing left ventricular hypertrophy; reduced subendocardial p erfusion during diastole, exacerbating the effects of relatively minor coronary stenoses. ischemic damage following coronary artery occlusion; diffuse muscular hypertrophy and \201 brosis. In addition to conventional risk factors it is increasingly rec- ognized that there are a n umber of factors peculiar to CKD that markedly increase the risk of cardiovascular disease. Each of these is discussed below. Pulse wave velocity is raised in: \200 \200 patients with CKD stage 3 or higher; patients with \211 1 g/24 h proteinuria. Albuminuria The presence of albuminuria suggests an increase in glomerular permeability and it may be an easily measured marker of diffuse endothelial dysfunction. Albuminuria is a p otent risk factor for cardiovascular dis- ease in individuals with and without diabetes, an d has been associated with increased cardiovascular risk independ- ently of GFR. It is now increasingly recognized that cardiovascular risk begins to rise at levels of urinary albumi n excretion within the currently de \201 ned normal range (albumin/creatinine ratio (ACR) as low as 0.5 mg/mmol) and that the risk increases along a continuum. Increased pulse wave velocity is correlated with the extent of cardiovascular disease in CK D and with poorer survival in dialysis patients. Anemia The prevalence of anemia increases with falling GFR and there is a strong associatio n between anemia and cardio- vascular disease. In observational studies, anemia is associat ed with LVH independently of HTN and is also associated with the development of LV dilatati on and death. 4 3.5 ) l a v r e t n o i t a r 3 d r a z a h 2.5 i e c n e d 2 d e t s u d A i f n o c % 5 9 ( 1.5 j 1 0.5 0 >60 45 \200\22359 15 \200\22329 30 \200\22344 Estimated GFR in mL/min/1.73 m2 <15 Fig. 11.5.1 Adjusted hazard ratio for cardiovascular events in adults according to estimate d GFR in an unselected population of 1 120 295 adults. CHAPTER 11.5 Cardiovascular risk factors in chronic kidney disease 413 Randomized controlled trials (RCTs) comparing different strategies for correcting anemia wi th erythropoiesis-stimu- lating agents (ESAs) have shown that partial correction of renal a nemia: \200 \200 \200 SHARP will compare the combination of simvastatin and ezetimibe with placebo on the risk of major vascular events among 9000 patients with CKD who do not have estab- lished coronary heart disease on enrolment. AURORA is examining the effect of rosuvastatin versus placebo o n cardiovascular disease in >2750 patients on hemodialysis. Pending the results of these tr ials, current UK guidelines suggest adoption of the guidelines for primary and second- ary prevention of cardiovascular disease that apply to the general population: \200 prevents the development of LVH; improves physical functioning; improves quality of life.