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. Several studies (the normal hematocrit study, CREATE, and CHOIR) comparing partial with ful l correction of anemia in CKD and in hemodialysis patients have both failed to show that fu ll correction reduces cardiovascular risk, and in fact they suggest an increased risk. Whet her this increased risk is due to the higher hemo- globin (Hb) concentration achieved per s e, or to the high doses of ESA (and iron) required in some (sicker) patients to achieve the higher target Hb, remains uncertain. The TREAT study, a large double-blind, RCT of treatme nt with an ESA versus placebo in diabetics is still ongoing. The NICE guidelines on correct ion of anemia state that ESA treatment should be initiated, after exclusion of other causes of anemia, in patients with CKD whose Hb <11 g/dL, and once on treatment, Hb concentration should be main- tained between 10.5 and 12.5 g/dL. statin treatment for those with a 10 year risk of cardio- vascular disease of \211 30%. The calculation is based on the Joint British Societies \200\231 chart or the cardiovascula r risk calculator (despite the fact that these have not been validated in patients with ren al disease). The dose of statin should be increased to achieve: \200 \200 \200 total cholesterol of <5 mmol/L; 30% reduction from baseline; or fasting LDL-cholesterol of <3 mmol/L. The aim is to achieve the target which represents the greatest reduction. Diabetes Patients with CKD and diabetes have a greatly increased risk of cardiovascular dis ease. Control of HTN and dyslipidemia is at least as important as good glycemic control in reducing this risk. Endothelial dysfunction Impairment of endothelial function is one of the initial steps in t he pathological process leading to atherosclerosis. Endothelial dysfunction is related to g eneric factors which can be present in patients without CKD: \200 \200 \200 \200 \200 hypertension; smoking; diabetes; obesity; dyslipidemia. Dyslipidemia Kidney disease is associated with alterations in lipoprotein structure and fun ction, including: \200 \200 \200 reduced high density lipoprotein (HDL) cholesterol; increased intermediate density lipoprot ein; increased proatherogenic lipid particles. In patients with CKD there are a number of additional fac- tors including: \200 In addition, a number of biochemical alterations in uremia contribute to increased oxidatio n of low density lipopro- tein (LDL). All of these changes promote atherogenesis. The evide nce that lipid-lowering drug treatment reduces cardiovascular event rates in patients with CKD is limited. This is partly due to the exclusion of patients with advanced CKD from larg e statin trials, although post hoc analyzes of these trials have suggested bene \201 t in subgroups with low estimated GFR. Competing cardiovascular risk from nonatherosclerotic vas cular disease (e.g. arteriosclerosis, vascular calci \201 cation, hypertensive heart failu re), may reduce the overall impact of lipid-lowering treatment on outcomes, particularly in advanced CKD. The Die Deutsche Diabetes Dialyse (4D) study showed no bene \201 t from low ering of cholesterol by atorvastatin in type II diabetic patients on dialysis. The ALERT st udy compared \202 uvastatin against placebo in kidney transplant recipients. There was no significant reduction in the prespeci \201 ed composite endpoint, but there were fewer ca rdiac deaths and fewer nonfatal myo- cardial infarctions. Two large ongoing RCTs, SHARP and AURORA, will pro- vide further evidence in the next few years. retention of homocysteine and asymmetric dimethyl- arginine (ADMA); reduced intrarenal gene ration of nitric oxide; oxidative stress; reduced activation of vitamin D; reduced producti on of erythropoietin, renalase, and bone morphogenic protein 7; insulin resistance; low lev el persistent chronic in \202 ammation; activation of the renin \200\223angiotensin system . \200 \200 \200 \200 \200 Hyperhomocysteinemia Raised plasma homocysteine levels are strongly associated with an incr eased risk of cardiovascular disease, both in the general population and in CKD, which is a ssociated with marked hyperhomocysteinemia. Hyperhomocystinemia in CKD is multifactorial, b ut can be partially corrected by B vitamin supplementation. A recent large RCT of reduction of homocysteine with folic acid, pyridoxine and cyanocobalamin in patients with advanced C KD showed no reduction in the vascular event rate. Nitric oxide and asymmetric dimethyl arginine One of the main factors involved in endotheli al dysfunction in CKD is the reduced bioavailability of nitric oxide. K. ANDERSON AND C. TOMSON 414 Nitric oxide is produced and released in the vascular endothelium by endothelial nitric oxi de synthase from L-arginine. ADMA is a competitive inhibitor of nitric oxide synthase which is retained as GFR falls. In CKD, ADMA levels in plasma are markedly elevated from an earl y stage, even when the GFR is still within the normal range. Increased ADMA levels have bee n associated with progres- sion to ESRD and increased mortality. Whether L-arginine supplem entation or administration of nitric oxide donors reduces cardiovascular events is unknown. may contribute to defective capillary supply to cardiac muscle. In patients, it is dif \201 cult to distinguish the effects of hyper- parathyroidism on the cardiovascular system from the con- ditions that contribute to it, including the duration of CKD, reduced 1,25-(O H) vitamin D concentrations, hyperphos- phatemia, and hypocalcemia. Correction of severe hy perparathyroidism is probably ben- e \201 cial in calci \201 c uremic arteriolopathy. The effect of correction of hyperparathyroidism by cinacal- cet on cardiovascular events is cu rrently being studied in the EVOLVE trial. Insulin resistance and hyperinsulinemia Insulin resistance and consequent hyperinsulinemia play a central role in the development of atherosclerosis. Insulin resistance and hyperinsu linemia are present very early in the course of kidney disease, even when GFR is still with in the normal range. Insulin resistance can be measured using the homeostatic model assessm ent (HOMA) technique, from fasting glu- cose and insulin concentrations. The HOMA index has been shown to predict survival in dialysis patients. Insulin resistance and endothelial dy sfunction are inextrica- bly linked with vascular damage. Diet, exercise and drugs may redu ce insulin resistance by a number of mechanisms and may reduce endothelial dys- function an d reduce cardiovascular mortality. It remains uncertain whether the \200\230glitazones \200\231 or other insu- lin-sensitizing drugs reduce cardiovascular events in CKD. Oxidant stress Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body \200\231s ability to inactivate them or easily repair the resulting damage. In CKD, levels of ROS are high, and levels of antioxidants suc h as vitamin E are often low. While studies of vitamin E supplementation in high risk peopl e in the general population (e.g. the Heart Outcomes Prevention Evaluation trial) have conc lusively shown no evidence of reduced cardiovascular risk, some still argue that antioxidan ts, including vitamin E and acetylcysteine, may be of bene \201 t in CKD. The existing tri als evidence suggests that the bene \201 t from vitamin E and acetylcystine were too small to allow any de \201 nite conclusions. Abnormalities of bone mineral metabolism Hyperphosphatemia Raised serum phosphate is associ ated with an increased risk of death in both early CKD and in patients receiving dialysis. Serum phosphate can be reduced by a combination of die- tary restriction of phosphate intak e and ingestion with meals of phosphate binders to reduce phosphate absorption. Phosphate b inders may contain: \200 \200 \200 \200 Low grade in \202 ammation Chronic in \202 ammation is strongly associated with athero- s clerosis both in the absence and presence of CKD. In CKD, chronic inflammation is also asso ciated with reduced levels of fetuin-A, a potent inhibitor of vascular calci \201 cation. Whether any speci \201 c strategies to identify and treat the cause of chronic low-grade i n \202 ammation are of bene \201 t remains uncertain. calcium carbonate; calcium acetate; sevelamer hydrochloride; lanthanum carbonate. Hypertension Hypertension (HTN) is frequently found in patients with CKD and is a powerful risk factor for cardiovascular disease. Although large short-term observational studies of patients on dialysis show that the highest risk of death is among those with the lowest blo od pressure, this is almost cer- tainly because low blood pressure is a marker for heart fa ilure, which may often have been caused by poorly con- trolled HTN over the longer term. Sevelamer also reduces serum cholesterol. It has been reported that sevelamer reduces the r isk of progression of established coronary artery calci \201 cation in patients starting d ialysis. Direct comparison of sevelamer with calcium acetate in 1068 hemodialysis patients followed for a mean of 20 months (the DCOR study) showed no clear advantage of one or other on cardiovascular deaths. Current recommendations in the UK are to achieve a serum phospha te of: \200 \200 Lack of exercise Exercise is of proven bene \201 t in reducing cardiovascular risk in the general population. In CKD, aerobic exercise: \200 \200 \200 decreases microalbuminuria; reduces oxidative stress; may increase GFR. 0.9 \200\2231.5 mmol/L in CKD 3 and 4; 1.1 \200\2231.8 mmol/L in dialysis patients. The choice of phosphate binder is up to individuals. Aerobic exercise in hemodialysis patients has been reported to: \200 \200 Hyperparathyroidism Parathyroid hormone has a number of adverse effects on cardiac myocytes in vitro, and in animal experiments enhance insulin sensitivity; improve lipid pro \201 le; CHAPTER 11.5 Cardiovascular risk factors in chronic kidney disease 415 \200 \200 \200 \200 Smoking Smoking is an important risk factor for progression of CKD and a major risk factor for atherosclerotic vascular disease in diabetic and nondiabetic patients. Cigarette smokin g causes: \200 endothelial dysfunction; \200 reduced synthesis and bioavailability of n itric oxide; \200 atherosclerosis and thrombosis; \200 coronary artery disease; \200 stroke. increase hemoglobin; increase strength; decrease BP; improve quality of life; improve survi val. Left ventricular dilatation Left ventricular dilatation may develop as an end result of: \200 \200 \200 LVH; valvular disease; ischemic injury. All patients with CKD and a reasonable life expectancy should be strongly advised to stop s moking. It carries a particularly poor prognosis. Left ventricular hypertrophy Left ventricular hypertrophy (LVH) is a strong predictor of mo rtality in patients on dialysis. LVH is present from the early stages of CKD and the preval ence of LVH correlates with the degree of renal impairment. In one series the prevalence of LVH was: \200 26.7% if the CrCl was >50 mL/min; \200 30.8% if the CrCl was 25 \200\223 49 mL/min; \200 45.2% if the CrCl was <25 mL/min. Valvular disease Calci \201 cation of the mitral valve annulus and the aortic valve cusps is common with failing renal function. Calci \201 cation may be associated with valvular r egurgitation or (particularly with the aortic valve) with signi \201 cant stenosis. Vascular calci \201 cation Vascular calci \201 cation may be the result of calci \201 ca tion of either atherosclerotic plaques or the media. It is increasingly recognized as an ac tively regulated process and not just the result of passive precipitation of calcium and ph osphorus crystals. Vascular calci \201 cation is a multistep process similar to bone forma tion. Vascular smooth muscle cells undergo a phenotypic switch into osteoblast-like cells a nd then express alkaline phosphatase, osteocalcin and osteopontin. Expression of these bone -associated proteins leads to mineralization of the extracellular matrix (ossi \201 cation ). There is now abundant evidence that phosphate retention is a major factor in vascular ca lci \201 cation. An increase in intracellular phosphate induces vascular smooth muscle cel ls to undergo the phenotypic changes described above. Several regulatory factors that induc e or inhibit vascular calci \201 cation have also been identi \201 ed. The \201 ve key inhibitors currently implicated in vascular calci \201 cation associated with CKD are: \200 \200 \200 \200 \200 Causes of LVH in CKD include: \200 \200 \200 \200 hypertension; volume overload; anemia; decreased conduit artery compliance. Aldosterone Raised aldosterone levels in CKD may contribute to left ventricular \201 bros is. The role of aldosterone antagonists in the prevention of cardiovascular events in CKD r emains uncertain. Obesity There is a strong association between body mass index, progression of CKD, and card iovascular disease. Obesity is associated with: \200 \200 \200 insulin resistance; oxidative stress; endothelial dysfunction. fetuin A (A2-Heremans-Schmid glycoprotein (AHSG); matrix-carboxyglutamic acid protein (MGP) ; bone morphogenic protein (BMP) 7; osteoprotegerin (OPG); pyrophosphate. Adipose tissue secretes a number of adipokines, the serum levels of which are elevated in C KD, probably due to decreased renal excretion. These adipokines are implicated in endotheli al dysfunction and insulin resistance. Weight reduction has been shown to have beneficial e ffects on: \200 \200 \200 \200 \200 Of these, BMP-7 shows the most promise as a future ther- apeutic agent. BMP-7 inhibits vasc ular calci \201 cation, maintains vascular smooth muscle cell differentiation and prevents osteoblas- tic transformation. BMP-7 is mainly expressed by the kidney and its expression is decreased from the early stages of CKD resulting in a progressive loss of ability to inh ibit vascular calci \201 cation. In mice, treatment with BMP-7 has been shown to reduce va scular calci \201 cation. Recombinant human BMP-7 in putty has been used in sev- eral huma n trials for osseous repair after bone fracture, and was shown to be safe and well-tolerate d. hypertension; glomerular hyper \201 ltration; albuminuria; insulin resistance; progression of CKD. There is no direct evidence that weight reduction (either through diet or bariatric surgery ) is of bene \201 t in patients with CKD. For reasons that are highly debated, obesity app ears to confer a survival advantage in dialysis patients. K. ANDERSON AND C. TOMSON 416 Calci \201 c uremic arteriolopathy (CUA) CUA (often referred to as \200\230calciphylaxis \200\231) is characterized by diffuse calci \201 cation of the media of small-to-medium ar teries and arterioles. Intimal proliferation and thrombosis occur resulting in painful skin ulceration and necrosis. Parathyroidectomy may be of bene \201 t if there is marked hyper parathyroidism. Warfarin may precipitate the syndrome, probably by inhibi- tion of factor V II-dependent anticoagulant proteins. CUA carries a very poor prognosis, with a high mortali ty from cardiovascular disease. Kaysen GA, Eiserich JP. The role of oxidative stress-altered lipopro- tein structure and fu nction and microin \202 ammation on cardiovas- cular risk in patients with minor renal dys function. J Am Soc Nephrol 2004; 15: 538 \200\223548. Internet resources NICE guideline on hypertension: http://www.nice.org.uk/CG034 Joint British Societies \200\231 Guidelines on prevention of c ardio- vascular disease in clinical practice: www.bcs.com/download/651/JBS2final.pdf UK CKD guidelines: www.renal.org/CKDguide/ckd.html KDOQI guidelines: Future prospects A number of large RCTs will report in the next few years which may help in the strati \201 cation and management of cardiovascular risk in CKD. These include: \200 \200 \200 \200 www.kidney.org/professionals/kdoqi/guidelines_ bp/index.htm SHARP trial website: SHARP; TREAT; AURORA; EVOLVE. http://www.sharpinfo.org/ See also Clinical approach to hypertension, p. 286 Renovascular disease, p. 292 Hypertensio n in CKD, p. 406 Chronic kidney disease in diabetic patients, p. 472 Medical management of dialysis patients, p. 528 Bone morphogenic protein 7 (BMP-7) shows the most promise as a future therapeutic agent. Further reading Cozzolino M, et al. Vascular calci \201 cation and uremia: what do we know? Am J Nephrol 2008; 28: 339 \200\223346. Go AS, et al. Chronic kidney disease and the risks of death, cardio- vascular events, and h ospitalization. N Engl J Med 2004: 351: 1296 \200\223305. This page intentionally left blank G. KOSMADAKIS 418 Gastrointestinal disorders in chronic kidney disease Introduction Three-quarters of patients with ESRD have gastrointestinal (GI) complaints. Th ere is an increased prevalence of irrita- ble bowel disease, bleeding from angiodysplasia, gas- troparesis, gastritis and duodenitis in ESRD patients compared with the normal populat ion. However, pre- valences of dyspepsia, ulcer disease, and Helicobacter pylori gastritis are not signi \201 cantly different from the gen- eral population. GI disorders are a lead ing cause of hospi- talization in ESRD patients and account for 8 \200\22315% of admissions . H. pylori eradication 14 days treatment with: \200 \200 omeprazole 20 mg bd, or lansoprazole 30 mg od; clarithromycin 500 mg bd and amoxicillin 1 g bd or met- ronidazole 500 mg tds. Biliary tract disease and pancreatitis There is no increase in the incidence of cholecystit is, cholelithiasis and pancreatitis in patients with ESRD. Patients with CKD often have ele vated serum amylase and lipase levels but they do not normally exceed three times the upper limit of normal. Upper GI tract Pathogenetic factors of upper GI disorders Serum levels of hormones involved in the modulation of GI motility and in the regulation of hunger and satiety (e.g. gastrin , cholecystokinin, neurotensin and glucagons) are signi \201 cantly raised as a consequenc e of renal failure. Humoral abnormalities (hypercalcemia, hypokalemia and acidosis) may pla y a role in GI dysmotility and acid secre- tion alteration. Lower GI tract Colonic perforation Spontaneous colonic perforation may occur as a conse- qu ence of: \200 \200 \200 \200 diverticulitis; fecal impaction; dehydration; dialysis-related amyloidosis. Anorexia. Loss of appetite is common, occurring in one-third of ESRD patients and associate d with increased morbidity and mortality. Pathogenesis is largely unknown. Therapy options include: \200 \200 \200 \200 The incidence of diverticular disease is no different from the general population except in cases of autosomal domi- nant polycystic kidney disease where there is an increased incide nce. In patients who have been on dialysis long-term, there may be B2-microglobulin deposit ion in the GI tract causing dys- motility, perforation or necrosis. dietetic counseling and nutritional supplements; appetite stimulants; improvement of dialys is adequacy; renal transplantation. Ischemic bowel disease Symptoms include sudden onset of fever, vomiting and abdominal pain. In patients on peritoneal dialysis this may mimic peritonitis. Predisposing factors: \200 atheromatosis; \200 increased blood viscosity; \200 constipation (high intraluminal p ressure); \200 digoxin (splachnic vasoconstrictor). Gastric emptying and gastroesophageal re \202 ux Patients with CKD have a high prevalence of: \200 \200 \200 \200 prolonged gastric emptying; GI dysmotility; anorexia; nausea and vomiting. Patients on PD and those with dialysis-related amyloidosis have a greater incidence of gast roesophageal re \202 ux. Precipitating factors: \200 \200 \200 \200 severe hypovolemia; congestive heart failure (decreased cardiac output); hypoxia; excessive ultra \201 ltration with intradialytic hypotension. The diagnostic method of choice is me senteric angiography. Pathogenesis Autonomic and enteric nervous system dysfunction due to uremia. Increased leve ls of GI peptides (gastrin, cholecystokinin, neurotensin) due to impaired renal clearance. PD patients show a higher prevalence of delayed gastric emptying compared with HD and predi alysis patients. Hemorrhoids and proctitis There is a high prevalence in ESRD, due to diet and drugs (phosph ate binders). Fecal impaction This may occur secondary to a number of medications commonly prescribed in CKD and ESRD including phos- phate binders, analgesics and oral iron supplements. Treatment includes: \200 \200 Peptic ulcer disease There is no evidence of a higher duodenal ulcer and H. pylori infectio n prevalence compared to the general population. Biopsy proven chronic active gastritis is the most common histological diagnosis among with upper Gl symptoms, patients and is closel y associated with H. pylori infection. The urea breath test remains a valid diagnostic tool for H. pylori infection in CKD and ESRD. stool softeners (e.g. sodium docusate); osmotive laxatives (e.g. lactulose, disacodyl). Idiopathic dialysis ascites This is an exudative ascites. The main cause is inadequate dial ysis. CHAPTER 11.6 Gastrointestinal disorders in chronic kidney disease 419 bacterial peritonitis or pseudoperitontis (due to icodex- trin sensitivity) in patients on peritoneal dialysis. Incidence is declining due to improvements in nutrition and delivered dialysis dose. It is a diagnosis of exclusion. The differential diagnosis includes: \200 \200 \200 \200 \200 \200 \200 Pneumoperitoneum and GI perforation in PD Important points to note are: Free subdiaphragmat ic air on an erect CXR has a low speci \201 - city for the diagnosis of GI perforation in CAPD patients. PD \202 uid may dilute the initial intraperitoneal contamina- tion and, to gether with intraperitoneal antibiotics, mask clinical signs. Perforation is suggested by t he presence of mixed Gram- negative or anerobic organisms in PD \202 uid cultures. The pr esence of feces, food or bile in the PD ef \202 uent indi- cates visceral perforation. constrictive pericarditis; cirrhosis; occult infection (e.g. tuberculosis); encapsulating p eritoneal sclerosis neoplasia; granulomatous peritoneal disease; inferior vena cava stenosi s. Treatment includes: \200 \200 \200 \200 \200 \200 salt and \202 uid restriction; aggressive ultra \201 ltration; intermittent paracentesis ; daily HD; switching from HD to PD; renal transplantation (best treatment). GI manifestations of polycystic kidney disease The most common are: Hepatic cysts which may be associated with: \200 \200 \200 \200 \200 \200 chronic abdominal pain; hemorrhage; infection; rupture; early satiety (stomach compression) ; lower limb edema (inferior vena cava compression). Renal cyst infection will require anti biotics that concen- trate inside the cysts (quinolones) and occasionally percu- taneous dr ainage. Colonic diverticulae which may be associated with: \200 \200 \200 \200 The prognosis is poor: 35% mortality at 1 year. Intestinal pseudo-obstruction Chronic intestinal pseudo-obstruction Symptoms are those of m echanical bowel obstruction but without an anatomical obstructing lesion. Clinical manifest ations include: \200 \200 \200 abdominal pain; vomiting; constipation or diarrhea. constipation; diverticulitis; hemorrhage; perforation. Several potential contributory factors can affect GI neu- romuscular function: \200 \200 \200 \200 amyloidosis (including B2-microglobulin amyloidosis); diabetes mellitus; scleroderma; medic ations (e.g. calcium channel blockers and anti- cholinergic antidepressants). Umbilical and inguinal hernias. Gastrointestinal bleeding There is an increased incidence of GI bleeding in patients with E SRD due to: \200 Investigations: \200 \200 a higher incidence of lesions producing bleeding (partic- ularly a high incidence of erosiv e gastritis and angiodys- plasia); impairment of hemostasis (anemia, uremia); intradialytic anticoagulation; drugs (e.g. antiplatelet agents and warfarin); coexistent GI tract diseas e (B2-microglobulin amyloi- dosis). plain abdominal X-ray; gastric and small bowel transit tests using either scintig- raphy or manometry. \200 \200 \200 There is no proven treatment other than supportive care: \200 temporary parenteral nutrit ion can be used in severe cases; prokinetic agents (e.g. erythromycin). Practical points: \200 \200 Acute intestinal pseudo-obstruction Predisposing factors: \200 \200 \200 high incidence of angiodysplasia in elderly patients; high incidence of amyloidosis in long -term dialysis patients; consider NSAID enteropathy in patients with rheuma- toid arthritis ; constipation due to phosphate binders or kayexalate exacerbating rectal bleeding; uremia- related coagulation abnormalities \200\223 often primary cause or exacerbating factor. chronic constipation; diabetic autonomic neuropathy; medications (e.g. kayexalate, opioid a nalgesics). The acute abdomen All common causes of an acute abdomen are seen in patients with renal fai lure. Common causes to consider include: \200 small bowel or colon obstruction (particularly if previ- ous PD and risk of intra-abdominal adhesions); visceral perforation; bowel ischemia or necrosis (high incidence of acceler- a ted atherosclerosis in CKD and ESRD); intracyst infection and hemorrhage in patients with p oly- cystic kidney disease; Upper GI tract bleeding The incidence of upper GI bleeding has decreased due to improvement s in dialysis practices and treatment with H2 antagonists/proton pump inhibitors. Neverthel ess, upper GI bleeding accounts for 3 \200\2237% of all deaths in ESRD patients. \200 G. KOSMADAKIS 420 Common causative conditions are listed in Table 11.6.1. Cardiovascular disease, current smo king and increasing debility are associated with a greater risk of upper GI bleeding in pat ients with ESRD. Gastric antral vascular ectasia (watermelon stomach) is an angiodysplastic lesion con \201 ned to the gastric antrum. It is characterized by submucosal capillary di latation and \201 bro- muscular hyperplasia. effects on colonic motility of iron supplements, digoxin, phosphate binders and antihyperte nsive therapy. Clostridium dif \201 cile-associated pseudomembranous colitis is more common, more severe and has a higher recurrence rate in patients with renal failure, due to a reduced thresh- o ld for use of antibiotics in relatively immunocompromised patients with ESRD, in older pati ents, and topical enteral factors (dysmotility, abnormal bile acid pro \201 les). Other pa thogens such as CMV in HIV-positive patients and Strongyloides stercoralis may be the causa tive agents of severe enterocolitis in patients with renal failure. General therapy \200 \200 \200 \200 \200 \200 \200 review need for antiplatelet agents and warfarin; maximize hematocrit (EPO and red cell tra nsfusion); minimize effect of uremia with increased dialysis dose; DDAVP (desmopressin); an ti \201 brinolytic agents (tranexamic acid); cryoprecipitate; recombinant activated factor VII. GI complications in patients on PD The most commonly seen are: \200 \200 \200 \200 gastroparesis; malabsorption; pancreatic dysfunction; protein-losing enteropathy. Tranexamic acid is a potent inhibitor of the \201 brinolytic sys- tem and can be used bot h orally and IV. One suggested protocol is 20 mg IV followed for the next 4 weeks by 10 mg/ kg/48 h orally. Additionally, increased intra-abdominal pressure can result in hernia formation, delayed ga stric emptying and gastro- esophageal re \202 ux. A reduction in supine intraperitoneal \202 uid with adjustment of dialysis prescription to maintain adequate clearance may help g astroesophageal re \202 ux. Oral or intraperitoneal erythromycin may improve gastroparesis . In women, pain on infusion of dialyzate and hemoperito- neum may be seen during menstruat ion and ovulation and can also be seen in endometriosis. Pain during dialyzate infusion is not uncommon and may be due to: \200 \200 \200 Speci \201 c therapy Bleeding peptic ulcer: endoscopic laser therapy, topical injection of adrenaline, ethanol or polidocanol. Esophageal varices: endoscopic sclerotherapy, endoscop ic variceal band ligation, balloon tamponade, somatostatin or octreotide infusion. Hemorrha gic gastritis: antacids, H2 receptor antagonists, proton pump inhibitors, sucralfate. Lower GI tract bleeding Angiodysplasia is the commonest cause (Table 11.6.1). Angiodysplasi a is a vascular abnormality affecting the microcirculation of the GI mucosa and submucosa. It commonly causes GI hemorrhage in the elderly. The incidence is increased in HD patients and responsible for 20% of all GI hemorrhages in HD population. Investigations include: \200 the acidic pH of lactate-buffered dialyzate; catheter malposition; hypertonic dialysis solu tions. Treatment options include: \200 \200 \200 \200 switching to bicarbonate-based PD solutions; catheter repositioning or replacement; slowing the infusion rate; injection of local anesthetic into the PD solution before infusion. endoscopic procedures (colonoscopy, \201 ne \201 bre entero- scopy); selective visceral angiography. Scrotal or labial swelling may be seen due to a patent processus vaginalis or a dissection through the peritoneal General therapy \200 \200 \200 \200 \200 \200 \200 review need for antiplatelet agents and warfarin; maximize hematocrit (EPO and red cell tra nsfusion); minimize effect of uremia with increased dialysis dose; DDAVP; anti \201 brinol ytic agents (tranexamic acid); cryoprecipitate; recombinant activated factor VII. Table 11.6.1 Common causes of GI bleeding in patients with ESRD Upper tract bleeding Esophageal varices Mallory \200\223Weis tear Gastritis/duodenitis Pept ic ulcer Angiodysplasia Gastric antral vascular ectasia Dieulafoy malformation B2-Microglob ulin amyloidosis Lower tract bleeding Angiodysplasia Diverticulae B2-Microglobulin amyloido sis Colorectal polyps Hemorrhoids/anorectal tears Stercoral ulcers Speci \201 c therapy \200 \200 estrogen/progesterone preparations; therapeutic endoscopy (electrocoagulation and laser the rapy); surgical resection. Diarrhea Diarrhea is frequently seen in patients with advanced CKD and ESRD and its cause i s often multifactorial: \200 \200 autonomic neuropathy; nonspeci \201 c antibiotic-induced diarrhea; CHAPTER 11.6 Gastrointestinal disorders in chronic kidney disease 421 membrane. This usually requires surgical repair of the her- nia or patent processus vaginal is. Abdominal wall edema, due to dialyzate leak into the ante- rior abdominal wall, may res olve following a period of rest- ing from PD or transfer onto automated PD. Surgical reposi tioning of the catheter may be required if conserva- tive measures fail. Encapsulating peri toneal sclerosis is a rare complication of PD and is associated with a number of GI complic ations, the most serious of which is malabsorption and conse- quent malnutrition. Diabetic enteropathy This presents with episodic watery and painless diarrhea due to: \200 diabetic autonomic neuropathy (vagal, sympathetic and enteric nervous system damage); and b acterial overgrowth (resulting in bile acid deconjuga- tion and fat malabsorption). Treatment involves both supportive therapy with lopera- mide and octreotide and treatment o f any contributing microbial cause of the diarrhea. Further reading Bossola M, Tazza L, Giungi S, Luciani G. Anorexia in hemodialysis GI complications in patients with diabetes Diabetic gastroparesis This is related to diabet ic autonomic neuropathy of the GI tract. Clinical signs include: \200 abdominal bloating; \200 early satiety; \200 episodic vomiting. patients: an update. Kidney Int 2006; 70: 417 \200\223422.