Management of renal anemia Many of the symptoms associated with ESRD such as fatigue, depre ssion, reduced exercise tolerance and dysp- nea are attributable to anemia. The treatment o f anemia was revolutionized by the introduction of recombinant human erythropoetin (EPO). M anagement of anemia in ESRD should also include: \200 \200 \200 \200 \200 prevention of blood loss; ensuring adequate iron stores; provision of adequate dialysis; co ntrol of hyperparathyroidism; avoidance of aluminum overload. Most anemia guidelines recommend a target hemoglobin level of >11 g/dL in ESRD. However, th erapy does carry side-effects (Table 13.6.1) and there is increasing evidence that there is little bene \201 t and possibly some risk in main- taining hemoglobin levels >13 g/dL. Resistant anemia Some ESRD patients are relatively resistant to therapy with ESAs. This sho uld be investigated in patients who fail to attain the target hemoglobin while receiving do ses of EPO >300 \200\223450 IU/kg/week. A variety a conditions may produce resistance (Tabl e 13.6.3); this is most often due to an absolute, relative or functional iron de \201 cien cy. A further escalation in the EPO dose will result in achieve- ment of the target hemoglo bin in up to 10% of patients with resistant anemia, in whom these conditions have been excl uded or treated. Iron management There is a synergistic relationship between iron and EPO therapy: EPO incre ases iron requirements by stimulating red blood cell formation while adequate iron increase s red blood cell production and reduces EPO requirements. This is especially important duri ng initial therapy when EPO is being used to correct rather than maintain hemo- globin. ESR D patients will typically require iron supplemen- tation. Historically, iron stores have be en assessed using ferritin and transferrin saturation, but it is now recognized that ESRD p atients with values in the normal range may still have both an absolute and functional iron deficiency. Several other tests have been introduced to determine iron stores (Table 13.6. 2). Typically these are assessed monthly in ESRD patients. Some PD patients will maintain h emoglobin level within the target range without EPO or supplemental iron ther- apy. Typical ly a proportion of PD patients will require oral iron supplementation, whereas most HD pati ents will require intravenous iron supplementation. Intravenous iron is available in severa l forms and is gener- ally safe. Rarely anaphylaxis may occur and careful moni- toring is r ecommended during administration. Management of renal bone disease Changes in bone and mineral metabolism appear early in CKD . Several types of lesions may be present in the ESRD patient. Typically these are thought of as disorders of high or low bone turnover (Table 13.6.4). Clinical manifestations The clinical symptoms of renal bone disease are often nonspeci \201 c and include: \200 \200 \200 \200 \200 \200 acute and chronic bone pain; pain around individual joints; muscle weakness; skeletal defor mities; pruritis; extraskeletal calci \201 cations including calciphylaxis. Treatment with erythropoiesis stimulating agents Diagnosis Double tetracycline labeling followed by bone biopsy remains the gold standard fo r the diagnosis of renal osteod- ystrophy but is not routinely performed in clinical practi ce. Conventional X-rays are frequently performed but are an insensitive test. Several erythropoiesis stimulating agents (ESAs) are com- mercially available although this varies from country to country. Available ESAs include: \200 \200 \200 epoetin alpha; epoetin beta; epoetin delta; CHAPTER 13.6 Medical management of the dialysis patient 529 Table 13.6.1 Potential bene \201 ts and risks of partial or complete correction of anemia with erythropoetin Mild bone disease Normal Improvements in: Cardiac function Quality of life Exercise capacity Cognition Sexual functi on/menses Nutrition Sleep Immune function Coagulopathy Increased risk of: Hypertension Graft thrombosis Pure red cell aplasia Seizures/encephalopa thy Cardiovascular disease (if Hb >13.5 g/dL) Osteomalacia Adynamic bone Osteitis fibrosa cystica Mixed osteodystrophy High bone turnover Low bone turnover Fig.13.6.1. The spectrum of renal bone disease. Table 13.6.2 Laboratory tests used to assess iron stores in ESR These are routinely measured in patients with CKD and ESRD and can be used to guide treatme nt. Ferritin Transferrin Transferrin saturation Serum iron Protoporphyrin Percent hypochromic r ed cells Reticulocyte hemoglobin Serum transferrin receptor Management Treatment should begin early in the course of CKD in order to prevent skeletal c hanges developing. In ESRD patients serum calcium, serum phosphate and calcium phosphate pr oduct should be assessed monthly and PTH concentration should be assessed 3-monthly. These parameters should be considered together when determining the appropriate management. Achie ving ideal targets is challenging with conventional dialysis and currently available therap ies. Table 13.6.3 Conditions associated with erythropoietin resistance in ESRD patients Absolute, relative or functional iron de \201 ciency In \202 ammation/infection Hyperpara thyroidism Aluminum overload Vitamin de \201 ciency (B12, folate) Myeloma/myelo \201 bros is/other hematological disorders Malignancy Malnutrition Patient concordance with treatment Control of serum phosphate Control of phosphate is the key to effective therapy and the ser um concentration of phosphate should be main- tained between 1.1 and 1.78 mmol/L. Initially a renal dietician should provide education and counseling about restriction of dietary int ake of phos- phate. If this is ineffective the next step is use of a phosphate binder. Vari ous agents have been used including: \200 \200 \200 \200 \200 aluminum hydroxide; magnesium salts; calcium salts; sevelemar; lanthanum carbonate. Table 13.6.4 Bone lesions in ESRD Osteitis \201 brosis cystica Characterized by very high bone turnover with marrow \201 brosis Mild bone disease Calcium salts are currently \201 rst-line therapy, although daily doses may need to be li mited due to the risk of hypercalcemia and the potential to worsen vascular calci \201 - c ation. Less severe disease characterized by an increase in the osteoid surface and high/normal bon e formation Osteomalacia Characterized by an excess of unmineralized osteoid Adynamic bone disease Control of serum calcium The serum calcium should be maintained in the range of 2.1 \200 \2232.4 mmol/L. This should be assessed using a predialysis sample in HD patients and ideal ly should be maintained at the lower range of normal unless this worsens hyperparathyroidis m. This may be achieved by oral calcium supplementation, use of calcitriol, which will incr ease both calcium and phos- phate concentrations, and by manipulating the dialyzate calcium . The ideal calcium dialyzate concentration is unclear. Characterized by low bone formation Mixed renal osteodystrophy There is both an increase in marrow \201 brosis and unmineralized osteoid Other, e.g. 2-microglobulin amyloidosis Serum biochemical markers are routinely used as surro- gate markers of renal bone disease a nd include: \200 \200 \200 \200 calcium; phosphate; parathyroid hormone; alkaline phosphatase. J.R. DE ZOYSA 530 Table 13.6.6 Clinical syndromes of 2-microglobin amyloidosis The calcium phosphate product The calcium phosphate product (serum calcium mulitplied by se rum phosphate) has been regarded as a risk factor for extraskeletal calci \201 cation. A c alcium phosphate product of <4.0 mmol2/L2 is ideal. Control of serum PTH In ESRD patients c oncentrations of intact PTH in the nor- mal range suggest low bone turnover whereas concent ra- tions >3 \227 normal are suggestive of high bone turnover. An iPTH level of 2 \200\2233 \227 normal (16.5 \200\22333 pmol/L) is thought to be optimal. This may be achieved by man ipulation of serum phosphate, calcium and use of calcitriol. Surgical parathyroidectomy may be indicated in certain patients (Table 13.6.5). Calcimimetic agents increase the sensitiv ity of the calcium- sensing receptors in the parathyroid glands, which is the dominant regu lator of PTH secretion and parathyroid gland hyperplasia. The exact role of these agents is as yet unclear but they are likely to prove important in the treat- ment of hyperparathyro idism and reduce the need for sur- gical parathyroidectomy. 2-Microglobulin amyloidosis E SRD patients typically have serum concentrations of 2- microglobulin ( 2M) 30 \200\22350 -fold greater than normal and are at risk of developing amyloidosis (A 2M) affecting the s keletal system. Risk factors for development of A 2M include: \200 \200 \200 Carpal tunnel syndrome Peripheral arthropathy Tendon rupture/contracture Spondyloarthropath y Osseous involvement Subcutaneous masses Renal calculi Although of unproven bene \201 t it is reasonable to consider the use of biocompatible HD membranes, hemo \201 ltration or hemodia \201 ltration at high blood \202 ow rates with ultrapure dialyzate. Patients with A 2M require symptomatic treatment and can require pro mpt surgical measures from orthopedic, neurosurgical or urological services. Nutrition Part of the routine care of the dialysis patient will include an initial and then regular review of their nutritional status, typically performed in conjunction with a rena l dietician. Malnutrition is common in dialysis patients and associated with worse morbidit y and mortality. The effect of dialysis on nutritional requirements Dialysis itself carries speci \201 c nu tritional demands for the patient. HD is associated with protein loss into the dialyzate an d an increase in protein catabolism. Thus when starting HD an increase in the protein and c aloric intake is required to maintain a neutral nitrogen balance. Water-soluble vitamins ar e removed in the dialyzate and should be supplemented. Recommended daily vitamin supplement s in patients on HD are: \200 \200 \200 older patients; duration on dialysis; loss of residual renal function. Other factors potentially involved include: \200 \200 \200 \200 type of HD membrane; high bone turnover renal osteodystrophy; use of impure dialyzate; skel etal accumulation of iron and aluminum. vitamin C, 100 mg daily; folic acid, 1 mg daily; vitamin B6, 10 mg daily. Several clinical manifestations occur (Table 13.6.6). The ini- tial presentation of A 2M i s often subtle and only becomes apparent with time. Often more than one clinical syndrome m ay occur. Conventional X-ray is an inexpensive, readily available screening test but will u sually underestimate disease. Ultrasonography, radionuclide scanning and CT scanning have a ll been used; if available, MRI is the best radiological test. Histological examination of affected tissue will con \201 rm the clinical and radiological diagnosis. Successful renal transplantation will restore 2M concen- trations to the normal range but it is unclear w hether this will cause established lesions to regress. Patients on PD absorb, on average, 70% of the glucose infused from the dialyzate. Patients will often reduce their oral carbohydrate intake to compensate for the glucose load from th e dialyzate. Typically 5 \200\22315 g of protein, mainly in the form of albumin, is lost ea ch day in the dialyzate. This loss increases, during episodes of PD peritonitis, and remain s increased for weeks after resolution of the episode. Other factors affecting nutrition in dialysis patients A number of other factors may contri bute to malnutrition in dialysis patients (Table 13.6.7). Progressive uremia is associated with a decline in appetite and inadequate dialysis may contribute to a reduced intake in ES RD patients. Other factors which need to be considered include slowed gastric emptying and depression. Metabolic acidosis stimulates protein catabolism and may contribute to a reduct ion in the level of the anabolic ster- oid IGF-1. Correction of metabolic acidosis will lim it this catabolic state. Endocrine abnormalities may also contribute to malnutition. Observ ational data have shown elevated levels of leptin in ESRD patients associated with reduced dietary intake. Table 13.6.5 Indications for parathyroidectomy Severe hyperparathyroism and: uncontrollable hyperphosphatemia; \200 unresponsive to calcium and calcitriol; \200 met astatic calci \201 cation; \200 a potential renal transplant recipient. Hyperparathroidi sim and calciphylaxis CHAPTER 13.6 Medical management of the dialysis patient 531 by the renal dietician. If repeated by the same person then interobserver error is small. M ore sophisticated measures such as dual-energy X-ray absorbimetry (DEXA) and bioimpedance a nalysis (BIA) are not commonly performed in routine clinical practice. Laboratory tests wil l also alert the clinician as to the nutri- tional state of the patient: serum potassium, p hosphate, albumin, prealbumin, transferrin, urea and creatinine may all decline in the maln ourished patient. The protein catabolic ratio (PCR), also known as the nor- malized protein equivalent of nitrogen appearance (nPNA), may be used to assess nutrition in ESRD patients in a steady state. In HD patients it is determined by measuring the interdia- lytic appear ance of urea in body \202 uids as well as any urea excreted in the urine, where there is residual renal function. In PD since the removal and generation of urea is relatively const ant, urea generation is estimated from measurement of dialyzate and urinary urea losses. A target of 1.0 \200\2231.2 g/kg per day or higher is recom- mended. Table 13.6.7 Causes of malnutrition in patients with ESRD Reduced intake Inadequate dialysis Poor dentition Cultural food preferences Inability to obtain or prepare food Slowed gastric emptying Depression Metabolic abnormalities Metabolic acidosis Altered amino acid metabolism Insulin resistance Endocrine abnormalities Hyperleptinemia Insulin resistance Catabolism from PTH IGF-1 resistance Systemic in \202 ammation Intercurrent illness Elevated PTH is also associated with increased protein degradation. In \202 ammatory proce sses are common in ESRD patients and may contribute to malnutrition. This may be related to increased frequency of infections, uremia, proin \202 ammatory cytokines and atherosclero sis. The malnutrition, in \202 amma- tion and atherosclerosis (MIA) syndrome describes was t- ing as part of an inflammatory state associated with cardiovascular disease, and is comm only seen in patients with ESRD on dialysis. Treatment of the malnourished ESRD patient. Often the etiology of malnutrition is multifact orial. Identifying any reversible causes of malnourishment by careful assessment is vital, with therapy then targeted to the underlying cause. Determining the adequacy of the dose of dialysis should be done at regular intervals and this may need to be increased as part of the treatment of malnutrition. Inflammation resulting from a specific source should receive targeted therapy. Metabolic acidosis should be corrected. Con \202 icting data exist as t o the effectiveness of nutritional support but this should be considered in all patients wi th malnutrition (Table 13.6.9). Initially, counseling, by a renal dietician, to increase di etary protein and energy intake should be under taken. If this is ineffective then various renal-speci \201 c oral products are available for the malnourished dialysis patient. If p roblems persist then nasogastric or nasojejunal feeding should be considered. Percutaneous endoscopic gastros- tomy (PEG) feeding is generally avoided in adult PD patients, due to th e increased risk of peritonitis, but may be considered in HD patients. Using the gastrointe stinal tract to support nutrition remains the most physiologic way of providing nutrition a nd when possible this should be used. Assessment of nutritional status Typically the nutritional status of the ESRD patients is a ssessed using several methods (Table 13.6.8). Symptoms such as anorexia, vomiting or weight loss should be elicited by direct questioning. Regular assessments of the target weight sh ould be per- formed \200\223 typically monthly in the stable HD patient and 3-monthly in t he stable PD patient. This should be com- pared with the recommended ideal weight and previ ous target weight assessments. Assessment of the food intake over a short period of time sh ould be performed, and the 3 day food diary is typically used. Body fat and muscle mass may be estimated using anthro- pometry which is rapid, noninvasive, and can be performed Table 13.6.8 Assessment of nutrition in patients with ESRD Table 13.6.9 Options for nutritional intervention Presence of GI symptoms, e.g. anorexia, nausea, vomiting Changes in the target weight Asses sment of food intake (food diary) Protein catabolic ratio (PCR) and normalized protein equi valent of nitrogen appearance (nPNA) Anthropometry Plasma proteins, e.g. albumin, transferr in Blood urea nitrogen/creatinine Dual-energy X-ray absorbimetry (DEXA) Bioimpedance analys is (BIA) Oral supplements Nasogastric/nasojejunal/PEG feeding Intradialytic parenteral nutrition (HD patients) Amino acid dialyzate (PD patients) Total parental nutrition Growth hormone Anabo lic steroids Appetite stimulants PEG, percutaneous endoscopic gastrostomy. J.R. DE ZOYSA 532 Table 13.6.11 Factors contributing to hypertension in ESRD Table 13.6.10 Factors contributing to uremic pruritis Inadequate dialysis Hyperparathyroidism Hyperphosphatemia Increased calcium and phosphate p roduct Elevated aluminum Increased 2-microglobulin Anemia/erythropoietin de \201 ciency Immune dysfunction Dry skin Peripheral neuropathy Sodium loading Hypervolemia Activation of the RAS system Activation of the sympathetic nerv ous system Activation of baroreceptors Use of erythropoietin Essential hypertension Atrial naturetic peptides Endothelium-derived vasoactive factors Calci \201 cation of the arteria l tree Total parenteral nutrition should be considered for the malnourished patient in whom entera l feeding is ineffec- tive. Typically this is in hospitalized patients with intercur- rent illness, and in whom more frequent dialysis can be provided to allow protein and \202 uid load to be optimized. Parenteral nutrition, delivered during HD, has been used to provide additional nutritional support and compensate for loss of amino acids into the dialyzate. O nly a few studies evaluating its long-term effects show bene \201 t, and these bene \201 ts have generally been modest. Amino acid peritoneal dialyzate is a novel form of nutrition al supplementation available for the PD patient that avoids glu- cose loading and allows ab sorption of infused amino acids. Most studies assessing effectiveness have been short-term, with small numbers of patients and variable benefits. Consistent long-term bene \201 ts h ave yet to be demonstrated. Growth hormone, anabolic steroids and appetite stimu- lants hav e all been used in small short-term trials, with no clear indications established for their use. important predictor of cardiovascular disease and control of BP is widely agreed to be of g reat importance in improv- ing long-term survival. The ideal target BP for dialysis patient s is uncertain. JNC-VII recommendations are to achieve a target BP of <130/80 mmHg. K/DOQI recommend pre- and postdialysis BP goals of 140/90 and 130/80 mmHg respectively. Treatment of hypertension Management of hypertension in the dialysis patient typi- cally re quires a combination of: \200 \200 \200 \200 lifestyle modi \201 cation; optimization of \202 uid and volume status with dialysis; op timization of the dialysis prescription; antihypertensive therapy. Lifestyle modi \201 cation This should include: \200 \200 \200 \200 dietary sodium restriction; encouragement of physical activity; restriction of ethanol inta ke; elimination of cocaine and amphetamine use. Uremic pruritis Uremic pruritis remains one of the most common and disabling symptoms in ES RD patients. There is increased release of histamines from skin mast cells. A number of oth er factors may also contribute (Table 13.6.10) but no speci \201 c etiology has been ident i \201 ed. It is important to note that ongoing scratching may lead to secondary skin cond itions, which may be treated by tar- geted therapy. The treatment of uremic pruritis remain s challenging. It is important to ensure that the patient is adequately dialysed and that c alcium, phosphate and PTH are normalized. Other therapies that may be used include oral ant ihista- mines, EPO, ultraviolet B light, opioid antagonists, topical capsaicin, oral evenin g primrose oil and gabapentin. Hypertension Hypertension occurs in up to 85% of patients wi th ESRD and is multifactorial (Table 13.6.11) with retention of sodium, water and activatio n of the sympathetic nervous system key factors. In dialysis patients the relationship betw een blood pres- sure and cardiovascular events does not follow a linear relationship. Low s ystolic BP (<110 mmHg) and high systolic BP (>180 mmHg) are associated with reduced surviva l. Controlled studies showing an improvement in survival with better BP control have not be en performed in ESRD patients. Nevertheless hypertension is recognized as an Achieving a \200\230dry weight \200\231 The \200\230dry weight \200\231 is typically de \201 ned as the body weight at the end of dialysis below which further reduction results in hypotension. When a patient is started on dialysis the optimal dry weight should be aimed for by reducing the target weight by 1 \200\2232 kg per week over the course of several wee ks. Overzealous ultra \201 ltration and concurrent use of antihy- pertensive agents may re sult in symptomatic hypotension and thus frequent review of the dry weight and cautious wit hdrawal of antihypertensive agents are usually required. High dose loop diuretics are a use ful in patients who have a degree of residual function. Excessive ultra \201 ltration duri ng a single HD session may also result in symptomatic hypotension. Patients should be advis ed to limit salt and \202 uid intake so that any ultra \201 ltration required to achieve the dry weight is modest. Optimization of dialysis For patients on HD the dialysis prescription may be altered to ach ieve better BP control. A \201 xed low dialyzate sodium (e.g. 135 mmol/L) may help to con trol hypertension but is often associated with more muscle cramps and symptomatic hypotensi on. CHAPTER 13.6 Medical management of the dialysis patient 533 Programmed variable dialyzate sodium is another strategy which may be employed for hyperten sion with, for exam- ple, a programmed exponential decrease of dialyzate sodium from 155 to 135 mmol/L. This strategy aims to limit hypotensive side-effects and postdialysis thirst a nd serum sodium rises. Observational data suggest that increasing the duration, frequency o r the duration and frequency of HD is the most effective method of controlling BP. Cardiovascular disease accounts for just under half of the deaths in patients with ESRD. Risk factors Patients with ESRD have a high prevalence of other disor- ders independently a ssociated with cardiovascular disease including hypertension and diabetes mellitus (Table 1 3.6.13). ESRD is also associated with a lower prevalence of some other traditional cardiova scular risk factors such as obesity, use of tobacco, and LDL-cholesterol. Several factors r elated to uremia are likely to contribute to accelerated artherosclerosis (Table 13.6.13). Antihypertensive therapy If hypertension persists then antihypertensive agents may be requi red. The presence of comorbidities may in \202 uence the choice of agents, i.e. -blocker s, may be avoided in patients with asthma, but used preferentially in patients with ischemi c heart disease. The pharmacokinetic pro \201 le of the agent should be con- sidered, incl uding the effect of renal failure and dialysis on the half-life of the drug and its active metabolites. Water-soluble drugs are more readily removed by dialysis than lipid-soluble dr ugs and this may contribute to post dialysis hypertension. Typically, agents inhibiting the renin \200\223angiotensin system are recommended as \201 rst line antihypertensive agent s. -Blockers are particularly indicated in patients who have underlying cardiac dysfuncti on. Calcium channel blockers do not require additional postdi- alysis dosing, are usually w ell-tolerated and may be useful in patients with cardiac disease unable to tolerate other a gents. Hyperhomocysteinemia Hyperhomocysteinemia is common in the dialysis popula- tion due to red uced renal clearance, low serum concentra- tions of vitamin cofactors and possible impaired metabolism. Studies using folic acid and vitamin B supplementation to lower homocystine co ncentrations have not demonstrated a lower cardiovascular event rate. Arterial calci \201 cation Arterial calci \201 cation is common in patients with ESRD and is associated with: \200 time on dialysis; \200 increased calcium intake; \200 eleva ted serum calcium and phosphate concentrations. Deposition of calcium may occur in both the intima and media of arteries and appears to be an active process with inhibitors of vascul ar calci \201 cation, such as fetuin-A, nor- mally being produced by vascular smooth muscl e cells. In the largest observational cohort study of dialysis patients mortality was indep endently predicted by: \200 phosphate concentration >1.62 mmol/L; \200 higher adjusted serum calcium concentrations; \200 moderate \200\223severe hyperparathyroidism (PTH>66 pm ol/ L). Resistant hypertension If patients have predialysis BP of >140/90 mmHg despite three drugs, after achieving their target weight, then they are labeled as having resistant hypertensio n. Several factors may need to be considered in this setting (Table 13.6.12). For nonconcor dant patients and those patients unable to take medications at home, administration of long - acting oral antihypertensive medications in the dialysis unit or long-acting transdermal clonidine patches may be useful. In the rare patient with signi \201 cant hypertension, un able to be otherwise controlled, bilateral nephrectomy should be considered. Calcium, phosphate and PTH are potentially modi \201 able cardiovascular risk factors in C KD and ESRD. The target for phosphate is 1.1 \200\2231.78 mmol/L and the tar- get for PTH i s 16.5 \200\22333 pmol/L. Oxidative stress Oxidative stress is increased in ESRD. Asymmetric dimethylarginine and oth er markers of oxidative stress Atherosclerotic vascular disease Artherosclerotic vascular disease is common in incident pa tients on dialysis, and accelerates in prevalent patients. Table 13.6.13 Risk factors for atherosclerotic vascular disease in ESRD Table 13.6.12 Causes of resistant hypertension in dialysis patients Traditional risk factors Hypertension Left ventricular hypertrophy Diabetes mellitus Reduced physical activity Low H DL-cholesterol Incorrect dry weight Inadequate sodium restriction Excessive \202 uid gain Unrecognized s econdary hypertension (e.g. pheochromocytoma, Conn \200\231s syndrome) Erythropoietin Inade quate drug regimen Patient concordance with medications Drug \200\223drug interactions (e.g . NSAIDs, oral contraceptive pill) Uremia-related risk factors Hyperhomocysteinemia Arterial calci \201 cation Oxidative stre ss Elevated lipoprotein (a) Malnutrition Anemia J.R. DE ZOYSA 534 Glycoprotein IIb/IIIa inhibitors Few data exist on the use of glycoprotein IIb/IIIa inhibit ors, as patients with renal dysfunction were excluded from published trials. Abciximab is n ot thought to require dose alteration for dialysis patients and should be the preferred age nt. accumulate. Antioxidant therapy, with N-acetylcysteine and vitamin E, has been trialed in d ialysis patients with some promise. Serum lipids Dialysis patients will often have lower than ideal HDL-cho- lesterol levels bu t also have low LDL-cholesterol. Lipoprotein(a), a cholesterol ester-rich lipoprotein, is t hought to be atherogenic in patients without kidney dis- ease and is typically elevated in dialysis patients. No clinical trials of prevention of coronary heart disease have evaluate d the effects of speci \201 c lipoprotein-(a)-low- ering therapies. The 4D study (Die Deut sche Diabetes Dialyse Studie) is the only published randomized control trial of cholesterol lowering therapy in dialysis patients and did not show a bene \201 t in reducing cardiova scular events. Other large randomized control trials evaluating the effect of lipid-lowerin g agents are currently underway. Invasive management of coronary artery disease Patients on dialysis with ischemic heart dis ease have poor long-term survival. Invasive intervention, with percutaneous coronary inter- vention (PCI), or coronary artery bypass grafting (CABG) is associated with better surviva l than standard medical therapy in patients with ESRD. However, the mortality and morbidity after both PCI and CABG is increased in patients with ESRD compared with nonuremic patient s. CABG surgery is associated with a better long-term prog- nosis when compared against PCI without stenting. Small studies suggest that PCI both with and without stenting is associa ted with signi \201 cant rates of restenosis or recur- rence of angina although some sugge st that this may be overcome by using drug eluting stents. When possible, CABG is the favor ed invasive treatment of severe coronary artery disease in ESRD. Clinical presentation of ischemic heart disease Atypical presentations of ischemic heart di sease are more common in ESRD than in the general population. Ischemic heart disease should be considered in dialysis patients with episodic hypotension, breathlessness or recurrent arrhythmias. Left ventricular dysfunction Left ventricular dysfunction is common in incident and prevale nt ESRD patients. Typically there is impairment of both systolic and diastolic function. Ob servational data suggest that the prevalence of heart failure in dialysis patients is \211 10-fold that of the nonuremic population. Risk factors for left ventricular dysfunction at the inception of dialysis include: \200 hypertension; \200 older age; \200 anemia; \200 ischemic heart disease; \200 baseline systolic dysfunction. Management of stable coronary artery disease Aspirin There are no randomized controlled tri als of therapy with aspirin in ESRD. However it is commonly prescribed for secondary preven tion and any increased risk of bleeding due to uremic platelet dysfunction appears minor. Treatment of anemia Partial correction of anemia to a target of 11 \200\22313 g/dL is gener ally recommended. Treatment of hypertension Hypertension should be controlled by removal of excess \202 uid . -Blockers should be considered in patients with ischemic heart disease. Antianginal age nts may reduce BP which may necessitate night-time dosing. These risk factors do not explain the progression of left ventricular dysfunction for patie nts who remain on dialysis. As with coronary artery disease, nontraditional risk fac- tors may play a role in the development of cardiac \201 brosis, with in \202 ammation, increa sed oxidative stress, calcium and phosphate abnormalities and a direct effect of uremia all likely to play a role. As in nonuremic patients, the presence of left ventricular dysfunct ion independently predicts early mortality in ESRD. In a cohort of almost 2000 ESRD patient s with diagnosed congestive heart failure mortality at 3 years was 83%. Management of acute coronary syndromes Patients with ESRD and unstable angina or acute myoc ar- dial infarction should be managed with standard therapy. Aspirin, -blockers and nitro glycerin should be used if no contraindications exist. Thrombolysis Although it is unclear if ESRD patients obtain the same benefits from thrombol ytic agents (most studies have excluded patients with signi \201 cant renal dysfunction) t his should be used as per standard criteria. Heparin Heparin should be considered in patients with unstable angina. Unfractionated hepar in is usually preferred for dialysis patients. Although the low molecular weight heparin en oxaparin is considered as effective as unfractionated heparin for the treatment of acute co ronary syndrome there are no clear dosing recommendations for patients with ESRD. A meta-an alysis of patients not on dialysis, with creatinine clearance <30 mL/min, concluded that st andard therapy with enoxaparin results in elevated concentrations of anti-Xa and an increas ed risk of major bleeding. Treatment Strategies to reduce left ventricular mass index and left ventricular dysfunction should include correction of ane- mia and correction of hypertension. Correction of volume overload and limiting interdialytic weight gain are also important. For some patients on H D this may require instituting a more intensive dialysis regime with longer hours, greater frequency of dialysis or a combi- nation of both. For patients on PD, manipulation of the d ialysis prescrip- tion may be required, and consideration given to the use of icodextrin or automated PD. CHAPTER 13.6 Medical management of the dialysis patient 535 First-line pharmacological therapy should be with carvedilol, the only agent that has been shown to be effec- tive at lowering all-cause mortality, cardiovascular mortal- ity and hos pitalization in HD patients with symptomatic left ventricular dysfunction. Consideration sh ould also be given to the use of ACEIs and digoxin as second- and third-line therapies. The K/DOQI guidelines recommend that, at initiation of dialysis, all patients should undergo b aseline echocardiog- raphy and electrocardiography. This should generally be deferred until the hemoglobin and the goal dry weight is achieved. Table 13.6.14 Surgery for ESRD: issues to be addressed Evaluation of hematological and biochemical parameters Fluid balance Nutritional state Card iac state Coagulation Vascular access Anesthetic considerations Antibiotics Analgesia Issues for patients on PD Diabetic ESRD patients The nephrologist will commonly have to deal with ESRD patients with diabetes and manage their multisystem com- plications. The glycated hemoglobin (HbA1C) is t ypically used to monitor glycemic control in ESRD patients. However the target HbA1C to ach ieve optimal outcomes is uncertain in ESRD patients and controversy exists as to whether ti ght control affects survival. Most nephrologists will aim to achieve an HbA1C of 6 \200\223 7%. Hypoglycemic agents Biguanides are generally avoided in ESRD patients due to the risk o f lactic acidosis and drug accumulation. -Glucosidase inhibitors are also avoided due to concerns about their pharmacokinetic pro \201 le. Shorter-acting sulphonylureas, which lac k active metabo- lites, such as glipizide and gliclazide, are usually preferred. The thiazo lidinedones are hepatically metabolized and active metabolites do not appear to accumulate in ESRD, although concerns as to the effects of rosiglitazone on car- diovascular events an d mortality have been raised. The dose of insulin needs to be reduced in ESRD patients due to decreased renal excretion. There is no consensus as to the choice of insulin regimen and type of insulin and treatment should be individualized to the patient. If patients are est ablished on PD then their insulin require- ments will change due to absorption of glucose f rom the dialyzate. Patients treated with PD can theoretically be treated with intraperitone al insulin although there are no proven advantages and the practice is now rare. PD patients should continue performing exchanges until the time of surgery and should be dr ained out just prior to surgery. If undergoing an abdominal procedure, which may disrupt th e peritoneal membrane, then placement of a HD cathe- ter under anesthetic is useful. If the patient is diabetic, stopping PD may alter any require- ment for hypoglycemic drugs. Hematological and biochemical parameters A full blood count should be performed and anemia should be corrected to the target range where possible. A base- line set of electrolytes in cluding serum glucose, urea, cre- atinine, potassium, bicarbonate calcium, phosphorus, magn esium and albumin should be evaluated and moni- tored closely in the immediate postoperativ e period. Nutritional state Malnutrition increases the risk of surgical complications and results in a prolonged length of stay due to infection, wound breakdown and multiple organ dysfunction . Where possible elective surgery should be delayed to optimize nutrition. Postoperatively the dose of dialysis should be optimized and may need to be increased as surgery will induc e a cata- bolic state. Drugs which impair appetite should be avoided. Gastro- paresis shoul d be treated aggressively and early, aggressive nutritional supplementation should be consi dered. Fluid balance An assessment of the volume state of the patient should always be performed p reoperatively. HD may be required prior to emergent surgery and should be performed prior t o elective surgery to optimize \202 uid and electrolyte balance. Dialyzate concentrations should be adjusted to normalize serum potassium and calcium concentrations. Perioperative \202 uid requirements should be determined, after discussion with the surgeon and anesthe tist. In patients without kidney disease, solutions such as Plasmalyte and Lactated Ringer \200\231s solution, which contain potassium, are frequently used peri- and intraoperatively . The acid \200\223base and electrolyte state of the ESRD patient will often require other solutions to be used. Close monitoring of \202 uid balance in the immediate post- operati ve period is essential. Multisystem effects Regular screening for other diabetic complications is essential with tr eatment by ophthalmology and podiatry services as required. Peripheral vascular disease is common and will often require input from interventional radiology or vascular surgical serv ices. Peripheral neuropathy is also common as a result of both diabetes and uremia. This ma y respond to increasing the dose of dialysis as well as standard medical treatment. ESRD patients undergoing surgery Patients with ESRD, compared to patients without kidney di sease, are at increased risk of prolonged hospital stay, morbidity and mortality associated with surgery. A number of issues should be addressed in the ESRD patient (Table 13.6.14). J.R. DE ZOYSA 536