0025-7125/90 $0.00 + .20

Renal Disease

Principles, Uses, and Complications of Hemodialysis Michael D. jameson, MD,* and Thomas B. Wiegmann, MDt

Hemodialysis removes metabolic waste products across semipermeable membranes. Technologic advances have simplified the process, and it has become a common form of treatment for patients with acute and chronic renal failure. Underlying principles, limitations, and complications as well as indications for acute and chronic hemodialysis are discussed.

HISTORICAL PERSPECTIVE The concept of dialysis was first described in 18.54 by Thomas Graham. Dialysis was first performed in laboratory animals in 1912.1 The first successful hemodialysis in humans was reported by Kolff in 1944. 23 Early attempts at hemodialysis were complicated by the lack of reliable techniques f()r repeated circulatory access. Hemodialysis was at first performed using metal or glass cannulas that were inserted into an artery and a vein. A major advance occurred in 1960, when Scribner and his associates:l9 introduced plastic indwelling vascular cannulas, the first long-term device for chronic dialysis. In 1966, Cimino and his associates' introduced surgical creation of an arteriovenous fistula that can withstand repeated needle puncture. Introduction of prosthetic materials for shunts and temporaryuse plastic dialysis catheters followed. 47 The combination of improvedaccess techniques, new plastic materials for dialyzer membranes, and technologic advances in production of dialyzers and dialysis machines has led to a remarkable growth in the number of patients on hemodialysis over the past 20 years. Presently, the Health Care Finance Administration From the University of Kansas Medical Center, Kansas City, Kansas

*Fellow,

Division of Nephrology tProfessor of Medicine; and Chief, :'IIephrology Section, Department of Veterans Aflairs Medical Center, Kansas City, Missouri

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estimates there will be over 100,000 hemodialysis patients in the United States in 1990.

BASIC PRINCIPLES The solute composition of the blood is altered by exposing the blood to a modified salt solution (dialysate) separated by a semipermeable membrane. Solutes and water pass across the semipermeable membrane through the processes of diffusion and ultrafiltration. The movement of solutes is directly proportional to the magnitude of existing concentration gradients. Flow of blood and fresh dialysate regenerate the blood-dialysate gradient in a continuous manner, an arrangement that is enhanced by the countercurrent direction of blood and dialysate flows. The concentration gradient can be manipulated by the measured addition of substances to the dialysate. Thus, diffusion of a given solute can be limited by increasing its dialysate concentration (e. g., potassium); eventually, the net direction of diffusion can be reversed (e.g., calcium). The rate of diffusion for a given solute is further defined by the permeability of the membrane, which is dependent on the effective size and number of membrane pores and the thickness and area of the membrane. Membrane surface and flow characteristics of blood and dialysate are important in that they determine the characteristics of un stirred fluid layers that hinder diffusion. For a given membrane, it is finally the size of the diffusing solute that determines its transfer with a rapid decrease in permeability with increasing molecular size. Ultrafiltration is the second mechanism by which solutes are transported across semipermeable membranes. It occurs when water is driven across membranes by either hydrostatic or osmotic forces. Solutes may be swept along with the water in a process called convective transport. During hemodialysis, the water moves from the blood to the dialysate side as the result of the hydrostatic pressure gradient between blood and dialysate, a composite of the positive systemic pressure existing on the blood side together with negative pressure generated on the dialysate side of the membrane. The pressure gradient can be modified at the dialyzer outlet during treatment, whereas the rate of ultrafiltration at any given pressure (mllmin/mm Hg) is a membrane characteristic (hydraulic permeability). Predictable removal of fluid by ultrafiltration is a major component of standard hemodialysis treatment. It is convenient to describe dialysis treatment in the familiar term of clearance, or Cl (mllmin). Solute removal during a single pass of blood across the dialyzer is determined as the product of blood flow (Qb) and the extraction ratio. The ratio is given by the difference (C i - CJ between inflow and outflow blood concentrations of solute in relation to systemic blood concentration (C.):

Clearance increases with blood flow; however, the extraction ratio also

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decreases with high flow rates, resulting in a nonlinear relationship between blood flow rate and solute clearance. For examplc, with a standard dialyzer at 200 ml/min blood flow rate, we find that urea clearance (molecular weight 60) is approximately 70% of blood flow, For substances of larger molecular weight, such as vitamin Bl2 (molecular weight 135,5), the clearance may only be 25% of blood flow. Thus, clearance of smallcr molecules depcnds more on incrcasing blood and dialysate flow rates. On the other hand, the resistance of the membrane bccomes increasingly important as the molecular size increases. Increased rcmoval of larger substances will rcquire larger dialyzer area, increased permeability, or prolonged treatment time. Clearance is increased by the convcctive componcnt from ultrafiltration (Quf)' A typical blood flow rate with standard equipment is between 200 and 300 mllmin. The removal of small solutes is also dependent upon the flow rate of the dialvsate solution, which maintains the concentration gradient. The dialysate s~lution flow rate is usually set at ,500 ml/min. Available dialyzers use different types of membranes, Cellulose membrane and cellulose ester membranes are most common (regenerated cellulose, cuprammonium cellulose, cuprammonium rayon, saponified cellulose ester membranes), Another type of dialyzer material is a substituted cellulose membrane. Here, the free hydroxyl groups of cellulose are chemically bonded to another molccule (acetate, e.g.). Other membranes are made of synthetic noncellulosic materials (polyacrylonitrile, polysulphone, polymethyl-methacrylate). An important membrane characteristic is its biocompatibility at the blood-membrane interface. For example, the free hydroxyl groups on the cellulose membrane are believed to activate the complement system in the blood as it flows through the dialyzer. Bloodmembrane interactions with activation of complement during dialysis are associated with formation of anaphylatoxins, leukocytopenia, and thrombocytopenia. g, 17, 27, 49 Membrane interactions may also be responsible for some of the complications for dialysis, including cramping, hypoxia, and headaches. Complement activation occurs most often with cuprophane membranes and, to a lesser extent, with substituted cellulose membranes and synthetic membranes. Dialyzers come with different surface area and deliver similar performance for a given size. An ideal dialyzer design limits extracorporeal blood volume and maximizes contact between blood and dialysate. Most dialyzers use a hollow fiber design in which blood courses through the lumen and in which the fibers are arranged in bundles that are exposed to dialysate inside a plastic cartridge. Othcr designs use parallel plates of membranes separating blood and dialysate. Clearance rates for some standard dialyzers in recent use in our unit are presented in Table 1. The choice of any specific dialyzer is based on size, permeability, ultrafiltration rate, biocompatibility, reliability of the product, availability, and cost. WATER During a dialysis treatment, concentrated dialysate is mixed with water to produce the final dialysate. Water for dialysis is generated through a

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Table 1. A Sample of Hollow-Fiber Dialyzers in Present Use CLEAR~~CE (\ILI~!ll'\i

IQb

SURFACE \IANUFACTCRER

MODEL

AREA Im')

CD Medical Organon Teknika

13.5-SCE Lento Allegro ST-12 CF 23.08 CA 110 CA 170 CA 210

1..5 0.7 0.9 0.7 1.3 1.1 1.7 2.1

BaxterlTravenol

= 200)

(Qb

= 3(0)

K./

Urea

BE

Urea

Bl2

3.1 2.3 .5.0 3.2 4.1 .5.3 7.6 10.1

177 143 178 1.58 180 176 189 192

43 26 48 36 47 .52 70 77

220 17.5 22.5 186 227 21.5 249 266

27 48 37 47 .53 72 87

*K,d (ml/min/100 mm Hg). Note changes in clearance with increase in dialysis blood flow rate (Qb) and membrane area.

series of steps, including water softening, charcoal filtration, reverse osmosis, and deionization. In the final step, dialysate is generated by a proportioning system (central supply or dialysis machine) that adds known amounts of dialysate concentrate to dialysis water. The dialysate has direct access across the semipermeable membrane to the patient's bloodstream, and with each dialysis session, the patient is exposed to approximately 120 L of dialysate. For this reason, maintaining a quality water supply is a major focus in dialysis units. Several contaminants of water can directly affect the patient's health. Aluminum is present in significant amounts in some arcas and is associated with bone disease, neurologic symptoms, and anemia. 2 Copper from plumbing can leach into the water and cause a hcmolytic anemia. Chloramine, used in many locations to chlorinate the public water supply, can cause a hemolytic anemia. 4 13 High levels of bacterial contamination may result in excessive levels of endotoxins, causing hypotension, fever, and chills. 4 VASCULAR ACCESS Heliable vascular access is a prerequisite for hemodialysis. Several forms of tcmporary vascular access are particularly useful in acute dialysis. 30 The most common type employs insertion of a double-lumen catheter into a subclavian vein. Subclavian catheterization is done mainlv to obviate the need for emergency-access surgery. JO Subclavian catheters 'can be used for several weeks, but their use is not without risk. 48 A wide spectrum of complications is seen and ranges from inadequate catheter flow and local hematoma formation to major vascular catastrophes (Table 2). Subclavian vein thrombosis or stenosis is recognized increasingly. Diagnosis is often delayed up to thc time when permanent dialysis access is constructed in the arm of the obstructed side. Massive arm edema may then occur and require the ligation of an otherwise usable arteriovenous fistula or graft. 15 More subtle forms of obstruction are indicated by increased resistance to vcnous flow during dialysis. Angiography is recommended to differentiate

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Table 2. Complications of SubclatJian Catheters Inadequate flow Kinking Malposition Catheter thrombosis Subclavian vein occlusion Thrombosis Stenosis Associated arm edema

Vascular injury Pneumothorax Hemothorax Mediastinal hematoma Pericardial tamponade Infection Bacteremia Sepsis Secondary osteomyelitis

between thrombosis and advanced stenosis amenable to angioplasty,lO, 44, 45 Recirculation may be diagnosed at this time and used to assess the access, Dual-lumen catheters may also be placed into the femoral or internal jugular vein, 10, 30 Single-lumen catheters and Scribner shunts are used less commonly, Complications include infection, thrombosis, and dislodgement with hemorrhage, 30 There are two basic types of permanent vascular access, The first is the arteriovenous fistula. Here an artery and vein are surgically anastomosed side-to-side or end-to-side. The most common site is the connection of the radial artery to an adjacent vein. Usually, the vein increases in size and wall thickness, but a considerable amount of time is required to allow the fistula to develop to a sufficient size for repeated needle puncture. The useful life of an arteriovenous fistula may be as long as 10 to 15 years, 7. 30 An arteriovenous prosthesis is used when a fistula cannot be created or when an existing fistula fails. A Dacron or polytetrafluoroethylene (PTFE) graft is utilized and placed in either a linear or loop fashion. Grafts can be used shortly after surgery, although we prefer to wait several weeks. Postoperative complications include local swelling and hematoma. Longterm complications include thrombotic occlusion, infection, and stenosis. 20 With few exceptions, an infected shunt must be removed. 21 Autologous saphenous vein grafts and bovine vein grafts have also been used successfully. The useful life of an arteriovenous graft may be as short as 2 to 4 years,30, 33, 38

ANTICOAGULATION Exposure of blood to dialysis membranes initiates the clotting cascade, and anticoagulation is used routinely to prevent occlusion of the dialyzer. Heparin is widely used as an initial bolus followed by a constant infusion. Coagulation is monitored using either the whole blood partial thromboplastin time, the activated clotting time, or the Lee-White clotting time, in which a 50% increase in clotting time is sufficient. Bleeding is a frequent complication of systemic heparin use and is particularly common in patients with bleeding disorders or liver disease. Additional contraindications to heparin use include pericarditis, surgery, or recent intracerebral hemorrhage, Bleeding complications during dialysis have prompted development of

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more accurate schemes for heparin administration or for alternative anticoagulants.2S Most simply, a low-dose heparin infusion can be tried. Regional anticoagulation with heparin is more complicated; measured amounts of protamine sulfate are added to the venous blood return to neutralize heparin. 46 Short-chain heparin molecules are currently under investigation. 6 Citrate is an alternative to heparin anticoagulation and is administered in a regional fashion that restricts anticoagulation to the dialyzer assembly.35 Citrate can be used acutely as well as chronically. 1\,51 Finally, patients may be dialyzed without any heparin or citrate. 8 , 44 Anticoagulant free dialysis is particularly useful in patients with prolonged bleeding times; however, steps must be taken to decrease the incidence of clotting in the dialyzer. Best results are obtained with high blood flow rates. Frequent saline rinsing of the dialyzer (i. e., every 15 to 30 minutes) may also be necessary to decrease clotting of dialyzer fibers.

HIGH-FLUX DIALYSIS AND DIALYZER REUSE High-flux dialysis is a major new development in the field of dialysis and is gaining rapid acceptance. In order to optimize clearance, patients are dialyzed with high blood flow rates (up to 600 mlimin), increased dialysate flow (up to 1000 mlimin), and a high permeability membrane with a large surface area. This allows greater clearance of small and middle molecular weight molecules as well as the removal of large volumes of fluid. Careful control of ultrafiltration requires specific equipment designed to monitor ultrafiltration rates. High blood flow rates require a wellfunctioning access together with large-bore needles and dialysis tubing. Dialysis must be bicarbonate based. The desired goal is to improve clearance while at the same time decreasing the amount of treatment time. Shortterm experience appears to indicate a high rate of success for high-flux dialysis of shorter duration. Improved psychological state and physical tolerance are claimed together with improved clearance of larger molecules. 13 However, longer -controlled studies are required. High-flux dialyzers are expensive at present. For economic reasons, most high-flux programs are not feasible without dialyzer reuse. Dialyzer reuse is a technique in which a used dialyzer is cleaned after each dialysis and used an average of four to eight times. Advantages of dialyzer reuse include a decreased incidence of first-use syndrome and a decreased cost of the dialyzer cartridge, which must be matched against the increased cost of sterilization of dialyzers. Most forms of sterilization currently in use are either a bleach solution or a formaldehyde solution, that is rinsed later from the dialyzer. Small amounts remain, however, and the patient is chronically exposed to these quantities of bleach or formaldehyde. 22 As the dialyzer is reused, it gradually loses its ultrafiltration and clearance capacity owing to gradual clotting of the semipermeable membranes as well as protein coating of the membranes. Altogether, studies have shown no difference in morbidity and mortality between programs with reuse and those without reuse. 14. 36

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INDICATIONS FOR HEMODIALYSIS Hemodialysis is performed as either an acute procedure or as a chronic procedure, and its acute use is not restricted to evolving renal failure (Table 3). For example, hemodialysis can be used in the treatment of fluid overload resistant to conservative therapy in patients with moderate renal dysfunction. Treatment varies with the volume offluid to be removed, ultrafiltration rate of the dialyzer, and transmembrane pressure. Severe hyperkalemia (2 7 mEq/L) with electrocardiographic changes is another indication for acute hemodialysis when conservative treatment fails. A potassium-free dialysate is used unless the patient was receiving digitalis when a lowpotassium (2 mEq/L) bath is used. Concurrent hyperfiltration will remove excess extracellular fluid and sodium that might have been administered during prior conservative therapy. Serum potassium should be monitored frequently, particularly in the setting of concurrent metabolic acidosis. The composition of dialysate can also be modified to contain various concentrations of bicarbonate (25 to 35 mEq/L), which diffuses across the membrane to the blood compartment. Dialysis therapy is sometimes indicated in patients with severe metabolic acidosis. Hemodialysis is also useful in selected cases of acute severe hypercalcemia. Drug overdose is an important indication for acute hemodialysis. Even in the presence of normal renal function, dialysis should be considered when rapid removal of the drug improves survivaL Drugs that are readily removed by hemodialysis are those that have a low molecular weight, are water soluble, and not extensively protein bound (e. g., ethanol, methanol, ethylene glycol, lithium, and salicylates). Drugs with a high molecular weight or protein binding are removed poorly by hemodialysis. With these drugs, a charcoal hemoperfusion cartridge may be placed in the blood line. The added cartridge increases the clearance of many protein-bound drugs (e.g., theophylline, phenobarbital, and methaqualone).52 The advent of renal failure is the most common indication for hemodialysis. When renal failure occurs acutely, hemodialysis is initiated early in the course, most commonly when serum creatinine concentration is less than 10 mg/dl and often in the absence of uremic symptoms. Hyperkalemia, fluid overload, and acidosis frequently force early application of dialysis. Frequency and duration of treatments depend on the underlying cause of renal failure. Early and frequent use of dialysis, particularly with bicarbonate dialysate, is thought to optimize survivaL 32 Daily dialysis treatments are often required to manage the hypercatabolic patient. Patient survival also depends on the underlying medical condition of the patient. Survival is limited in the presence of ventilator support, gastrointestinal dysfunction, hypotension, sepsis, and congestive heart failure. Even in the absence of these complications, half of all patients do not survive. 25 Table 3. Indications for Acute Hemodialysis Congestive heart failure Pulmonarv edema Iatrogeni~ fluid overload Hyperkalemia

Hypercalcemia Drug overdose Uremic syndrome Evolving renal failure

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Initiation of hemodialysis in patients with chronic end-stage renal disease is based on the combination of laboratory evidence for diminishing clearance and increasing symptoms. Generally, patients become symptomatic from uremia when their creatinine clearance falls to 0.1 to 0.15 mll min/kg body weight. However, creatinine clearance is not a good marker for glomerular filtration, and it remains unclear to what extent creatinine accumulation directly represents accumulation of other metabolic toxins. 24 Hence, it is not surprising that the relationship between creatinine clearance and uremic manifestations is weak. 3.50 U remia has many manifestations, and the presence of uremic symptoms is an indication for initiation of dialysis. Early-morning nausea is a frequent symptom, followed by loss of appetite and aversion to meats. Weakness, lethargy, lack of interest, and memory loss are noted. A variety of changes in mental status appear, including subtle personality changes and increasing confusion, that progress to seizures and coma. 12 A motor neuropathy is also seen and is usually manifested as a foot or wrist drop. This may be difficult to differentiate from other polyneuropathies, especially in diabetic patients. The motor neuropathy is often reversible with the institution of hemodialysis. A pericardial friction rub is an indicator of a generalized serositis and serves as an urgent indication for hemodialysis. U remia is also associated with prolongation of the bleeding time. Its pathophysiology is complex, and dialysis therapy does not always correct an abnormal bleeding time. Additionally, patients with uremia develop a sallow skin color. A urine-like odor to the breath and deposition of urea crystals on the skin (uremic frost) may be noted on rare occasions in advanced disease. The variety of symptoms and lack of a simple and predictable laboratory measure for uremic toxicity lead to uncertainty regarding the initial timing of dialysis. These uncertainties will continue as patients show wide individual variations in symptoms for a given level of laboratory abnormalities. 3. 5. 50 In deciding to initiate therapy, we favor symptoms over laboratory findings. There are no absolute contraindications to hemodialysis, but several relative contraindications need to be considered (Table 4). Patients must be able to withstand repeated vascular access. This excludes patients with pronounced circulatory instability or advanced vascular disease and small children. Relative contraindications to hemodialysis therapy include Alzheimer's disease and multiple-infarct dementia. However, it may be difficult to separate the neurologic manifestations of an established organic brain syndrome from the temporary changes associated with uremic toxicity. In these instances, we recommend a therapeutic trial of "acute" hemodialysis for a clearly defined period of time, followed by a reassessment of the patient prior to committing to chronic dialysis. Patients with advanced liver disease are also poor candidates for hemodialysis. Malignancy is sometimes considered a relative contraindication to hemodialysis. However, we accept Table 4. RelatitJe Cantraindicatians ta Hernadialysis Marked circulatory instabilitv Severe vascular disease . Alzheimer's disease Multiple-infarct dementia

Hepatorenal syndrome Advanced cirrhosis with encephalopathy Advanced malignancy

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patients for dialysis when thcir survival is expected to exceed several months. Acquired immunodeficiency syndrome (AIDS) is frequently associatcd with renal failure. There are no special technical concerns, and protective measures for staff are similar to those used in patients with hepatitis. Growing clinical experience has shown a predictable progression of disease and early death after the occurrence of renal failure and initiation of dialysis. ll , 34 Dialysis is probably indicated in patients with HIV carrier state and those with AIDS-related complex. In the absence of firm guidelines, we would consider dialysis in ambulatory, functioning patients despite the short survival. The decision to undergo hemodialysis is one that should always be reached after discussion between the patient, family members, and the physician. Hemodialysis is only one form of dialytic therapy and must be considered in comparison to peritoneal dialysis. Whenever possible, we encourage patients to participate in choosing the form of therapy after a visit to the dialysis facility, an interaction with other dialysis patients and staf{ and a review of films and booklets on dialysis. Medical factors that influence the decision include the patient's underlying medical condition, body habitus, catabolic state, the ability to tolerate rapid solute and water removal, and lifestyle preferences. Hypercatabolic or very large patients generate large amounts of metabolic products, and hemodialysis may provide the only means to provide adequate removal of solute and waste products. Patients with severe vascular disease or borderline cardiac function often are unable to tolerate the rapid fluid shifts that occur during hemodialysis; peritoneal dialysis may provide a better option. Hemodialysis requires the commitment of approximately 4 hours, three times per week by the patient. Treatment in a dialysis center requires additional adherence to relatively inflexible treatment schedules as well as additional travel and waiting time. In many cases, hemodialysis may be successfully undertaken at home. Home hemodialysis provides for flexible adjustment between lifestyle and treatment schedules and may be the only treatment for patients who live some distance from a center. Treatment can always be stopped with mutual agreement. SIDE EFFECTS AND COMPLICATIONS The dialysis procedure is associated with several complications, Hypotension is common; it occurs in 20 to 30% of dialysis sessions. Common causes for hypotension include a target "dry" weight that is set too low, a low dialysate sodium concentration, too rapid removal of water (high ultrafiltration rate), and excessive use of antihypertensive medications. 41 It occurs more frequently when acetate is added as base precursor to the dialysate compared to bicarbonate. 13, 16, 32 Hypotension also occurs when the temperature of the dialysate is too high. Hypotension due to these causes usually corrects with infusion of saline, mannitol, or plasmanate. These common events must be differentiated from life-threatening causes of hypotension. For example, hypotension should be anticipated in patients with compromised myocardial function and myocardial infarction; electro-

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lytc shifts may induce cardiac arrhythmias during dialysis. 29 Pericardial tamponade may occur in patients who have pericarditis and develop bleeding into thc pericardium during dialysis. Early sepsis is frequently signaled by hypotension and increasing temperature during dialysis. Rare causes of acute hypotension include anaphylactic reaction, hemolysis, and air embolism. Muscle cramps are a frequent complication of dialysis and occur in up to 20% of treatments. Muscle cramping is often associatcd with the common causes of hypotension. Patients dialyzed against a low sodium or low ionized calcium dialysate may also experience muscle cramps.41 Initial management of hypotension and cramps during dialysis includes a reduction in the ultrafiltration rate and blood flow. Normal saline (100 to 500 ml) can be given rapidly to the patient to expand the intravascular space. In addition, hypcrtonic glucose (.50 ml of D.5o) or 23.5% saline (5 to 10 ml) is effective. This latter approach reflects observations that link hypotension and cramps to intradialytic changes in solute concentration. Finally, the dialysate sodium concentration can be increased during treatment or quinine may be given orally.Cl7 Headaches, nausea, and vomiting occur in 5 to 15% of dialysis sessions. It is seen in association with hypotension, acetate dialysis, and the disequilibrium syndrome. This syndrome occurs as a result of too rapid removal of solutes from the blood stream with a concurrent lack of equilibration bctween blood and tissues, especially of the brain. The brain tissue has a higher osmolality than the blood and swells. The disequilibrium syndrome begins as a headache and may progress to obtundation, seizures, or coma. It is generally seen in new patients who are initially treated aggressively, and it can be avoided by stepwise increases in dialysis treatment. 12. 18. 40. 41 An increased dialysate sodium is usefulY Headaches during chronic treatment may also be related to caffeine withdrawal, as caffeine is readily dialyzed. On rare occasions, patients may experience an anaphylactic reaction with new dialyzers that may be related to residual amounts of ethylene oxide, which is used for sterilization of dialyzers. 22 Another type of first-use syndrome is manifested by chest and back pain and is seen with cellulose dialyzers and activation of complement. 9 . 17 A decrease in blood oxygen tension (5 to 10 mm Hg) routinely occurs during dialysis. Patients dialyzed against an acetate bath can develop hypoxemia during the first hour of dialysis owing to hypoventilation and increased oxygen consumption. Hypoventilation, in this instance, is a result ofhypocarbia related to the dialysance of carbon dioxide and bicarbonate and the lag time for regeneration of bicarbonate from acetate metabolism. 32 Patients dialyzed against a high bicarbonate bath (35 mM/L) can develop metabolic alkalosis and hypercapnia, leading to hypoventilation. This latter complication can be avoided by lowering the dialysate bicarbonate concentration. Hypoxemia has also been related to an intrapulmonary block to oxygen diffusion based on membrane alterations and alveolar sequestration of neutrophils. This occurs most often in patients who are using a dialyzer with unsubstituted cellulose membranes and is related to blood-membrane interaction with activation of comple-

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ment. 9, 17 Complement activation and leukopenia are diminished with synthetic membranes and during citrate anticoagulation. 13,27,49 DIALYSIS PRESCRIPTION There is considerable debate about the amount of dialysis required to provide control of uremic symptoms with clinical safety at reasonable expense of money and time. Current dialysis strategies have evolved around the concept of "adequate" dialysis, with an individualized dialysis prescription for a given patient. Adequate dialysis seeks to control fluid and solute concentrations over the short term, whereas symptom-free survival and quality of life may be considered as a more essential long-term goal. Assessment of therapy requires a combination of laboratory testing and clinical assessment. Adequate dialysis requires consideration of the individual patient's metabolic and nutritional state and residual renal function. Formulation of treatment strategy involves mainly selection of a dialyzer and dialysate composition and determination of blood flow rate and the amount of weekly dialysis. Twelve hours of weekly dialysis usually suffice. Kinetic mode ling of solute concentrations has advanced quantification of hemodialysis. 43 In particular, urea kinetics have been studied extensively because its blood concentration and appearance rate are linked to protein catabolism, which in turn is linked to many uremic manifestations. Given a dialyzer and knowledge of patient plasma concentrations over time, treatment conditions and dialysis time can be predicted to achieve a selected urea concentration. Conversely, one can also predict the patient's future plasma urea concentrations from known treatment conditions. Concern remains about the validity of urea as a marker for dialysis prescriptions. An extensive national cooperative dialysis study (NCDS) has compared the morbidity of different treatment strategies based on urea concentrations averaged over time (TACurea)' Morbidity and mortality increased with a target TAC urea = 100 mg/dl compared to TAC urea = 50 mg/dl. Observations resulted in recommendations for adequate dialysis based on the relationship of urea clearance (k) by time (t) normalized for the urea distribution volume (v). 19,26 Simple evaluation of urea concentrations is inadequate because low concentrations may reflect protein malnutrition. Evaluation of the kt/v index in individual patients is therefore complicated by the requirement for evaluation of protein catabolic rate. A kt/v index of 0.9 to 1.1 is considered adequate, given a protein catabolic rate of about 1.1 g/kg. A typical example of acute dialysis orders is given in Table 5. The initial dialysis is usually 2 hours in order to avoid the disequilibrium syndrome, The blood flow rate is gradually advanced. Lower blood flow rates are usually necessitated by the use of temporary-access catheters and the clinical condition of the patient. Final sodium, potassium, and bicarbonate concentrations can be modified in the dialysate, and a goal for fluid removal must be specified. Anticoagulation requires careful consideration in the acute setting. Chronic hemodialysis orders are similar to acute orders, but usually three dialysis sessions are performed per week with an average length of 4 hours. A dry weight for the patient is specified, and

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Table 5. Example of Acute Hemodialysis Orders* Acute hemodialysis (first session) Session length Blood flow rate Dialvzer Dial}'sate

Fluid removal Anticoagulation

Td = 2 hrs Qb = 1.50 mllmin (increase to 200 mllmin, if hemodynamically stable) CA-11O (Kuf 5,3 mllmin/lOO mm Hg) Na 140 mEq/L K 3.0 mEq/L Dextrose 200 mg/dl HCO, 30 mEq/L Ca 3.5 mEq/L Mg 1.0 mEq/L 4 Ll2 hr (steady rate) Citrate

*The patient is a 67-year-old woman with congestive heart failure, ischemic cardiomyopathy. and moderate renal insufficiency. The main goal was fluid removal.

this goal is reached by variable rates of ultrafiltration. Dialysate sodium, potassium, and buffer (bicarbonate or acetate) concentrations are selected. Blood flow rates of 200 to 350 mllmin are standard and limited only by patient tolerance. Factors that limit blood flow during dialysis include acetate intolerance, needle size, size of vascular access, and recirculation within the access. Secondary orders complement dialysis orders and round out the individualized patient strategy. Among these, particular emphasis is placed on a well-balanced diet that includes 1.0 to 1.5 g of protein/kg body weight and sufficient calories. Vitamin supplements are prescribed, and iron replacement, which is monitored by serum ferritin level, is started. Decadurabolin is being replaced by recombinant erythropoietin for the treatment of anemia. Calcium citrate is our preferred phosphate binding/ calcium replacement drug. Hypotensive drugs and diuretics are discontinued and reinstituted only after extensive efforts of ultrafiltration have failed to normalize existing hypertension.

MORBIDITY AND OUTCOME A variety of complications can be observed in dialysis patients over the long term. Such complications are not merely the result of direct hemodialysis side effects. Rather, they represent the ongoing evolution of underlying disease, in conjunction with treatment side effects and a state of uremia that is permanently undertreated. A typical example is given by renal osteodystrophy, in which hyperparathyroidism and vitamin D deficiencies must be differentiated from aluminum toxicity. Other forms of dialysis arthropathy are thought to reflect abnormal accumulation of ~2micro globulin-related amyloid. Amyloid deposition has also been seen in conjunction with carpal tunnel syndrome. Dialysis dementia features aluminum toxicity as well as other cases of uremic encephalopathy without a distinctive mechanism. Peripheral neuropathy and autonomic dysfunctions occur to a variable degree. Another common problem is anemia, whose

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etiologies combine erythropoietin deficiency, hyperparathyroidism, vitamin deficiency, aluminum toxicity, and chronic dialysis-related blood losses and hemolysis as well as excessive blood sampling and gastrointestinal bleeding. Complex nutritional abnormalities occur as a result of anorexia or inadequate diet as well as dialysis losses of water-soluble amino acids and vitamins. In many cases, dietary management is complicated by the presence of delayed gastric emptying, especially in diabetic patients. Gastroesophageal reflux, hiccups, and ulcers are frequent. Specific to dialysis is the occurrence of hemosiderosis in the liver due to frequent blood transfusions. Endocrine abnormalities are present but difficult to interpret; e. g., thyroid function tests are highly variable in uremia, but there is little clinical evidence for a significant disturbance of thyroid function. On the other hand, sexual dysfunction is common in male patients and probably due to low testosterone levels. Zinc supplementation may be beneficial. Acquired cystic disease occurs in nonfunctioning kidneys and is accompanied by a significant increase in bleeding complications as well as the incidence of renal cell carcinomas. Hyperlipidemia is common. Finally, a great many abnormalities are seen in the cardiovascular system, especially an increased incidence of hypertension, angina, myocardial infarctions, and strokes. It is easy to see how fluid intake and weight gain between dialysis treatments contribute to periodic volume expansion and hypertension with deleterious long-term effects on the cardiovascular system. All long-term complications must be considered in the context of underlying disease. Many patients on dialysis have multisystem disease that, together with the patient's age, define the outcome. Arteriovascular disease, hypertension, and diabetes are the most common comorbid conditions. Cardiovascular disease causes 50% of deaths, particularly in the first years on dialysis. 42 Sepsis is not infrequent. Finally, patients may withdraw voluntarily from treatment. Although this has been rare in our experience, others have described it as a growing problem. Annual mortality averages 20% in the first year and declines in subsequent years. Comparison of mortality on hemodialysis with other treatment modes for end-stage renal disease suffers from lack of controlled studies. Improved survival has been indicated for home-dialysis patients, but this may reflect a bias in treatment selection. Comparison with transplantation is also difficult, because many of the older dialysis patients with multisystem disease are no longer considered for transplantation. Results can be excellent with full productivity, particularly in patients with little comorbidity. On the other hand, increasing liberalization of selection criteria has increased the number of patients who are more ill, have an increased need of full hospital-based care, and are increasingly dependent on outside support and care.

SUMMARY Hemodialysis replaces missing renal function, and it does so incompletely. Current technology provides for reliable and flexible treatment strategies guided by patient's well-being and careful evaluation of plasma urea concentrations. Hemodialysis is indicated in many medical emergen-

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cies, notably fluid overload and hyperkalemia, and all types of renal failure. Hemodialysis requires a sizable effort and a Significant commitment of time by both patients and professionals and is not suited for every patient with renal insufficiency. Notable treatment-related side effects include cramps, hypotension, problems with blood access, and reactions to dialyzer membrane materials. Far from treating underlying disease, hemodialysis extends life and permits the expression of much progressive multisystem disease. Cardiovascular disease is the most common comorbid condition and cause of early mortality.

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,51. Wiegmann TB, MacDougalI ML, Diederich DA: Long-term comparisons of citrate and heparin as anticoagulants for hemodialysis. Am J Kidney Dis 9:430, 1987 52. Winchester JF, Gelfand MC, Knepshield JR, et al: Dialysis and hemoperfusion of poisons and drugs-update. Trans Am Soc Artif Intern Organs 23:762, 1977

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