Role of Hemodialysis in the Management of Dogs and Cats with Renal Failure

RENAL DYSFUNCTION

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ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF DOGS AND CATS WITH RENAL FAILURE Larry D. Cowgill, DVM, PhD, and Cathy E. Langston, DVM

Traditional strategy for the management of chronic renal failure has focused on dietary restriction to minimize the solute load requiring renal excretion.54 Conversely, for acute uremia the strategy is forced excretion of excessive fluid and solutes through crippled kidneys by diuresis and voluminous fluid administration.35 These conventional approaches become increasingly ineffective and problematic as renal function declines. The ultimate fate for uremic animals is a predictable death from the polysystemic consequences of renal failure or progressive morbidity from the imposed therapy. For the vast majority of human patients with severe uremia, renal function is replaced by hemodialysis in which a surrogate (artificial) kidney is used to correct imbalances of body fluid volume and composition and eliminate accumulated toxins. The application of hemodialysis in veterinary practice has been limited by ·technical aspects of dialysis delivery. These constraints have been largely eliminated by modem equipment and procedures better suited to dogs and cats, increasing the enthusiasm and indications for renal replacement therapy in veterinary therapeutics. 15• 17 DEFINITION AND HISTORICAL PERSPECTIVE

Hemodialysis is the therapeutic application of diffusion and ultrafiltration to promote removal of toxic solutes and normalization of the volume and composition of body fluids disrupted by the loss of renal function. With hemodio alysis, the clinical consequences of uremia can be ameliorated or forestalled by

From the Department of Medicine and Epidemiology (LDC), and the Center for Companion Animal Health (CEL), School of Veterinary Medicine, University of California, Davis, California; and The Animal Medical Center, New York, New York (CEL)

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 6 • NOVEMBER 1996

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correcting the disordered electrolyte, hydrogen ion, and fluid balances and removing accumulated "uremia toxins." Thomas Graham must be credited with recognition in 1854 of the "osmotic membrane," which permitted passage of water, urea, and other solutes while retaining colloidal substances. 25 His discovery serves as the foundation for all modem dialytic therapy, but it would take the contributions of many investigators over many decades to develop the techniques (hemodialysis) to replace the function of an organ as complex as the kidney. Hemodialysis first was performed in 1913 by Abel, Rowntree, and Turner1 on experimental dogs with an "artificial kidney" composed of celloidin tubes, the predecessor of the modem hollow fiber dialyzer, but their pioneering efforts were halted during World War I and discarded for more than a decade. The first human hemodialysis was performed by Georg Haas in 1924, but it was not until 1943 that Willem Kolff revolutionized hemodialysis with invention of the rotating dhlm dialyzer, which incorporated a new membrane material, cellophane, and highly purified heparin as an anticoagulant. 25 The subsequent five decades have been punctuated with advancements in dialyzer design, biocompatible and highly permeable membrane materials, angioaccess, and dialysis delivery systems making modem hemodialysis widely available, safe, and highly effective. Veterinary application of hemodialysis was described first by Butler in 1968 despite its initiation in experimental dogs a half century earlier.U These early efforts were encumbered by large extracorporeal circuits (400 to 500 mL), poor vascular access, "batch-type" recirculated dialysate, and unsophisticated dialysis delivery systems. Parker, Gourley, and Bell33• 52 extended these techniques by use of ~ dialysate proportioning system permitting continuous generation and single passage of the dialysate and silicone-teflon arteriovenous shunts for angioaccess. The first clinical application of hemodialysis in dogs was reported from the University of California and Purdue University in the early 1980s.16• 24• 62 These experiences documented the efficacy and feasibility of hemodialysis as a treatment for severe uremia in dogs and forecast its promise in veterinary therapeutics. The first clinical dialysis program started with establishment of the Companion Animal Hemodialysis Unit at the University of California in 1990. With the advent of neonatal dialyzers, vascular access devices, and blood tubing sets feline hemodialysis was initiated in 1993.43 Since these beginnings, other veterinary hemodialysis centers have evolved, and the future for this therapy in veterinary medicine appears promising (see Appendix). PRINCIPLES GOVERNING HEMODIALYSIS

To perform hemodialysis, blood is exposed to a contrived solution, the

dialysate, formulated to transfer solutes across a transposed semipermeable membrane. The efficacy of solute transfer is governed by {1) the diffusion (concentration) gradients across the membrane, (2) the diffusive properties of the solutes, {3) the permeability and surface area of the membrane, (4) the volume of blood exposed to the membrane, and (5) the volume of ultrafiltration. 23• 61 Diffusive Dialysis

The diffusive principles that govern hemodialysis are based on the random nature of molecular motion. As solutes in the blood and dialysate arbitrarily

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encounter pores in the interfacing membrane, they are transposed to the opposite side through diffusion channels. The probability of solute interaction with a diffusion pore increases with its molecular activity and concentration in the solution. If the concentration of solute on one side of the membrane is higher than its concentration on the opposing side (i.e., urea), more solute movement occurs from the higher to the lower concentration than in the opposite direction, yielding a net movement down the concentration gradient (Fig. 1A). If the concentrations are equal on opposing sides of the membrane, equal numbers of solute particles move bidirectionally with no net change in composition of the respective solutions (see Fig. 1B). When diffusion results in equal concentrations in the opposing solutions, filtration equilibrium is achieved and net solute movement ceases. Continuously replenishing the solutions prevents filtration equilibrium, maintains the diffusion gradient, and maximizes solute movement. By applying these principles to the artificial kidney, uremia toxins can be removed while crucial electrolytes are preserved. Solutes depleted by renal failure, like bicarbonate, can be replenished by formulating the dialysate concentration to be higher than the prevailing blood concentration. Molecular motion is inversely proportional to molecular size. Small solutes like urea (60 d) diffuse faster than larger solutes like creatinine (113 d) or vitamin B12 (1352 d), and the plasma concentration of urea decreases faster than that of larger solutes during the course of dialysis. 46 Membrane thickness, effective surface area, pore size, and pore density influence the permeability of dialysis membranes and independently affect the rate of solute transfer. 46 Membrane pore size additionally limits the selectivity or molecular weight cutoff of filterable solutes, and ultimately all dialysis membranes must have permeability limits to restrict the passage of macromolecules (proteins) and the cellular components of blood. Conventional cellulosic hemodialyzers are constructed from derivatives of natural cellulose with small pore channels, low hydraulic permeability coefficients, and sieving coefficients that restrict the passage of solutes greater than 1000 d and offer greater resistance to solute and fluid transfer. Newer, high-flux dialyzers use synthetic membranes with shorter diffusion distances, larger pore channels, greater pore density, and less resistance to diffusion. Consequently, high-flux dialyzers have a molecular weight cutoff approaching 12,000 d and promote greater transfer of "middle molecules" with a molecular weight between 500 and 5000 d. 46 Ultrafiltration and Convective Dialysis

The blood pump generates an outwardly directed hydrostatic pressure on the blood side of the dialysis membrane that is opposed by the hydrostatic pressure generated by the flow of dialysate on the opposite side of the membrane. The average pressure on the blood side of the dialyzer minus the pressureon the dialysate side of the dialyzer establishes a transmembrane pressure, which serves as the driving force for hydraulic fluid transfer across the membrane (see Fig. 1C). If fluid removal is required to manage overhydration, increasing the transmembrane pressure forces water across the membrane as an ultrafiltrate of plasma analogous to the ultrafiltration of plasma at the glomerulus. The rate of ultrafiltration is determined by the magnitude of the transmembrane pressure and the hydraulic permeability of the dialysis membrane. The ultrafiltration capacity of the dialyzer is measured by its ultrafiltration coefficient (KUf) as the number of milliliters of fluid transferred per mm Hg of transmembrane pressure

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Figure 1. Principles of dialysis and ultrafiltration across a stylized hollow fiber dialysis membrane. A, Diffusive dialysis; outwardly directed transfer of solute (urea) down a diffusion (concentration) gradient. 8, Diffusive dialysis; zero net transfer (filtration equilibrium) of a solute (Na+) at equal concentrations across the membrane.

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Figure 1 (Continued). C, Ultrafiltration; outwardly directed water transfer down a hydrostatic pressure gradient, transmembrane pressure (300 mm Hg) equals average venous pressure ( + 100 mm Hg) minus dialysate pressure (- 200 mm Hg). 0, Convective dialysis; outwardly directed solute transfer (stipple) by solution drag during ultrafiltration .

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per hour. In modern dialysis delivery systems, the rate of ultrafiltration (within the permeability limits of the dialyzer) is precisely controlled by adjustments of the dialysate pressure. Applying vacuum to dialysate creates a negative dialysate pressure, increases transmembrane pressure, and promotes greater fluid removal from the patient. High-flux synthetic membrane dialyzers have very high KUf characteristics and are capable of removing liters of excessive fluid per hour of dialysis. The fluid removed by ultrafiltration carries with it by "solute drag" the dissolved solutes that can permeate the dialysis membrane. This process is termed convective dialysis and significantly increases the efficacy of solute removal, especially larger-weight solutes, in patients undergoing ultrafiltration (see Fig. 1D). Convective dialysis occurs independent of the diffusion gradients that may exist across the membrane. DELIVERY OF HEMODIALYSIS TO THE PATIENT

Hemodialysis is technically demanding because of the interactions of the patient and the extracorporeal circuit, the precarious clinical status of uremic animals, and the complexity and sophistication of dialysis delivery equipment. Dialysis delivery requires (1) repeated, reliable, and high-volume access to the patient's blood, (2) a hemodialyzer (artificial kidney), and (3) a dialysis delivery system that formulates, monitors, and delivers the dialysate and regulates the flow of blood in the extracorporeal circuit. Vascular Access

Vascular access is required to deliver blood to the dialyzer and to return the treated blood to the animal. In 1960 the development of the exteriorized arteriovenous shunt revolutionized delivery of both acute and chronic hemodialysis to human patients. 60 The arteriovenous shunt has been largely replaced by alternative angioaccess in human patients, but remained the major access device in veterinary hemodialysis until recently. 14• 16• 24 The arteriovenous shunt is composed of exteriorized silastic tubes connected to teflon vessel cannulas that are surgically inserted in a peripheral artery and vein (Fig. 2). For hemodialysis treatments, the arterial limb of the shunt supplies blood to the dialyzer and the dialyzed blood is returned to the patient via the venous cannula. In the interdialysis period, the free ends of the silicone tubes are reconnected to establish a free-flowing arteriovenous circuit or shunt. The low thrombogenicity of the shunt materials and the rapid flow of blood through the access were designed to maintain patency until the next dialysis treatment without the need for systemic anticoagulation. Arteriovenous shunts require meticulous surgery placement, impose the risks of arterial catheterization, are prone to clotting, and are poorly suited for ambulatory animals. Transcutaneous (double-lumen) venous dialysis catheters are a recent and more desirable choice for short-term or long-term vascular access in animals and have replaced use of exteriorized arteriovenous shunts. Polyurethane catheters (Mahurkar Dual Lumen Catheter, Quinton Instrument Co., Seattle, WA; Flexicon II, Vas-Cath, Mississauga, Ontario, Canada) are designed for short-term angioaccess or for critical patients who require immediate placement with only local analgesia. Long-term or semipermanent catheters are silicone based and may be placed with percutaneous or simple surgical techniques. In large dogs the

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Figure 2. Silicone-teflon arteriovenous shunt connecting the femoral artery (left) and vein (right) in a dog. For dialysis treatments, the shunt is disconnected at the intraluminal teflon connecting cannula (arrow) and attached to the extracorporeal blood lines. Between dialysis sessions, the arterial and venous segments are reconnected over the teflon connector to reestablish blood flow through the shunt.

permanent catheters (Permcath Dual Lumen Catheters, Quinton Instrument Co., Seattle, WA) may be inserted percutaneously into the external jugular vein using guide wire and vessel dilator techniques. However, the percutaneous approach is rarely quicker, and for small dogs it often promotes more vascular damage and hemorrhage than does placement by a surgical "cut down" and venotomy. In both cases the catheter is advanced to the right atrium or cranial vena cava (Fig. 3). The extravascular portion of the catheter is tunneled subcutaneously to exit the skin in the cranial cervical area of the neck. A subcutaneous Dacron cuff on the catheter stabilizes its position, prevents accidental displacement from the vessel, and impairs extension of local infection. The external jugular vein in cats generally is too small to accommodate percutaneous placement, but neonatal dialysis catheters (Pediatric Hemo-Cath [Diameter: 8 Fr; Length: 18 em], MEDCOMP, Harleysville, PA) can be inserted through a transverse venotomy in the external jugular vein. The catheter lumen is filled with heparin (500 to 1000 U I mL in cats, 1000 to 2500 U/mL in d ogs) between dialysis sessions to avoid intraluminal thrombosis. The heparin lock should be replaced every 3 to 4 days regardless of the dialysis schedule. Heparin probably diffuses slowly from the ports of the catheter causing low level systemic heparinization such that the balance between patient size and heparin load must be monitored to avoid overheparinization. Aspirin at 1 to 5 mg/kg per day (dogs) or every 48 hours (cats) is administered

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Figure 3, Lateral thoracic radiograph of a dog illustrating the transcutaneous dual-lumen dialysis catheter placed in the external jugular vein to the position of the right atrium.

long term to prevent thrombosis around the catheter. Transcutaneous venous catheters can remain serviceable for many months if properly maintained. Catheters are replaced if they become physically damaged, occluded, or infected. In most cases replacing a catheter in the opposite jugular vein rather than · the previous access site is preferable. Polyurethane catheters used for temporary vascular access are less flexible and are prone to kinking and physical damage but often can be replaced with a permanent catheter without additional surgery using a wire guide. Dialysis catheters must be reserved only for dialysis procedures and handled only by knowledgeable personnel to prevent inadvertent injection of the heparin lock, bacterial contamination, or convenience use for any other purpose. Arteriovenous fistulas and arteriovenous grafts are surgically constructed subcutaneous anastomoses created from native vessels or synthetic vessel material, respectively. Both interconnect a peripheral artery (usually the radial artery) with a peripheral vein (cephalic vein) and are the access of choice for hum<\n patients with chronic renal failure. 6• 10 When fully serviceable, they provide a large subcutaneous channel with a natural endothelial lining and fast blood flow. During dialysis sessions blood is withdrawn through a needle placed at the proximal (arterial) end of the vessel and returned downstream through a needle at the distal (venous) end. Recirculation of dialyzed blood is minimized by the distance between the needles and the rapid flood of blood through the access. 6• 10 Neither arteriovenous fistulas nor grafts have been used for routine dialysis in dogs and cats. Fistulas require weeks to heal before they become serviceable and therefore are not suitable for animals with acute renal failure when immediate dialysis is require9.. Artificial Kidneys (Hemodialyzers)

The artificial kidney is ·the core of the hemodialysis process and must possess many characteristics in common with the native kidney it replaces. The

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artificial kidney must have a high capacity to remove both small and middle molecular weight molecules from the blood while selectively retaining essential solutes, plasma proteins, and the cellular components of blood. It must regulate water removal independently of solute flux, and it must be sterile, nontoxic, and free of adverse biologic interactions with the patient. Innovations in dialyzer design and membrane materials and manufacturing technology have evolved to more closely approach these objectives.36• 46• 64 Modern hemodialyzers are compact, disposable, efficient, reliable, and may be tailored to the size, biologic compatibility, and excretory requirements of individual patients. 36• 46 Hemodialyzers are classified as "hollow fiber" or "parallel plate" according to the physical characteristics and arrangement of the membrane used in their construction. The hollow-fiber artificial kidney was introduced in 1965 and has become the standard dialyzer design in the United States (Fig. 4).46 Hollow-fiber dialyzers incorporate a bundle of small-diameter capillary fibers encased in a plastic housing. Blood is channeled through the center of the fibers while the dialysate is distributed around the fiber bundle in a counter-current direction. This design

Figure 4. Pediatric cellulosic hollow fiber dialyzer (artificial kidney) illustrating the arterial (top, right) and venous (bottom, right) blood ports and dialysate ports (left, top, and bottom).

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provides a large surface area-to-blood volume ratio and low blood-flow resistance. The thinness of the fiber wall (between 5 and 60 1-1m) allows efficient solute diffusion, yet the wall is sufficiently rigid to accommodate high transmembrane pressures for ultrafiltration. These dialyzers are available with effective surface areas between 0.22 and 2.5 m 2 • Pediatric hollow-fiber dialyzers have blood compartment volumes between 18 and 60 mL, which makes them well suited for animal hemodialysis. 15• 17• 46 The parallel-plate dialyzer design consists of multiple layered (stacked) sheets of semipermeable membrane sandwiched between plastic supports that disperse blood and dialysate over opposing sides of the membrane. Parallel-plate dialyzers were among the first designs to be successfully used for maintenance hemodialysis in human patients, but they have diminished in popularity since the late 1960s.42 Hemodialyzers are further classified according to the material and diffusion characteristics of the membrane used in the dialyzer. Conventional (cellulosic) dialyzers are composed of chemically modified cellulose membranes (cuprophan, regenerated cellulose, cellulose acetate, cellulose triacetate, hemophan). 36• 46 Conventional dialyzers have good diffusion characteristics for small molecular weight solutes ( <500 d) but are less effective for middle-weight molecules. Cellulosic dialyzers generally have lower ultrafiltration coefficients and tend to be more thrombogenic and bioreactive than are synthetic membrane dialyzers. Because of their low cost, disposability, and adequate solute removal and ultrafiltration characteristics, cellulosic dialyzers have remained the standard for animal dialysis. High efficiency and high flux dialyzers use synthetic polymer membranes (polycarbonate, polyacrylonitrile, polysulfone) that have superior diffusion and ultrafiltration characteristics, greater mechanical strength, lower thrombogenicity, and better biocompatibility than do cellulosic dialyzers. Their high-flux characteristics also permit shortened treatment intervals and improved fluid, solute, and middle-weight molecule removal. Synthetic membrane dialyzers, although superior in all regards, are more costly than conventional dialyzers and must be reused multiple times in the same patient to remain cost effective.

Dialysis Delivery Systems

The dialysis delivery system (the hemodialysis machine) is the integrative apparatus that (1) proportionally dilutes the dialysate from concentrated salt solutions and regulates its flow to the dialyzer, (2) continuously monitors the composition, temperature, and pH of the final fluid, (3) controls and monitors the extracorporeal flow of blood, (4) regulates the rate of ultrafiltration, and (5) maintains the delivery of anticoagulant to prevent clotting in the blood circuit. The design and sophistication of the delivery system determine the type of dialytic therapy that can be provided and the supervision required during dialysis sessions. The proportioning system also monitors the composition of the dialysate by measuring its conductivity and pH to ensure that it remains within safe tolerances. Internal alarms are activated if any alteration of conductivity, pH, temperature, or blood leaks are detected, and the dialysate is diverted (bypassed) away from the dialyzer to protect the patient until the abnormality is corrected. The dialysate proportioning system mixes a concentrated solute solution with highly purified water to generate the diluted dialysate solution. Older proportioning systems produce a fixed-ratio dilution (i.e., 1:35) in which the

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composition of the preformed concentrate determines the final dialysate composition. More sophisticated proportioning systems use variable-ratio dilution which permits moderate adjustment and modeling of dialysate composition throughout the treatment. Severe azotemia and a relatively large extracorporeal volume predispose small animals to hypotension and osmotic-shift complications at the start of dialysis. With sodium modeling techniques, the dialysate sodium concentration can be set high during the beginning of dialysis to counter the transcellular urea gradient when the potential for osmotic-shift complications is greatest. Dialysate sodium is lowered later in the session so the patient ends the treatment with a normal sodium concentration eliminating the adverse effects of hypernatremia and hypertonicity. 47• 50 Modeling dialysate sodium appears to improve hemodynamic stability throughout the dialysis session and lessens the incidence and severity of dialysis disequilibrium. 56 Bicarbonate is now accepted as the most appropriate replacement buffer in the dialysate. The instability of bicarbonate in solution and the difficulty of formulating a bicarbonate-based dialysate that would not precipitate calcium and magnesium prompted the industry-wide utilization of acetate for basegenerating equivalents in commercial dialysate. Bicarbonate-based dialysate requires separate proportioning systems for bicarbonate concentrate and the concentrate for all other solutes. The interim solutions are mixed when appropriately diluted to prevent precipitation of calcium and magnesium with the bicarbonate. All modern dialysis delivery systems are capable of separately proportioning bicarbonate concentrates to generate a bicarbonate-based dialysate that does not precipitate in solution. The low cost and availability of acetate-based dialysis machines make them seemingly attractive for veterinary facilities, but acetate dialysis is not recommended for small animal patients. The high acetate load delivered by dialysis to relatively small and critically ill animals produced vasodilation, reduced myocardial contractility, and alterations in myocardial energetics resulting in hypotension and hemodynamic instability. 39• 63 Acetate-based dialysis may be associated with hypoxemia, hypoventilation, nausea, vomiting, and fatigue. Current veterinary experience affirms the benefits of using bicarbonate-based dialysis to alleviate intradialysis hypotension, vomiting, fatigue, and hypoxemia when compared to acetate dialysis. 15• 17 Animals probably could not tolerate the acetate loads produced by today's efficient dialyzers and the intensive hemodialysis prescriptions currently used for intermittent dialysis in animals. The dialysis experience in cats has been entirely bicarbonate-based, but the small blood volume of cats relative to extracorporeal volume would exacerbate the hemodynamic effects of acetate intolerance. Purified Water System

The most abundant component of dialysate is water. During a single dialysis session, the animal is exposed to approximately 150 L of water. The magnitude of this exposure mandates that the water used to generate the dialysate be chemically pure. Minute traces of routine impurities, water treatment chemicals (fluorine, chloramine), herbicides, bacteria, viruses, or endotoxins, which are perfectly safe and tolerated in drinking water, constitute a formidable health risk to dialysis patients. To ensure water quality meets these exacting standards, supply water must be processed sequentially with particulate filters, carbon sorbants to absorb organic solutes, water softeners to reduce excessive minerals,

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and deionization beds to remove inorganic cations and anions. Reverse osmosis is used as a final treatment to remove residual contaminants. The supply plumbing must be maintained free of bacterial and chemical contamination so that the purified water is not altered in route to the delivery system.

Extracorporeal Circuit

The extracorporeal circuit comprises the route of the patient's blood to and from the dialyzer via the vascular access (Fig. 5). Pressure and flow monitors detect any compromise to safe blood flow within the pathway. Blood leaks, disconnected tubing, and kinks or clots in the blood circuit are detected by changes in pressure in the circuit and alarm the machine, discontinue blood flow, and place the system in standby until the alarm conditions are corrected. For animal dialysis the inclusive volume of the extracorporeal circuit is kept at a minimum by use of neonatal and pediatric components containing small internal volumes. The extracorporeal circuit should not contain more than 10% of the patient's blood volume unless the circuit is primed with compatible blood or volume expanders. 26 A typical pediatric circuit may contain 100 to 130 mL of blood and would safely accommodate a dog larger than 14 kg. The volume of typical neonatal circuits is 50 to 60 mL and is appropriate for dogs larger than 7 kg. For cats, a 60-mL extracorporeal circuit represents approximately 17% to 33% of the animal's total blood volume and imposes extreme risks of hypotension and hypovolemia throughout the dialysis session. Cats weighing 2.5 kg can be safely and successfully hemodialyzed, but extreme caution and regard for their hemodynamic status must be maintained. To prevent hypovolemia in animals less than 7 kg, the extracorporeal circuit can be primed with a 3% to 6% dextran 70 solution (6% Gentran 70, Baxter Healthcare, Deerfield, IL). Sixpercent dextran may dramatically decrease the hematocrit and exacerbate systemic hypertension and should be used cautiously. Three-percent dextran 70 solutions, however, preserve blood pressure and intravascular volume in most cats and small dogs throughout the dialysis treatment.

Ultrafiltration Control Systems

The ultrafiltration control system regulates the rate and volume of ultrafiltration during dialysis. On older dialysis machines, the rate of ultrafiltration is regulated by manually adjusting the dialysate pressure to achieve a transmembrane pressure appropriate for the desired fluid removal. Transmembrane pressure fluctuates continuously as blood flow and dialysis conditions change and must be closely monitored on manual systems to prevent excessive ultrafiltration and overt volume depletion in small animals. Newer dialysis machines incorporate precise volumetric measuring systems in which the desired volume or rate of fluid removal is selected at the start of the dialysis session and ultrafiltration controllers automatically and accurately regulate fluid removal throughout the treatment. Ultrafiltration controlled systems are essential for small animal dialysis to ensure that subtle or undetected fluctuations in transmembrane pressure do not induce unknowing volume depletion or hypotension. Ultrafiltration controllers are also required with use of high-flux dialyzers with high ultrafiltration coefficients to prevent excessive ultrafiltration.

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Arterial pressure

I __.. Dialysate back to machine and out to drain

~

Dialysate from machine

Venous pressure

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patient

Venous sample port (Cso)

Figure 5. Illustration of a typical extracorporeal blood path for hemodialysis. C8 , = input blood concentration; Qb = blood flow rate; Cso = output blood concentration. (From Burrows-Hudson S, Hudson MV: Module IV: Hemodialysis devices. In Core Curriculum for the Dialysis Technician. Thousand Oaks, CA, Medical Media Publishing, 1992, p 34).

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Miscellaneous Monitoring Equipment

A variety of peripheral monitoring equipment is required to maintain safety during hemodialysis and to identify trends in the clinical condition of critically ill animals (see box). Blood pressure must be measured throughout the dialysis treatment because of continual and unpredictable changes in the flow of blood in the extracorporeal circulation, ultrafiltration, vasodilation, hemorrhage, and cardiopulmonary stability. Hypotension is an omnipresent complication during hemodialysis treatments, and blood pressure must be monitored regularly. The inconsistencies of blood pressure monitoring techniques in animals make having both indirect Doppler and oscillometric blood pressure monitors preferable to ensure accurate and consistent measurements regardless of the animal's size.

Monitoring Equipment for Hemodialysis Sessions Indirect blood pressure monitor Indirect oscillometry Indirect doppler Coagulation monitor Activated clotting time Partial thromboplastin time Electrocardiogram or electronic heart monitor Accurate animal balance or scale Miscellaneous In-line hematocrit monitor Pulse oximeter In-line urea monitor Serum chemistry analyzer Blood gas monitor Serum electrolytes

The coagulation status of the patient must be determined to calculate the initial dose of heparin (to anticoagulate the patient) and to serially monitor and regulate ongoing heparin administration (to prevent either clotting in the dialyzer or spontaneous bleeding). Activated clotting time (Automated Coagulation Timer, HemoTec, Englewood, CO) or partial thromboplastin time (Endpoint, Edson Institute, Edison, NJ) can be conveniently measured by automated devices using small blood samples to determine the heparinization status of the patient.

INDICATIONS AND PATIENT SELECTION

Hemodialysis is indicated when the morbidity or potential mortality from renal failure cannot be alleviated by conventional therapies. The decision to start dialysis cannot be delayed unnecessarily or potential benefits to the patient are diminished; however, the technical and manpower demands of dialysis, its expense; and the limited facilities offering dialytic therapy have restricted its use in uremic animals. General indications for hemodialysis and guidelines for patient selection are outlined in the following box. The current interest and

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increased availability of hemodialysis ensures that a greater number of uremic animals can be benefited.

Indications for the Institution of Hemodialysis in Dogs and Cats

Acute renal failure Uncontrolled biochemical or clinical manifestations of uremia Failure to induce an effective diuresis-severe oliguria or anuria Life-threatening electrolyte disturbances (hyperkalemia, hyponatremia, hypernatremia) Life-threatening fluid overload-pulmonary edema, congestive heart failure, severe systemic hypertension Severe azotemia (blood urea nitrogen [BUN] ?: 100 mg/dl, serum creatinine ;:::: 10 mg/dl) Nonresponsive clinical course-12 to 24 hours Chronic (end-stage) renal failure Refractory azotemia (BUN ?: 100 mg/dl, serum creatinine ;:::: 8 mg/dl) Intractable uremic signs Preoperative conditioning for renal transplantation Finite extension of life without overt manifestations of uremia to permit owner adjustment and acceptance of diagnosis and prognosis Acute poisoning/drug overdose Antifreeze poisoning-initial 72 to 96 hours but especially the initial 1 to 6 hours Environmental/agricultural toxins Overdose of iatrogenically administered toxic drugs Fluid overload/excessive fluid administration Fulminant congestive heart failure or pulmonary edema Iatrogenic fluid administration Parenteral nutrition in oliguric/anuric animals

Acute Renal Failure

Acute renal failure is the prevailing indication for dialysis in animals. 15, 17 Dialysis should be initiated when conventional therapy is inadequate to alleviate the azotemia and fluid and electrolyte disturbances or to promote an appropriate diuresis. Selection criteria include severe uremia and the likelihood for repair of the renal damage and return of adequate function. Without dialysis, most animals die before renal repair can occur. Animals with severe oliguria or anuria in whom an effective diuresis cannot be initiated or maintained with replacement fluids, osmotic or chemical diuretics, and renal vasodilatory therapy should be started on dialysis immediately. Further attempts with conservative therapies are generally unproductive, delay the start of dialysis, and predispose the animal to life-threatening fluid burdens that are difficult to resolve. Additional indications include vomiting, diarrhea, seizures, acid-base and electrolyte abnormalities, or severe azotemia (blood urea nitrogen [BUN) > 100 mg/ dL, serum creatinine > 10 mg/ dL) that cannot be controlled within 24 hours with conventional medical therapy. 34' 35 Longer delays cause deterioration in the animal's condition that may be impossible to correct. If the facilities or technical

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expertise for dialysis do not exist, the patient should be transferred to a referral center where it can be performed (see the Appendix for available referral centers). Chronic Renal Failure

The primary application for hemodialysis in human medicine is to manage chronic, end-stage renal disease. In animals, the efficacy of conventional dietary and medical therapy to alleviate the clinical consequences of chronic renal failure becomes limited as the disease progresses to an end stage.54• 55 Intermittent hemodialysis is clearly indicated in animals with chronic renal failure to lessen the azotemia and clinical signs of uremia and to make the animal a more acceptable pet. Improvements in dialysis techniques and delivery systems, increasing sophistication of veterinary practice, and nondialytic advances for the management of chronic renal failure now make intermittent dialysis a realistic adjunct to the conservative management of end-stage renal disease in companion animals. Hemodialysis is most beneficial in animals whose BUN exceeds 90 mg/ dL or whose serum creatinine exceeds 8 mg/ dL. At this stage of uremia medical therapy alone has limited efficacy and the clinical consequences of uremia become profound. Many pet owners desire finite periods of dialytic support when initially confronted with the diagnosis and the inevitable outcome of chronic renal disease to provide their pets an interim of quality life. A short course of dialysis is useful for the preoperative support and conditioning of animals awaiting renal transplantation. Hemodialysis extends the viability and available pool of patients who would otherwise be unsuitable for transplantation and reduces the attendant risks of their surgery. 15• 17 Postoperatively, hemodialysis can be used during acute transplant rejection to maintain the animal until the rejection episode is resolved. Acute Intoxications and Fluid Overloads

Dialysis is uniquely indicated in the management of acute poisoning when the offending toxin can be dialyzed. 27 Rapid and effective clearance of the toxin from the body prevents or ameliorates its harmful effects. For toxicants like antifreeze, dialysis is superior to therapies that merely delay the rate of metabolism of the toxin without promoting its removal from the body. With timely application, hemodialysis can eliminate ethylene glycol and its toxic metabolites completely from the body before they initiate irreversible renal damage (Fig. 6). Selection criteria include a strong history or known exposure to a dialyzable toxin, persistence of a significant blood toxin concentration, and lack of an effective medical antidote. The ultrafiltration capabilities of dialysis permit removal of excessive fluid loads associated with oliguric renal failure, life-threatening pulmonary edema, congestive heart failure, or therapies requiring delivery of large fluid volumes in animals with limited capacity to handle the fluid burden. Therapeutic Objectives of Hemodialysis

In acute uremia, dialysis sustains the patient's life, providing time for the native kidneys to repair and resume functional capability. The goals of therapy

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o+---~----~--~--~~==~ 5 4 1 2 3 pre

Time (hours) Figure 6. Hourly changes in serum ethylene glycol (solid line) and glycolic acid (dashed line) concentrations during a hemodialysis treatment in a dog 24 hours after ingesting antifreeze. The figure documents the nearly complete removal of both toxicants during the single dialysis treatment.

are to minimize the azotemia and correct life-threatening fluid, electrolyte, and acid-base imbalances. The attending azotemia and retained "uremia toxins" promote anorexia, nausea, vomiting, diarrhea, lethargy, hypothermia, and gastrointestinal hemorrhage. Dialytic removal of "uremia toxins" alleviates these signs and lessens the morbidity and mortality associated with acute renal failure. It facilitates the management of fluid balance and dissipates the fluid loads associated with implementation of parenteral alimentation and intensive diuresis, which otherwise could lead to overhydration and become contraindicated. For chronic renal failure, the objectives of dialysis are to boost the limited excretory capacity of the animal through the exogenous removal of retained solutes and water. Lessening the azotemia improves the clinical signs of uremia, permits feeding less restricted diets, promotes better nutrition, and provides a more acceptable pet. For animals exposed to accidental or iatrogenic toxicants the goals of hemodialysis are to promote the rapid and complete elimination of the toxin from the body preventing initiation or perpetuation of its toxic effects. Secondarily, hemodialysis supports renal function when the agent is nephrotoxic. HEMODIALVSIS PRESCRIPTION

The prescription for hemodialysis is formulated to the specific needs of the patient and is influenced by the available facilities and the medical conditioq and species of patient. The following guidelines refer to a contemporary bicarbonate-based, volumetric-controlled dialysis delivery system (Centrysystem 3 Dialysis Delivery Systems, COBE Laboratories, Lakewood, CO). Acute Hemodialysis

Dialyzer

Conventional hollow-fiber dialyzers with a surface area between 0.6 and 1.0 m 2 and a priming volume of approximately 50 mL are appropriate for dogs

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greater than 10 kg body weight (Cobe Centrysystem 200 HG or 400 HG, COBE Laboratories, Lakewood, CO). For initial hemodialysis treatments in which the predialysis BUN is greater than 200 mg/ dL, a smaller dialyzer with a surface area between 0.2 and 0.5 m 2 helps to minimize the risk of dialysis disequilibrium (see later). No clinical comparisons have been made of cellulosic and synthetic membrane dialyzers in animal patients, but anecdotal experience has shown Hemophan to be less thrombogenic and better tolerated than Cuprophan materials. For cats and dogs less than 5 kg, a dialyzer with a surface area between 0.2 and 0.3 m 2 and a priming volume of less than 20 mL is well tolerated (Cobe Centrysystem 100 HG, COBE Laboratories, Lakewood, CO). Blood Flow Rates

Extracorporeal blood flow should be restricted to 3 to 5 mL/kg/min for initial treatments to prevent excessive urea clearance and dialysis disequilibrium. By the second or third sessions blood flow can be increased progressively (10 to 15 mL/kg/min) for more intensive dialysis. For severely uremic cats or small dogs with BUN concentrations greater than 250 mg/dL, "extended-slow" treatment sessions (5 to 8 hours) using total blood flow rates no greater than 2 mL/ kg/min provide a more gradual and safer reduction of azotemia (Fig. 7). Dialysis Time

For dogs larger than 10 kg, the initial one to three sessions, when the risk of dialysis disequilibrium is highest, should be limited to approximately 60 to 120 minutes. Blood flow rate and length of the dialysis session largely determine the intensity of the dialysis treatment. These parameters should be selected to achieve a urea reduction ratio [1 - (postdialysis/predialysis) BUN] no greater than 0.5 (see subsequently). When the predialysis BUN is less than 100 mg/ dL, subsequent treatments in both dogs and cats can be extended to 180 to 300

300 ;::5'

250

~200

!.1so ~ 100 p::j

50 0+----...--....,.-----,---,.-----, 500 200 300 400 100 0 Time (min)

Figure 7. Changes in BUN during the initial hemodialysis treatment in cats with acute uremia. The solid lines depict extended treatments using very slow blood flow rates (1.5 mUkg/min) resulting in a gradual decline in BUN. The dashed line represents a short initial treatment at a conventional blood flow rate (5 mUkg/min) and is characterized by a precipitous drop in BUN. The faster therapy induced severe osmotic-shift disequilibrium necessating cessation of dialysis. The extended treatments were well tolerated.

ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF RENAL FAILURE

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minutes and can incorporate faster blood flow rates to achieve urea reduction ratios greater than 0.9. Dialysate Composition

The dialysate must be formulated to achieve the diffusive and convective requirements of the dialysis prescription without adversely disrupting the normal composition, pH, and volume of body fluids. Sodium is the major solute in the dialysate, and recommendations for its concentration have undergone revision in recent years. Dialysate with a sodium concentration lower than plasma (130 to 135 mmol/L) was advocated to facilitate fluid and sodium removal for hypertension control. Hyponatric dialysate exaggerates transcellular osmotic gradients as both urea and sodium are removed rapidly from the extracellular fluid, promoting nausea, vomiting, muscle cramps, extracellular fluid volume contraction, and hypotension. 2• 59 Currently, dialysate is formulated at physiologic concentrations of sodium to minimize the signs of osmotic-shift disequilibrium and hypotension and to permit higher rates of ultrafiltrationY· 48• 58 • 59 Commercial concentrates can be obtained with a variety of predefined potassium concentrations to meet the requirements of the dialysis session. Animals with acute oliguric renal failure, sepsis, or severe catabolism may be hyperkalemic and require rapid correction of serum potassium with a low potassium dialysate (0 to 3 mmol/L). Later in the course of therapy, before the patient is eating and vomiting or diarrhea is controlled, the dialysate potassium may need adjustment to more physiologic values (3 to 4 mmol/L) to minimize the potential for potassium depletion. The composition of a suitable dialysate for acute uremia is as follows: sodium, 145 mmol/L (dogs), 150 mmol/L (cats); potassium, 0.0 to 3.0 mmol/L; bicarbonate, 25 to 35 mmol/L; chloride, 99 to 112 mmol/L (dogs), 112 to 122 mmol/L (cats); calcium, 3.0 mmol/L; magnesium, 1.0 mmol/L; dextrose, 200 mg/dL. Dialysate flow is conventionally 500 mL/min. If the delivery system permits variable proportioning, a modeled dialysate with sodium concentrations of 155 mmol/L for the initial 20% of the session, 150 mmol/L for the next 40% of the session, and 145 mmol/L for the remainder of the session has been effective in dogs to minimize dialysis disequilibrium and hypotension. For cats, the respective sodium concentrations are 160 mmol/L, 155 mmol/L, and 150 mmol/L. A universal dialysate with a potassium concentration between 3.0 and 3.5 mmol/L rapidly corrects hyperkalemia in most animals and eliminates the need to stock alternative concentrate solutions with lower potassium concentrations. For short dialysis sessions, this formulation may not completely resolve the hyperkalemia and a dialysate with zero potassium may be more suitable and effective. If hypokalemia persists, a concentrate formulated for a higher potassium concentration may be prescribed. For bicarbonate-based delivery systems, the bicarbonate concentration should be 25 to 35 mmol/L. A lower bicarbonate value is chosen for an animal with severe metabolic acidosis in whom rapid correction of the bicarbonate deficit might predispose to dialysis disequilibrium or paradoxical cerebral acidosis. A lower bicarbonate concentration should be selected for animals with preexisting metabolic alkalosis. If an acetate-containing dialysate is used, the acetate concentration should be approximately 35 mmol/L for animals that are hemodynamically stable and not alkalemic.

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Ultrafiltration

The fluid removal rate is prescribed according to the clinical condition of the patient. Most animals with acute uremia are hypovolemic when initially evaluated for acute uremia. 34• 35 However, institution of aggressive fluid therapy to replace fluid deficits and to induce a diuresis usually results in fluid overloading before the animal is presented for hemodialysis. An ultrafiltration volume and rate is selected to lessen the preexisting fluid burden, correct pulmonary edema and vascular congestion, compensate for fluids administered during dialysis sessions, and facilitate ongoing fluid therapies like parenteral nutrition and blood or plasma transfusions. Eliminating large fluid loads during the first dialysis session is usually unnecessary and dangerous, but 5 to 10 mL/kg/h of ultrafiltration can be prescribed on successive sessions to achieve a suitable dry weight. The influence of ultrafiltration on blood volume can be assessed continuously with specialized monitors to achieve maximal fluid removal without the risk of hypotension and intravascular volume depletion57 (Fig. 8). Heparinization

Heparin is used during dialysis to inhibit clotting and platelet adhesion in the dialyzer and extracorporeal path. Clotting in the dialyzer reduces the surface area available for dialysis and contributes to blood loss during the treatment. Depending on the predialysis activated clotting time (ACT), heparin is given as an intravenous loading dose at 50 to 100 U /kg and is continued as a constant infusion (200 to 1200 U /h) to maintain an ACT at approximately twice normal, 150 to 200 seconds. During initial treatments, heparin kinetics are difficult to predict and frequent monitoring of ACT is required to avoid over- or underheparinization. For animals at severe risk of life-threatening hemorrhage, no heparin procedures can be performed, but preventing clotting in the dialyzer is very difficult. Due to the extent of heparinization, surgical procedures, biopsies, catheterization, venipuncture, or intramuscular injection should be steadfastly avoided

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Figure 8. Percent change in blood volume determined by in-line blood volume profiling in response to ultrafiltration during hemodialysis. The rapid drop in blood volume at the start of the session reflects an excessive ultrafiltration rate (1000 mUhr) with inadequate vascular refilling and was associated with a concurrent hypotensive event. Decreasing the rate of ultrafiltration to 250 mUhr (arrow) permitted refilling of intravascular volume and normalization of blood pressure. At the slower ultrafiltration rate, fluid removal was accomplished without attendant hypotension.

ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF RENAL FAILURE

1367

before, during, and after dialysis until the activated clotting time is normal. Heparin management may be problematic for animals with bleeding tendencies, gastric ulceration, pulmonary vascular abnormality, or hyphema or after surgical placement of the dialysis catheter. If bleeding persists after discontinuing dialysis, heparin can be antagonized cautiously with protamine sulfate at 1 mg per 100 U of estimated residual heparin.

Chronic Intermittent Hemodialysis

Intermittent hemodialysis for the supportive management of animals with end-stage renal disease is a new and provocative approach to veterinary therapeutics. In contrast to human patients, the therapeutic objective for animal patients is to provide an "excretory boost" to lessen the persistent azotemia and urea exposure. How much hemodialysis is necessary to adequately control uremia is a topic of considerable interest and controversy in human nephrology. Adequacy of the hemodialysis prescription can be predicted by kinetic models of urea removal during dialysis that correspond to clinical predictors of patient well-being. 9• 20• 29 The establishment of similar adequacy standards in animals with chronic renal failure awaits future definition; however, intensive intermittent hemodialysis can be provided every 2 to 4 days to supplement the residual excretory capacity of chronically diseased kidneys. The dialysis prescription is formulated to maximally reduce the azotemia during each session. Animals with severe end-stage renal disease or decompensated chronic renal failure should be treated with an acute dialysis prescription during the initial 2 to 3 dialysis sessions until the predialysis BUN is less than 100 mg/ dL. Thereafter the animal can undergo a more intensive dialysis schedule to reduce the clinical signs of uremia, minimize the degree of azotemia, and facilitate conservative medical therapiesY· 54• 55 The dialysis prescription should promote a predialysis BUN of less than 90 mg/ dL and a time-averaged BUN of less than 60 mg/ dL over the interdialysis interval. The time-averaged BUN concentration is a kinetically modeled v:alue that reflects the effective urea exposure or total body burden of urea over the dialysis cycle (Fig. 9). The choice of dialyzer and dialysate composition is generally the same as with acute dialysis sessions. The dialysate bicarbonate concentration is generally set at 30 to 35 mmol/L to maintain adequate buffer reserves in the interdialysis interval. Blood flow and dialysis time are the major variables altered with . maintenance dialysis. After initial dialysis sessions, the risk of dialysis disequilibrium is small and more intensive prescriptions can be used for maximum efficacy. Blood flow rates between 8 and 12 mL/kg/min are well tolerated, but an acetate-based dialysate will not support blood flow rates greater than 5 mL/kg. For "high-efficiency" dialysis treatments, blood flow can be increased cautiously to 15 to 20 mL/kg/min. At these flow rates, blood pressure and pulse rate must be carefully monitored to ensure that the animal remains hemodynamically stable. Dialysis sessions between 240 to 300 minutes are used to maximize urea removal. The session length can be shortened if the patient has appreciable residual renal function, if a high-efficiency dialyzer is used, or if the frequency of dialysis is increased to 3 times per week. Three treatments per week is a traditional schedule for human patients and is used as an intermediate schedule for animals with acute renal failure. The inconvenience, expense, and client commitment of thrice weekly dialysis is impractical for animals who require dialysis indefinitely. Consequently, a less frequent but more intensive

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COWGILL & LANGSTON

100

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75

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25 TAC (39 mgldL)

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Sun Figure 9. Kinetically modeled effects of hemodialysis on BUN and time-average-urea concentration (TAC) in a 25 kg dog with no residual renal function receiving 5 hours of intermittent hemo,dialysis (KW = 2.59) thrice weekly. With this prescription, the average predialysis urea can be maintained at approximately 65 mg/dl and TAC, the effective urea exposure, is maintained at 39 mg/dl.

dialysis regimen must be used . The sched ule is determined by the animal's residual renal function and its dietary protein intake and catabolic status. Animals with a serum creatinine concentration between 8 and 10 mg/ dL need a twice-weekly schedule for minimal adequacy, whereas animals with a serum creatinine greater than 10 mg/ dL require a thrice-weekly dialysis schedule. Each dialysis session m ust achieve a urea red uction ratio approaching 0.85 to 0.95 (Fig. 10). This requires use of blood flow rates approaching 20 mL/ kg / min and a d ialyzer w ith a high urea clearance. Despite the efficiency of the

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ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF RENAL FAILURE

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individual dialysis session, a once-per-week schedule is generally inadequate for animals with moderate to severe uremia. Acute Intoxications/Fluid Removal

For the removal of permeable toxins in nonazotemic animals at low risk of osmotic-shift disequilibrium, the size of the dialyzer, blood flow rate, and duration of the session should be maximized to the limits of hemodynamic stability. Blood flow rates of 10 to 20 mL/kg/min and treatment times of 240 to 360 minutes are selected as appropriate to ensure complete toxln removal. For azotemic animals, the imposed risks of osmotic-shift complications limit the intensity of the dialysis prescription. In such cases sequential treatments or extended slow procedures may be required. For fluid removal, the rate and volume of ultrafiltration is contingent upon the hemodynamic stability of the animal and the potential for osmotic-shift disequilibrium. In very uremic animals, in which urea removal must be mini~ mized, the duration of the session can be extended for slower and more complete fluid removal by prescribing ultrafiltration without hemodialysis. After the required interval of hemodialysis with ultrafiltration, the dialysate is diverted away from the dialyzer to prevent further dialysis while blood flow and trans· membrane hydrostatic pressures are maintained to prolong the ultrafiltration session. Efficacy and Outcome

The efficacy of dialysis is generally predicted by the control and regulation of urea metabolism. 20 The adequacy of dialysis to control the consequences of uremia is influenced by the amount and frequency of the dialysis delivered, residual renal function, dietary protein intake, and catabolic state of the patient. In veterinary medicine the dialysis prescription has been derived empirically, and little attempt to justify or standardize dialysis prescriptions has been made. The most empirical way to assess the effects of dialysis is to exainine the changes in serum chemistries in response to the treatment. As depicted in Figure 9 and Table 1, the serum concentrations of most plasma solutes are quickly and effectively normalized by the end of a typical dialysis session. With an intensive dialysis prescription, BUN can change from a predialysis value greater than 100 mg/ dL to a postdialysis value less than 10 mg/ dL. The greatest change occurs at the beginning of the session when the transmembrane concentration gradient is largest. Similarly, serum bicarbonate, potassium, phosphate, and calcium concentrations normalize during the treatment, but the magnitude of change and their final concentration depend on the formulation of the dialysate. The concentration of most solutes increases during the interdialytic interval, reflecting lack of renal excretory function and redistribution from cellular pools, but with adequate scheduling predialysis values never climB to the steady-state values seen before starting dialysis. The difference between "on dialysis" and "no dialysis" serum chemistries is determined by the "dose" of each dialysis treatment and the interval between treatments. The lower the dialysis dose or the longer the interdialysis interval, the greater the solute accumulation and the higher the predialysis concentrationsP The efficacy or "dose" of an individual dialysis treatment can be quantitated by a variety of indices based on changes in urea concentration over the dialysis

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Table 1. CHANGES IN SERUM CHEMISTRIES WITH A SINGLE HEMODIALYSIS TREATMENT IN A UREMIC CAT* Presentation Creatinine (mg/dL) BUN (mg/dL) Phosphorus (mg/dL) Calcium (mg/dL) Anion gap (mEq/L) Sodium (mEq/L) Potassium (mEq/L) Bicarbonate (mEq/L) Albumin (g/dL)

16.6 173 16.5 9.2

Predialysis

12.8 79 11.4 9.7

23

32

156 4.8 15 2.6

156 7.8 16 2.2

Postdialysis

1.5 3 1.7 10.5 11 148 4.5 21 2.1

%Change

-88 -96 -85

+8 -65

-5 -42 +31

-5

*Presenting and pre- and postdialysis (12th treatment) serum chemistry values for an anuric cat with chronic glomerulonephritis and unilateral ureteral obstruction. The dialysis treatment was performed with a 0.2 m2 cellulosic dialyzer at a blood flow rate of 15 mUkg/min for 240 minutes. The dialysate potassium was 3.0 mEq/L, bicarbonate was 28 mEq/L, and sodium modeling was used. BUN = blood urea nitrogen

session. Kt/V is a kinetically modeled index reflecting the fractional clearance of urea duririg a single dialysis session, wherein K = the dialyzer urea clearance (mL/min), t = the time on dialysis (min), and V = the volume of urea distribution (liters), which is approximately equal to total body water. 23• 29• 61 The higher the Kt/V, the higher and more effective the dose of dialysis. Kt/V correlates with morbidity and mortality of dialysis patients and is a standard index to predict adequacy of the dialysis prescription. 29 Kt/V values from 1.0 to 1.4 ·are considered adequate doses in human patients; however, conventional dialysis prescriptions in animals often result in Kt/V values of 2.5 to 2.9, reflecting highly effective dialysis doses (see Fig. 9). The urea reduction ratio (URR) provides a less rigorous evaluation of urea kinetics but has shown good correlation to Kt/V calculations. 18 Urea reduction ratio is defined as [1 - (postdialysis/predialysis) BUN]. As can be seen in Figure 10, the more intense the dialysis prescription (liters of blood dialyzed), the greater the urea removal. A URR between 0.6 and 0.7 is considered an adequate dose of dialysis for human patients, but achieving ratios between 0.85 and 0.95 is possible in animal patients receiving standard dialysis prescriptions. For initial dialysis treatments a URR between 0.25 and 0.5 is often required, and the prescription to achieve this goal can be more accurately predicted from a kinetic analysis (like that provided in Figure 10) than from empirical guesses. Kt/V and URR are useful indices to monitor the delivery of individual dialysis treatments, but fail to assess the long-term adequacy of dialysis because they ignore the frequency of dialysis and other factors (nutritional adequacy, dietary nitrogen, and catabolic state) that modify urea metabolism. The longterm effects of dialysis over multiple dialysis treatments can be evaluated by the time-average-urea concentration (TAC). Time-average-urea is a kinetically modeled value for urea that reflects the effective urea exposure over successive dialysis treatments. 15• 17• 20 Much like steady-state BUN, the higher the TAC, the greater the degree of urea toxicity and the more severe the clinical expression of uremia. TAC is influenced by both the dose of each dialysis session and the dialysis schedule. TAC is also influenced by extrarenal (and extradialysis) influences on urea metabolism and provides a more global perspective of adequacy than can dialysis dose alone. As seen in Figure 9, a dog with no residual renal function can be maintained

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with a mean predialysis BUN concentration less than 70 mg/dL and a TAC less than 40 mg/ dL with an intensive (Kt/V = 2.59) thrice-weekly dialysis schedule. A twice-weekly schedule with the same dialysis prescription would result in a less satisfactory mean predialysis BUN (98 mg/dL) and TAC (54 mg/dL). 17 In general, the lower the TAC and predialysis BUN, the greater the clinical benefits, but the prescription and frequency should promote an average predialysis BUN of less than 90 mg/dL and a TAC of 60 mg/dL or less over the week. The outcome for survival with complete resolution of renal function, partial resolution manageable with conservative therapy, or successful renal transplantation has improved dramatically in the past 5 years with improved technology and increased experience in veterinary dialysis centers. Today in contrast to earlier years, the mortality for all patients has declined from 85% to 90% down to 50% (personal observations). COMPLICATIONS OF HEMODIAL VSIS

Complications of hemodialysis affect a variety of extrarenal systems because of the complexity of the dialysis procedure itself and the multisystemic aftermath of renal failure. Hemodialysis effects dramatic changes in the metabolic make up of ure)llic animals. Despite this attraction of hemodialysis, some complications are related to imbalance between the resultant decrease in uremic toxins and the reestablishment of homeostasis. At times distinguishing whether an adverse event is due to the uremia per se or to its treatment is difficult. The frequency and intensity of these events diminish as the patient adapts to dialysis and the uremia is controlled. Neurologic Complications

Abnormalities of the central nervous system (CNS) predisposed by both the uremia and its dialytic management include dialysis disequilibrium (osmoticshift diseq:uilibrium) and uremic encephalopathy. Dialysis disequilibrium is a syndrome induced by rapid dialysis in severely azotemic patients. The pathogenesis of this syndrome is poorly characterized, but it results secondary to the development of cerebral edema. The disproportionate mobilization of urea and hydrogen ions from the extracellular fluid and intravenous spaces relative to the CNS causes an interposed osmotic gradient with influx of water, leading to cerebral edema and paradoxical cerebral acidosis. Paradoxical cerebral acidosis in turn exacerbates the osmotic gradient by induction of "idiogenic osmoles" within the brain, causing further brain swelling.3' 4, 31 Dialysis disequilibrium is seen predominantly in cats and small dogs during initial dialysis treatments when azotemia is greatest. Signs may occur during or up to 24 hours after hemodialysis and may include tremors, restlessness, disorientation, vocalization, amaurosis, seizures, and coma. Treatment consists of intravenous mannitol (to increase plasma osmolality and dissipate the osmotic gradient), diazepam (to control seizures), and slowing or discontinuing the hemodialysis treatment. 53 Preventive measures in high-risk patients with preexisting CNS disease, BUN concentrations greater than 150 mg/ dL, or a weight of less than 5 kg include slowing the blood flow rate, lowering the dialysate bicarbonate concentration, and prophylactic administration of mannitol. Mild signs often resolve immediately with mannitol administration, whereas severe signs may require multiple doses of mannitol and 24 to 48 hours of supportive care before resolution.

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Respiratory arrest from severe CNS edema and brain stem compression requires ventilatory support until the edema resolves. Respiratory

Mild to severe hypoxemia is common during dialysis both in human and animal patients. 19 The effect is maximal within 30 to 60 minutes of the start of dialysis and resolves within 120 minutes after its discontinuation. Activation of the alternate complement pathway by contact of blood with the dialyzer membrane causes leukocyte and platelet aggregation in the pulmonary microvasculature that interferes with oxygen diffusion. The effect is more pronounced with cellulosic compared to more biocompatible synthetic membrane dialyzers. 19• 30• 37 Acetate-based dialysate causes hypoventilation from loss of carbon dioxide into the dialysate and exacerbates the hypoxemia. This effect is not seen with bicarbonate-based dialysate. 19 Pulmonary thromboembolism, from platelet aggregation and thrombus formation induced by the catheter, can cause acute onset of mild to severe dyspnea during or between dialysis treatments. Other causes of hypoxemia including volume overload, pulmonary edema, and uremic pneumonitis can be related directly to the uremia. Uremic pneumonitis is a facet of adult respiratory distress syndrome, in which uremic toxins directly alter the permeability of pulmonary capillaries, allowing leakage of a high protein fluid into alveoli and pulmonary interstitium.8• 51 Radiographically, uremic pneumonitis appears as an interstitial or mixed interstitial/ alveolar pattern; but it is frequently overshadowed by concurrent pulmonary edema and may be underrecognized. 5• 44• 51 Ultrafiltration can resolve the fluid overload and pulmonary edema, but is ineffective at correcting uremic pneumonitis. Adequate dialysis is used to resolve the azotemia perpetuating the condition, but established cases are difficult to rectify, and the prognosis for recovery is grave even with ventilatory support. Hematologic

Decreases in white blood cell and platelet counts occur routinely during dialysis sessions and are related to membrane biocompatibility reactions. 21 • 28• 32• 4°Contact of blood with the hemodialysis membrane activates the alternate complement pathway causing decreases in total hemolytic complement and development of reactive C3 and CS fragments. This reaction proceeds within minutes of starting dialysis, is maximal after 15 minutes, and resolves within hours due to down-regulation of the complement system. The binding of complement to the dialysis membrane activates leukocytes and platelets as they circulate through the dialyzer, causing neutropenia and thrombocytopenia as these cells aggregate in the pulmonary vasculature (see above). 19• 32• 37• 40• 64 These transient changes in leukocytes have no known clinical significance, but complement activation is thought to induce chills, mild discomfort, and hypoxemia. 12• 22 Anemia is a persistent problem in dialyzed animals and involves many mechanisms relating to both the uremia and blood loss during the treatment. 13• 17 Blood loss due to clotting in the dialyzer can be minimized by carefully managed heparinization and rapid blood flows to avoid sludging in the dialyzer. Repeated diagnostic blood sampling, bleeding from excessive heparinization and platelet function defects, and gastrointestinal hemorrhage additionally contribute to the blood loss. Rarely, hemolysis may result from improper adjustment of the blood

ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF RENAL FAILURE

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pump, excessive pressures in the extracorporeal circuit, impurities (e.g., copper, aluminum, zinc, nitrates, or formaldehyde), overheating, or hypotonicity of the dialysate.' All blood loss is significant in uremic patients who are unable to regenerate red blood cells because of a deficiency of erythropoietin, and it may necessitate administration of blood transfusions and/ or recombinant erythropoietin treatment.B Gastrointestinal

Anorexia, nausea, and vomiting are common complications of renal failure but also may be seen at the start of hemodialysis secondary to hypotension and diversion of blood flow from the gastrointestinal tract, biocompatibility reactions to the membrane, or contaminants in the dialysate. 12• 37 Dialysis disequilibrium can also cause centrally mediated nausea and vomiting. Using slow blood flow rates at the start of dialysis treatments with a gradual increase to the prescribed rate minimizes these signs and patient discomfort. Technical

Complications relating to the technical aspects of hemodialysis are relatively uncommon due to safeguards built into modem delivery systems. Inappropriate dialysate composition from improper proportioning or overheating is monitored by internal sensors and dialysate is diverted before contact with the dialyzer. Air embolus is prevented by air detection sensors in the return blood path that stop blood flow before the air reaches the patient. Inadvertent separation of blood lines is monitored, and flow is stopped before significant blood loss can occur (see Fig. 5). Vascular Access

Complications with vascular access are some of the most serious and troublesome aspects of hemodialysis. Thrombosis within the access and major vessels is the most frequent complication and a major factor limiting the delivery of dialysis. Despite development of less thrombogenic materials, all access devices can activate platelets. Thrombosis within the catheter lumen can be managed by careful thromboaspiration or low-dose fibrinolytic agents (urokinase or streptokinase), but clots surrounding the catheter or in the vascular space or right atrium are more difficult to control. These thrombi can obstruct the ports of the catheter, restricting blood flow to the dialyzer. Pulmonary vein thromboembolization from vena caval or right atrial thrombi infrequently causes acute respiratory dysfunction, which may be life threatening. Long-standing thrombi in the right atrium tend to adhere to the wall of the heart and become endothelialized (Fig. 11). Central venous thrombi also cause pleural effusion that resolves with catheter removal. Attempts at clot dissolution using urokinase, streptokinase, or tissue plasminogen activator have been less than 60% successful when attempted in people. 49 The incidence of thrombosis with percutaneous catheters appears to be higher in dogs and cats than in human patients, suggesting differences in their respective coagulation mechanisms and/or catheter interactions. Access infection can lead to premature loss of the access, whether it is a catheter, shunt, or fistula.

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Figure 11. Cardiac ultrasound image and necropsy specimen demonstrating a large thrombus (arrow) adherent to the right atrium (RA) in a dog with a transcutaneous venous hemodialysis catheter. AO = aorta.

Hypotension

Hypotension is a common and multifaceted occurrence during hemodialysis.38· 43 In cats and small dogs, the volume of the extracorporeal circuit relative to vascular volume is large (up to 35%), and establishing extracorporeal flow may deplete intravascular volume. Removal of fluid from the vascular space by ultrafiltration faster than it can be replaced from the extravascular space causes relative hypovolemia and transient hypotension (see Fig. 8).57 Additionally, the decrease in plasma osmolality induced by hemodialysis opposes movem ent of fluid from the extravascular space into the vascular compartment. The extracorporeal circuit in small dogs and cats is routinely primed with colloidal solutions to minimize the hypovolemia and hypotension . Sodium modeling promotes fluid movement from the interstitium into the vascular space, making the fluid more available for ultrafiltration and blunting the hypovolemia.56 Dialysis-induced hypotension responds quickly to fluid supplementation, which transiently refills the vascular volume while fluid from the extravascular space is mobilized. FUTURE DIRECTIONS Continuous Therapies

As technologic advances are made and more experience is gained with veterinary hemodialysis, changes are likely to be implemented. Continuous dialytic therapy for 72 to 96 plus hours with very slow blood flow rates is a more physiologically balanced method of removing uremic toxins than is intermittent dialysis. Simplified delivery systems that can be monitored by intensive care personnel are being developed and will permit delivery of continuous therapy to acutely ill patients on a more physiologic and cost-effective basis. Continuous therapies seem particularly well suited for azotemic cats whose small size and high urea concentrations (> 150 mg / dL) predispose them to osmotic-shift disequilibrium during intermittent therapy. As the priming volume required for

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the extracorporeal circuit becomes miniaturized, this form of dialytic therapy holds promise for the future. Reuse

Because of the increased cost of more biocompatible synthetic dialyzers, most human dialysis centers clean and disinfect dialyzers for multiple reuses in the same patient. The cost of automated reuse equipment will probably remain prohibitive for veterinary facilities, but with suitable manual techniques, biocompatible synthetic dialyzers could be used on animal patients. Carefully monitored procedures must be used to avoid microbial contamination or exposure of the patient to residual disinfectant, but a reuse program could allow patients the benefits of the more biocompatible dialyzers in addition to improved biocompatibility from the reuse procedure itself. CONCLUSIONS

Hemodialysis is a technically feasible, safe, efficacious, and indispensable therapy for both dogs and cats with life-threatening renal failure. Its complexity and the limited indications for its application restrict widespread use of hemodialysis in veterinary practice. However, for many dogs and cats with acute and chronic uremia, no alternative to dialysis exists except death. Increased awareness and acceptance of dialysis by primary care veterinarians, increased sophistication of specialty veterinary practice and academic centers, increased training of veterinary internists with interest and knowledge in nephrology, and increased demand by pet owners for this service promise its further expansion and availability on a regional referral basis. ACKNOWLEDGMENT Dr. Lan:gston was supported in part by a grant from the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis, California.

References

JJ, Rowntree LC, Turner BB: On the removal of diffusible substances from the circulating blood by means of dialysis. Trans Assoc Am Physicians 28:41, 1913 Acchiardo SR, Hayden AJ: Is Na + modeling necessary in high flux dialysis. Trans Am Soc Artif Intern Organs 37:M135-M137, 1991 Andrew RD: Seizure and acute osmotic change: Clinical and neurophysiological as~ pects. J Neurol Sci 101:7-18, 1991 Arieff A: Dialysis disequilibrium syndrome: Current concepts on pathogenesis and prevention. Kidney Int 45:629--{;35, 1994 Bass HE, Singer E: Pulmonary changes in uremia. JAMA 144:819-823, 1959 Berkoben MS, Schwab SJ: Vascular access for hemodialysis. In Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 3. Norwalk, Appleton & Lange, 1995 Blagg CR: Acute complications associated with hemodialysis. In Maher JF (ed): Replacement of Renal Function by Dialysis: A Textbook of Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 Bleyl U, Sander E, Schindler T: The pathology and biology of uremic pneumonitis. Intensive Care Med 7:193-202, 1981

1. Abel

2. 3. 4. 5. 6. 7. 8.

1376

COWGILL & LANGSTON

9. Bosch JP: Prescribing high-efficiency treatments. In Bosch JP (ed): Hemodialysis: HighEfficiency Treatments (Contemporary Issues in Nephrology, vol 27). New York, Churchill Livingstone, 1993 10. Brescia MJ, Cimino JE, Appel K, et al: Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med 275:1089-1092, 1989 11. Butler HC: Advanced therapy for renal failure. In Proceedings of the 35th Annual Meeting of the American Animal Hospital Association, Las Vegas, 1968, pp 174-182 12. Charoenpanich R, Pollak VE, Kant KS, et al: Effect of first and subsequent use of qemodialyzers on patient well-being: The rise and fall of a syndrome associated with new dialtzer use. International Society for Artificial Organs 11:123-127, 1987 13. Cowgill LD:. Medical management of the anemia of chronic renal failure. In Osborne CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Baltimore, Williams & Wilkins, 1995 14. Cowgill LD, Bovee KC: Current status of hemodialysis and renal transplantation. In Kirk RW (ed): Current Veterinary Therapy VI: Small Animal Practice. Philadelphia, WB Saunders, 1977 15. Cowgill LD, Maretzki CH: CVT update: Veterinary applications of hemodialysis. In Bonagura JD, Kirk RW (eds): Kirk's Current Veterinary Therapy Xll: Small Animal Practice. Philadelphia, WB Saunders, 1995 16. Cowgill LD: Current status of veterinary hemodialysis. In Kirk RW (ed): Current Veterinary Therapy VII: Small Animal Practice. Philadelphia, WB Saunders, 1980 17. Cowgill LD: Application of peritoneal dialysis and hemodialysis in the management of renal failure. In Osborne CA, Finco DR (eds): Canine and Feline Nephrology and . Urology. Baltiinore, Williams & Wilkins, 1995 18. baugirdas JT: Second generation logarithmic estimates of variable single-pool Kt/V. J Am Soc Nephrol4:1205-1212, 1993 19. PeBroe ME: Haemodialysis-induced hypoxaemia. Nephrol Dial Transplant 9:173-175, 1994 20. Depner TA: Urea modeling: Introduction. In Prescribing Hemodialysis: A Guide to Urea Modeling. Boston, Kluwer Academic Publishers, 1991 21. Donovan L, Pacholok S, Phillips A, et al: Effect of dialyser composition and reuse on neutrophil count and elastase u-1 proteinase inhibitor complex formation. Int J Artif Organs 15:139-143, 1992 22. Dumler F, Zasuwa G, Levin NW: Effect of dialyzer reprocessing methods on complement activation and hemodialyzer-related symptoms. Artif Organs 11:128-131, 1987 23. Depner TA: Single-compartment model. In Prescribing Hemodialysis: A Guide to Urea Modeling. Boston, Kluwer Academic Publishers, 1991 24. Dhein CRM: Hemodialysis in the dog. Compendium Continuing Educ Practicing Vet 3:1031-1045, 1981 25. Drukker W: Haemodialysis: A historical review. In Maher JF (ed): Replacement of Renal Function by Dialysis: A Textbook of Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 26. Fine RN, Tejani A: Dialysis in infants and children. In Daugirdas JT, Ing TS (eds): Handbook of Dialysis, ed 2. New York, Little, Brown, 1994 27. Carella S, Lorch JA: Hemodialysis and hemoperfusion for poisoning. AKF Nephrology Lette.r 10:1-19, 1993 28. Gawaz M, Bogner C: Changes in platelet membrane glycoproteins and platelet-leukocyte interaction during hemodialysis. Clinical Investigator 72:424-429, 1994 29. Gotch FA, Sargent JA: A mechanistic analysis of the national cooperative dialysis study (NCDS). Kidney Int 28:526-534, 1985 30. Hakim RM, Lowrie EG: Hemodialysis-associated neutropenia and hypoxemia: The effect of dialyzer membrane materials. Nephron 32:32-39, 1982 31. Harris CP, Townsend JJ: Dialysis disequilibrium syndrome. West J Med 151:52-55, 1989 32. Heierli C, Markert M, Lambert PH, et al: On the mechanisms of haemodialysis-induced neutropenia: A study with five new and re-used membranes. Nephrol Dial Transplant 3:773-783, 1988 33. Gourley IM, Parker HR, Bell RL, et al: Responses of nephrectomized dogs during hemodialysis. Am J Vet Res 34:1421-1425, 1973 34. Grauer GF, Lane IF: Acute renal failure: Ischemic and chemical nephrosis. In Osborne

ROLE OF HEMODIALYSIS IN THE MANAGEMENT OF RENAL FAILURE

35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

1377

CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Baltimore, Williams & Wilkins, 1995 Grauer GF, Lane IF: Acute renal failure. In Ettinger SJ, Feldman ED (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, ed 4, vol 2. Philadelphia, WB Saunders, 1995 Hoenich NA, Woffindin C, Ward MK: Dialyzers. In Maher JF (ed): Replacement of Renal Function by Dialysis: A Textbook of Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 Jameson MD, Wiegmann TB: Principles, uses, and complications of hemodialysis. Med Clin North Am 74:945-960, 1990 Kinet J, Soyeur D, Balland N, et al: Hemodynamic study of hypotension during hemodialysis. Kidney Int 21:868-876, 1982 Ledebo I: Bicarbonate in high-efficiency hemodialysis. Contemporary Issues in Nephrology 27:9-25, 1993 Levett DL, Woffindin C, Bird AG, et al: Complement activation in haemodialysis: A comparison of new and re-used dialysers. Int J Artif Organs 9:97-104, 1986 Levine T, Falk B, Henriquez M, et al: Effects of varying dialysate sodium using large surface area dialyzers. Trans Am Soc Artif Intern Organs 24:139-141, 1978 Kiil F: Development of a parallel flow artificial kidney in plastics. Eur J Surg Suppl 253:142-150, 1960 Langston CE, Cowgill LD, Spano J: The application of hemodialysis in uremic cats: A review of 24 cases [abstract 77]. In Proceedings of the Fourteenth Annual Veterinary Medical Forum, San Antonio, 1996, p 750 Moon ML, Greenlee PG, Burk RL: Uremic pneumonitis-like syndrome in ten dogs. J Am A11irn Hosp Assoc 22:687-691, 1986 Mujais SK, Ivanovich P: Membranes for extracorporeal therapy. In Maher JF (ed): Replacement of Renal Function by Dialysis: A Textbook of Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 Mujais SK, Schmidt B: Operating characteristics of hollow fiber dialyzers. In Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 3. Norwalk, Appleton & Lange, 1995 Muriassco A, France G, Leblond G, et al: Sequential sodium therapy allows correction of sodium volume balance and reduces morbidity. Clin Nephrol 24:201-208, 1985 Port FK, Johnson WJ, Klass DW: Prevention of dialysis disequilibrium syndrome by use of high sodium concentration in the dialysate. Kidney Int 3:327-333, 1973 Poulain F, Raynaud A, Bourquelot P, et al: Local thrombolysis and thromboaspiration in the treatment of acutely thrombosed arteriovenous hemodialysis fistulas. Cardiovasc Intervent Radiol14:98-101, 1991 Ogden DA: A double blind cross-over comparison of high and low sodium dialysis. Proc Clin Dial Transplant Forum 8:157-165, 1978 Rackow EC, Fein IA, Sprung C, et al: Uremic pulmonary edema. Am J Med 64:10841088, 1978 Parker HR, Gourley IM, Bell RL: Current developments in peritoneal and hemodialysis. In Proceedings of the 22nd Gaines Veterinary Symposium, Stillwater, 1972, pp 3-15 Rosa AA, Shideman J, McHugh R, et al: The importance of osmolality fall and ultrafiltration rate on hemodialysis side effects. Nephron 27:134-141, 1981 Polzin DJ, Osborne CA, Bartges JW, et al: Chronic renal failure. In Ettinger SJ, Feldman ED (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat, ed 4, vol 2. Philadelphia, WB Saunders, 1995 Polzin DJ, Osborne CA: Conservative medical management of chronic renal failure. In Osborne CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Baltimore, Williams & Wilkins, 1995 Sadowski RH, Allred EN, Jabs K: Sodium modeling ameliorates intradialytic and interdialytic symptoms in young hemodialysis patients. J Am Soc Nephrol 4:11921198, 1993 Steuer RR, Harris DH, Conis JM: A new optical technique for monitoring hematocrit and circulating blood volume: Its application in renal dialysis. Dial Transplant 22:260265, 1993

1378

COWGILL & LANGSTON

58. Stewart WK, Fleming LW: Blood pressure control during maintenance heamodialysis with isonatric (high sodium) dialysate. Postgrad Med J 50:260-264, 1974 59. Stewart WK: The composition of dialysis fluid. In Maher JF (ed): Replacement of Renal 60.

61. 62. 63.

64.

Function By Dialysis: A textbook of dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 Quinton W, Dillard D, Scribner BH: Cannulation of blood vessels for prolonged hemodialysis. Trans Am Soc Artif Intern Organs 6:104-113, 1960 Sargent JA, Gotch FA: Principles and biophysics of dialysis. In Maher JF (ed): Replacement of Renal Function by Dialysis, ed 3. Dordrecht, Kluwer Academic Publishers, 1989 Thornhill JA: Hemodialysis. In Bovee KC (ed): Canine Nephrology. Media, PA, Harwal, 1984 Ward RA: Acid-base homeostasis in dialysis patients. In Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 2. Norwalk, Appleton & Lange, 1990 Walton DF, Cheung AK: Membrane biocompatibility. In Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis, ed 3. Norwalk, Appleton & Lange, 1995

Address reprint requests to Larry D. Cowgill, DVM, PhD Department of Medicine and Epidemiology School of Veterinary Medicine University of California Davis, CA 95616

Appendix HEMODIALYSIS REFERRAL CENTERS IN THE UNITED STATES

Companion Animal Hemodialysis Unit, Veterinary Medical Teaching Hospital, University of California-Davis, Davis, CA 95616. Phone: 916-7521393 Veterinary Referral Associates, Inc., 15021 Dufief Mill Road, Gaithersburg, MD 20878. Phone: 301-340-3224 Veterinary Clinical Center, Michigan State University, East Lansing, MI 48824. Phone: 517-347-5034 The Animal Medical Center, 510 E. 62nd Street, New York, NY 10021. Phone: 212-838-8100