TLC for AKI and IMHA: A Brief Review of HD, TPE, and HP

By Courtney Peck, DVM, DACVECC
angell.org/emergency
emergency@angell.org
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October 2023

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Over the past ten years, many advances have been made in our ability to diagnose and treat severely life-threatening illnesses, including acute kidney injury (AKI), immune-mediated hemolytic anemia (IMHA), and toxin exposure. The use of extracorporeal therapies has become a significant player in our ability to successfully treat these illnesses through early intervention and the ability to gain rapid control of ongoing disease processes. While the pathophysiology of acute kidney injury and immune-mediated diseases are beyond this lecture’s scope, extracorporeal therapies are becoming more common and accessible for veterinary patients. Clients may ask their family veterinarian whether these modalities could help their pets. This presentation aims to provide basic information about the modalities of hemodialysis, therapeutic plasma exchange, and hemoperfusion so that you are well-prepared to have these conversations with your clients and feel confident when considering referral of your patients.

Basic Overview of Modalities

The broad mechanism of each of these modalities focuses on “treating” or processing a patient’s blood outside the patient’s body. Blood is removed from the patient using a large bore jugular catheter, pumped through a filter (or centrifuge) to remove molecules from the blood, and then the patient’s blood is returned to the patient. We select a process to do this based on the treatment goals. Understanding the basic principles of each helps decide which modality is ideal for a given patient.

Hemodialysis (HD)

Hemodialysis uses a semipermeable membrane to remove unwanted substances from a patient’s blood selectively. In renal failure, the goal is to remove uremic toxins, including creatinine, BUN, and potassium, which lead to the clinical signs of renal failure. We use hemodialysis to take over this role of the kidneys when they are too injured to do it successfully in an attempt to reduce the adverse consequences of severe azotemia. In renal failure, many uremic toxins accumulate. However, we tend to use BUN and creatinine as representatives because they are easily measured and monitored. Hopefully, the kidneys will recover from the insult and regain their normal function with time. We can also use dialysis to remove select unwanted toxins, such as ethylene glycol, to limit their detrimental effects on the kidneys.

Hemodialysis uses two main mechanisms to remove these unwanted substances and toxins from the blood: diffusion and convection. Diffusion is the movement of solutes (molecules, toxins) across a semipermeable membrane along a concentration gradient. Blood flows along one side of the semipermeable membrane, while dialysate (which contains no uremic toxins) flows along the other side. Diffusion occurs due to the random movements of small molecules coming into contact with the semipermeable membrane (located inside the dialysis filter or dialyzer) and then moving across the membrane into dialysate. In renal failure, there is a high concentration of uremic toxins in the patient’s blood. We expose the blood to dialysate, and the uremic toxins move down the concentration gradient out of the blood and into the dialysate, which is then discarded. The blood and fresh dialysate are circulated through the filter multiple times during the treatment, gradually decreasing the level of uremic toxins in the blood. Solute concentration is the main determinant of diffusion.

Convection uses a different method for solute removal. In convection, a positive pressure is exerted across the semipermeable membrane, pushing water and larger solutes into the dialysate, which are then removed. This process can also be used to only remove water, such as in cases where patients are fluid-overloaded (this is called ultrafiltration). Convection does not rely on a concentration gradient to move solutes across the membrane, so it is more effective in removing larger solutes.

There are two main types of platforms for hemodialysis, based on which process (diffusion or convection) you want to use. Historically, the platforms are intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT). IHD primarily uses diffusion, whereas CRRT mainly uses convection (although this platform can also perform some diffusion). No data (human or veterinary) supports that one modality is more beneficial in treating renal failure. A lot of the time, which platform is used is determined by which machine is available (if you aren’t lucky enough to have both types). As the name suggests, IHD is usually a shorter, more aggressive treatment – it allows for more rapid shifts in solutes and fluid, which may be risky in critical patients. Treatments are usually performed over a four- to six-hour period each day over the course of days. IHD machines also create their own dialysate, combining processed water (reverse osmosis), acids, and electrolytes.

Traditionally, CRRT patients are hooked up to the machine, which continuously filters the blood until a goal is reached; these treatments often last 24 to 48 hours. While this platform has higher requirements for staffing and monitoring, it produces more gradual shifts in fluid and solutes and tends to be safer in critical patients. In veterinary medicine, those programs with a CRRT machine will often do a hybrid treatment, where a combination of convection and diffusion are used to increase the efficiency of the treatment and shorten treatment time. CRRT machines require bags of pre-made dialysate instead of the machine making it.

Regardless of the platform used, the workhorse of dialysis is the dialyzer or filter. Many different types of dialyzers are available, again based on what solute(s) need to be removed and patient size. Within the filter are hundreds of tiny tubes, each of which is a semipermeable membrane. The pores in these membranes are of various sizes but are generally effective in allowing small to medium-sized solutes to pass through (either through diffusion or convection). Larger molecules, or solutes bound to proteins in the blood, are not effectively removed by dialysis. These membranes keep the blood and the dialysate separate, which creates the concentration gradient during diffusion. The structure of the dialyzers creates a huge surface area, mimicking the kidney and allowing for the efficient removal of solutes and toxins.

Indications for Hemodialysis

As discussed, hemodialysis is effective for removing small- to medium-sized solutes and toxins, which is why it is effective in treating acute kidney injury (urea, creatinine, and electrolytes are fairly small). Currently, the most common reason we treat patients with hemodialysis is Leptospirosis; however, other causes of AKI, such as pyelonephritis and toxin exposure, are possible. It used to be thought that patients with ureteral obstruction should be treated with hemodialysis, but this has fallen out of favor, and current recommendations support immediate surgical intervention with SUB placement.

Acute Kidney Injury

Acute kidney injury and azotemia can develop due to three main causes: Pre-renal (such as hypotension, dehydration), intrinsic renal disease (infection, immune-mediated disease, toxicity), or post-renal (urethral obstruction). It is essential to determine which of these causes is causing renal failure in a given patient, as the treatment for each cause will vary.

There are four identified phases of AKI: Initiation, extension, maintenance, and recovery. Initiation is the inciting event (development of infection, exposure to toxin) and usually lasts hours. The extension phase includes sustained injury or exposure to a toxin and can last days to weeks. During the maintenance phase, renal response to and repair from the injury occurs and may last for months. The recovery phase can last for years; if too much damage has occurred and recovery is not achieved, renal death will occur. We do not see an increase in BUN and creatinine on routine blood work until 75% of renal function has been lost. Currently, we tend to identify acute kidney injury during the maintenance phase when treatment addresses the systemic effects of renal failure and is less effective in definitive healing. Ideally, we would identify acute kidney injury during the initiation or extension phases, when intervention could play a more significant role in preventing ongoing and further renal damage. This is why there is so much investigation into renal biomarkers such as SDMA, which may be more sensitive in identifying early AKI. More recent evidence suggests that approximately half of those patients who sustain a significant acute kidney injury will develop chronic kidney disease at some point during their life; being able to identify a kidney injury early, allowing earlier intervention and prevention of further injury may reduce the risk of CKD in some patients.

Hemodialysis is recommended in patients with acute kidney injury who have developed severe and/or progressive azotemia despite adequate fluid resuscitation. Additional criteria include severe hyperkalemia or acid-base disturbances, fluid overload, and oliguria/anuria. Ideally, hemodialysis would be initiated before these life-threatening sequellae develop in our patients.

Fluids and AKI

The kidneys typically receive approximately one-quarter of cardiac output and normally exist in a relatively low-oxygen state. This makes them extremely sensitive to decreases in perfusion and oxygen delivery and poorly capable of dealing with hypoxemia. While fluid therapy can effectively improve perfusion and oxygen delivery to the kidneys, it requires a careful balance because too much fluid volume can negatively impact renal function. When interstitial edema develops, it increases the distance oxygen must diffuse to reach the renal cells, promoting renal hypoxia. Additionally, the kidneys are enclosed in a capsule that cannot expand. As renal interstitial edema develops, it also creates increased pressure within the kidney, leading to damage to the renal cells and decreasing renal blood flow. There has been a demonstrated association in human medicine between fluid overload and worsening patient outcomes, and it is reasonable to assume the same holds for our patients. In a recent study, approximately 70% of veterinary patients presenting for hemodialysis were significantly fluid-overloaded. The historical belief that more fluids are better for acute kidney injury has led to a new movement of mindful fluid therapy stewardship.

Total Plasma Exchange (TPE)

In this modality, patient blood is separated from the plasma to remove larger and/or protein-bound molecules or toxins. This can be done either by a filter that uses a membrane or via centrifugation. If the separation occurs via a filter, the patient plasma is removed (including the substance we want to remove) and discarded; donor plasma is combined with the rest of the patient’s blood components before returning it to the patient. This process is called therapeutic plasma exchange (TPE). Alternately, the components in a patient’s plasma can be removed via centrifugation, and the patient’s plasma is then returned to the patient. This process is called plasmapheresis. The modality chosen depends on the machine available. This discussion will focus on TPE; however, both modalities are primarily used to remove larger and/or highly protein-bound substances from the blood. In veterinary medicine, TPE is used mainly to remove antibodies in immune-mediated diseases and specific toxins (covered later).

During total plasma exchange, a treatment is based on processing a certain volume of the patient’s plasma. Research has found that treating one-and-a-half plasma volumes (based on patient size and PCV) will reduce the substance by approximately 85%; this is what most treatment protocols are based on. For immune-mediated diseases, current treatment guidelines recommend daily treatment for three days in a row, followed by a rest day and subsequent treatments as indicated by the patient’s clinical progression. One treatment may be sufficient for the removal of a toxin.

Currently, the main indications for TPE in veterinary patients include immune-mediated diseases and exogenous toxicities. Immune-mediated diseases result from auto-antibodies against a particular cell type or receptor. These antibodies circulate in the plasma before binding to a specific cell or receptor. By removing patient plasma, TPE effectively also removes circulating auto-antibodies, essentially taking immediate control of the disease process in hopes of allowing standard immunosuppressive therapy to take action. The use of TPE in treating IMHA has been most commonly reported in veterinary literature, with a landmark case series reported in 2019 by Cowgill et al. This paper showed a significant improvement in survival in those patients who received TPE compared to traditional medical management alone. TPE does not replace the current recommended standard of treatment with immunosuppressive therapy; it aims to rapidly control the disease to allow those therapies to take effect. TPE has also been evaluated in treating immune-mediated thrombocytopenia, fulminant myasthenia gravis syndrome, and rattlesnake envenomation in veterinary patients.

Hemoperfusion is another modality becoming more popular, particularly when treating exogenous toxicities in veterinary patients. This modality uses the process of adsorption (not to be confused with absorption), where molecules or solutes bind to a medium when exposed to it. Instead of a filter, the patient’s blood is passed through a cartridge containing a substance such as charcoal, carbon, or other polymer. Adsorption is non-specific for a particular substance, and its efficacy is not determined by molecular size or degree of protein binding. Hemoperfusion also binds molecules that we do not necessarily want to remove from the blood, such as glucose, albumin, electrolytes, and platelets. To counteract this, blood passing through a hemoperfusion cartridge is often passed through a dialyzer to re-equilibrate electrolytes and glucose before returning the blood to the patient.

Toxicities

Based on recent ASPCA poison control reports, the most common types of exogenous toxins that veterinary patients are exposed to include ibuprofen, human antidepressants, human cardiac medications, and grapes/raisins. Immediate intervention to decontaminate is recommended, but in cases where the overdose is significant, extracorporeal therapy may improve patient outcomes by removing the toxin in a matter of hours. The modality used will depend on the characteristics of the exogenous toxin, most importantly, its molecular size and degree of protein binding. Hemodialysis is preferred for small molecular weight, non-protein-bound toxins such as phenobarbital, whereas TPE is preferred for larger, protein-bound substances such as non-steroidal anti-inflammatories.

Tips for Transfer

With an increased knowledge about these modalities and their uses in veterinary medicine, our referral community plays a significant role in identifying patients who might benefit from them and preparing the clients with appropriate expectations. Immediate intervention is ideal in cases of toxin exposure, with these modalities being most effective six to 12 hours post-exposure. Patients with azotemia should be evaluated carefully, including urine output monitoring and tailored fluid therapy. Clients should be urged to consider hemodialysis earlier, as opposed to later, with suspected AKI if the patient is developing progressive azotemia, oliguria, or electrolyte or acid/base disturbances. For patients with IMHA, TPE should be discussed with the client if a second transfusion is required to proceed with TPE if a third transfusion is needed.

For patients who may be appropriate candidates for transfer for extracorporeal therapy, we recommend avoiding jugular venipuncture, as the jugular veins need to be preserved for the hemodialysis/TPE catheter. Some patient characteristics are also essential to consider; patients under five kilograms can increase the challenges and risks of extracorporeal therapy, while large patients often require more supplies and subsequently incur a higher cost for therapy. Ideally, patients are behaviorally amenable to close contact with staff, as they are closely monitored and frequently handled during the treatments. Any concurrent co-morbidities that may complicate extracorporeal therapy should also be considered. A final consideration in determining if therapy can proceed is the availability of blood products, which are often required (packed red blood cells in smaller or anemic patients and plasma for all TPE patients).

Hemodialysis, TPE, and hemoperfusion require a significant investment from the client, not only financially but also in terms of time and emotional energy. These modalities do come with some risks, including catheter complications, coagulation complications, and failure to respond to therapy. However, these modalities can be life-saving in appropriate patients, and if clients are aware of the short-term commitment, it can be gratifying. If you have any questions about a potential case transfer, please do not hesitate to contact our team.

References

1. Prowle, JR, Echeverri, JE, Ligabo EV et al. Fluid balance and acute kidney injury. Nat Rev Nephrol 2010; 6: 107-115.
2. Bouchard, J, Soroko, SB, Chertow, GM et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney International 2009; 76: 422-427.
3. Melchert, A, Barretti, P, Okamoto PT et al. Intradialytic complications in dogs with acute renal failure submitted to intermittent hemodialysis. Asian J Anim Vet Adv 2017; 12(6): 288-293.
4. Cowgill, LD, Polzin, DJ, Elliott, J et al. Is progressive chronic kidney disease a slow acute kidney injury? Vet Clin Small Anim 2016; 46: 995-1013.
5. Adin, CA and Cowgill, LD. Treatment and outcome of dogs with leptospirosis: 36 cases (1990-1998). J Am Vet Med Assoc 2000; 216: 371-375.
6. Eatroff, AE, Langston, CE, Chalhoub, S et al. Long-tern outcome of cats and dogs with acute kidney injury treated with intermittent hemodialysis: 135 cases (1997-2010). J Am Vet Med Assoc 2012; 241: 1471-1478.
7. Harison, E, Langston, C, Palma, D et al. Acute azotemia as a predictor of mortality in dogs and cats. J Vet Intern Med 2012; 26: 1093-1098.
8. Kjaergaard, AB, Davis, JL, Acierno, MJ. Treatment of carprofen overdose with therapeutic plasma exchange in a dog. J Vet Emerg Crit Care 2018; 28(4): 356-360.