Inflammation of the pancreas, which can either be acute or more chronic in nature, is an important disease process affecting dogs and cats. Pancreatitis develops when there is excessive activation of digestive enzymes (e.g., trypsin) within the pancreas, which overwhelms local defences, leading to intrinsic damage of the organ.¹ The resulting inflammation can vary in severity, which corresponds to variability in clinical symptoms and illness severity in affected pets. Some cases of acute pancreatitis may lead to considerable morbidity and potentially mortality. The ensuing systemic inflammatory response triggered by acute pancreatitis may lead to downstream organ failure (e.g., acute kidney injury [AKI]).² This lecture will review the pathophysiological mechanisms underpinning pancreatitis associated AKI and outline the clinical approach to these cases.

Pathophysiology of Pancreatitis Associated AKI

The pathophysiology of pancreatitis is quite complex. Under normal circumstances pancreatic digestive enzymes do not cause intrinsic damage to the pancreas since they are stored as zymogens (biologically inactive enzymes) within compartmentalized organelles.¹ In addition, endogenous inhibitors of these enzymes (e.g., pancreatic secretor trypsin inhibitor) are produced within the same region of these enzymes. Therefore, in the event of inappropriate zymogen release and activation, safeguards are present to limit any potentially deleterious effects. There are also circulating antiproteases within the blood should there be systemic release of activated pancreatic enzymes.¹ In cases of pancreatitis, these safeguards become overwhelmed and an acute inflammatory response is triggered. Inflammation is characterized by vasodilation and increased vascular permeability, which promotes tissue oedema, as well as extravasation of neutrophils into the local tissues. Further complications may develop associated with excessive cytokine release leading to systemic inflammation, as well as oxidative damage. Therefore, severe acute pancreatitis can lead to patients exhibiting systemic signs of severe inflammation (systemic inflammatory response syndrome or SIRS). These include, but are not limited to, tachycardia, hypotension, altered respiratory function, pyrexia, leukocytosis, and third spacing of fluids.

Animals with severe signs of acute pancreatitis are at risk of developing other organ dysfunctions. In some instances, several organ dysfunctions may occur simultaneously and fulfill criteria of multiple organ dysfunction (MODS). MODS describes a situation where acute organ dysfunctions develop such that homeostasis cannot be mainted.³ Mechanisms underpinning MODS development are complex and only partially understood. Different theories exist regarding the development of MODS. The one hit theory suggests that a very severe primary insult leads to organ dysfunction. The two hit theory, in contrast, describes a situation where a primary insult (e.g., pancreatitis) leads to a second insult (e.g., AKI). An alternative explanation is described as the sustained hit theory where there is an ongoing disease process. AKI secondary to pancreatitis may best fit with either the two hit or sustained hit theories, although there may be variation in individual patients. Other important considerations for organ dysfunction during inflammation, are that there is cross talk between inflammation and coagulation. Consequently, there is a prothrombotic tendency during inflammation that may lead to ischaemic end organ damage.

AKI is an important organ dysfunction, since its impact on mortality can be so profound, as well as contributing to the morbidity of an individual animal. Several mechanisms may be relevant to the development of pancreatitis associated AKI.^3,4 Third spacing of fluids, as well as gastrointestinal fluid losses, from patients with pancreatitis may lead to hypovolaemia. This, therefore, risks renal hypoperfusion and upregulation of the renin-angiotensin-aldosterone system that will impair glomerular filtration rate. There may also be renal tubular cell death via apoptosis or necrosis. In some instances, marked abdominal fluid accumulation may cause rapid rises in intra-abdominal pressure risking abdominal compartment syndrome. In these situations, intra-abdominal hypertension will also severely limit renal perfusion and risks AKI development. Cross talk with inflammation may also lead to intravascular coagulopathy (thrombotic microangiopathy) that will further contribute to the pathophysiology of AKI.

Diagnosing Pancreatitis and AKI

The symptoms of pancreatitis in dogs can vary in terms of severity. More severe cases may be accompanied by vomiting, inappetence, lethargy, fever, dehydration, abdominal discomfort, and diarrhoea. Symptoms in cats can be quite vague and typically less severe than symptoms in dogs. In severe cases, other symptoms related to organ dysfunction can be identified. In instances of AKI, this may include oligoanuria or polyuria depending on the phase of their disease. Other organ system dysfunctions may include respiratory dysfunction (e.g., tachypnoea, hypoxaemia), coagulation abnormalities (e.g., thrombocytopenia, prolonged coagulation times), and cardiovascular instability (e.g., hypotension, arrhythmia). Definitive diagnosis of pancreatitis would require histopathology (e.g., biopsy) but is rarely performed in clinical cases. More commonly a clinical diagnosis is made based on a compelling clinical picture based on symptoms, diagnostic imaging findings, and laboratory abnormalities. Although radiographic findings may be suggestive of pancreatitis, ultrasonographic changes are typically more helpful. Classic changes on ultrasound for acute pancreatitis are hypoechoic pancreas with regional surrounding hyperechoic mesentery. One consideration for ultrasonographic pancreatitis changes, however, is that the severity of clinical symptoms imperfectly relates to the ultrasound images. Several laboratory abnormalities may also be encountered in patients with pancreatitis. These may include increased amylase, lipase, liver enzymes, and potentially hyperbilirubinaemia. Canine and feline specific pancreatic lipase (cPLI and fPLI) are also commonly measured. Based upon the sensitivity and specificity of these tests, negative results are helpful for ruling out pancreatitis, although false positives may be encountered with other acute GI disorders.⁵ A combination of compatible clinical signs, compelling diagnostic imaging findings, and fitting laboratory abnormalities can usually allow a clinical diagnosis of pancreatitis to be made. In cats, consideration for whether concurrent inflammation in the GI tract and liver may be present (i.e., triaditis) is also an important consideration.

Traditionally, measurement of serum urea and creatinine have been used to identify kidney disease. Any level of azotemia is then ideally interpreted in light of urinalysis, particularly urine concentrating ability, as well as other clues towards chronicity (e.g., body condition score, muscle scoring, haematocrit). The limitation of creatinine is that it is a relatively late stage marker of kidney dysfunction. Consequently, small rises in creatinine in the hospitalized patient are considered relevant and are used to clue clinicians into the possibility of acute kidney injury. Commonly an increase in serum creatinine of 26 µmol/L (0.3 mg/dL) or more is used in AKI scoring schemes.⁶ There is growing interest in novel urinary and serum biomarkers that may clue us into the presence of AKI sooner than conventional renal biomarkers. Two additional clinical indicators when monitoring an animal for AKI are serial body weights and urine output.⁷ In the hospitalized pet, fluctuations in body weight can be very helpful gauges of water shifts (e.g., loss of water will reduce body weight). Weighing hospitalized animals at least once daily or even more frequently is both a cheap and helpful monitoring tool when there is concern for volume overload. This is especially helpful when used in combination with urine output. For example, an animal that is receiving intravenous fluids and gaining weight but not urinating reliably may be third spacing fluids. The most accurate means of quantifying urine output is by placement of an indwelling urinary catheter. While this is a common procedure in more severely compromised pets, there is a risk of infection associated with the procedure and a risk-benefit analysis should be considered before placing a catheter. When a urinary catheter is not placed, more subjective assessment of voided urine is a reasonable alternative. When an animal is weighed serially, it is good practice to weigh them after they have voided urine.

Clinical Management of Pancreatitis Associated AKI

Management of pancreatitis associated AKI involves both treatment of the primary insult (i.e., pancreatitis), as well as specific considerations for AKI. Treatment directed at the likely trigger for pancreatitis is uncommonly possible. Infection is rarely the primary cause of pancreatitis, although antibiotics may be considered if there is concern for GI translocation in dogs or concurrent cholangitis in cats. Other triggers for pancreatitis include dietary indiscretion and dyslipidaemias in certain breeds of dogs (e.g., Miniature Schnauzers). Most therapy for pancreatitis is largely supportive in nature. This includes anti-emetics, gastroprotectants, and assisted feeding (e.g., nasogastric tubes). Analgesia is an incredibly important aspect of pancreatitis management. Providing systemic analgesia, for example opioids, ketamine, and lidocaine, is commonly done. There are some disadvantages with this approach, however, since opioids can be associated with adverse systemic effects including nausea and ileus. Alternative approaches to analgesia, for example epidural analgesia may be good alternatives in some pets. Antithrombotic strategies (e.g., heparin) may be considered given the prothrombotic tendency associated with pancreatitis in dogs.

Fluid therapy for pancreatitis has particular relevance when considering the risk for pancreatitis associated AKI. Replacement fluids (e.g., lactated Ringer’s solution) are often used for treatment of hypovolaemia and dehydration. Ongoing fluids for maintenance while patients are not eating and drinking are also commonly provided. As mentioned earlier, very careful monitoring of fluids is needed in animals with pancreatitis since it may worsen third spacing. In animals with acute kidney injury, intolerance of fluid therapy risks worsening kidney infection. Consequently, a fairly restrictive fluid therapy plan is recommended for pancreatitis cases. In situations where patients remain hypotensive despite fluid therapy, the use of vasopressor agents (e.g., noradrenaline) can be very helpful additions. In the event of AKI development associated with oligoanuria, discontinuation of fluids and diuretic therapy (e.g., furosemide) is indicated to facilitate offloading excessive fluid. When extracorporeal techniques are available, haemodialysis would be reasonable to offer in animals with AKI. The benefits of dialysis include clearance of nitrogenous wastes/uraemic toxins, assistance with acid-base and electrolyte balance, as well as to expedite correction of volume overload by removing excessive water. Although fish oils may be beneficial in some cases of AKI, they are likely best avoided in cases of pancreatitis given the fear of exacerbating symptoms with an oral fat source. Although prognosis for animals with pancreatitis associated AKI is more guarded, it is certainly possible to manage these cases successfully with good attention to detail and careful tailoring of therapeutics for the individual patient.

References

1.  Mansfield C. Pathophysiology of acute pancreatitis: potential applications from experimental models and human medicine to dogs. J Vet Intern Med. 2012;26:875–887.

2.  Zhang XP, Wang L, et al. The pathogenic mechanism of severe acute pancreatitis complicated with renal injury: A review of current knowledge. Dig Dis Sci. 2008;53:297–306.

3.  Osterbur K, Mann FA, et al. Multiple organ dysfunction syndrome in humans and animals. J Vet Intern Med. 2014;28:1141–1151.

4.  Manokaran S, Edwin Fernando M, et al. A study of acute kidney injury in severe acute pancreatitis in a tertiary care hospital from South India. Journal of Dental and Medical Sciences. 2018;17(3):45–48.

5.  Haworth MD, Hosgood G, et al. Diagnostic accuracy of the SNAP and SPEC canine pancreatic lipase tests for pancreatitis in dogs presenting with clinical signs of acute abdominal disease. J Vet Emerg Crit Care. 2014;24(2):135–143.

6.  Cowgill LD, Langston C. Acute kidney insufficiency. In: Bartges J, Polzin DJ, eds. Nephrology and Urology of Small Animals. Ames, IA: Wiley & Sons; 2011.

7.  DeLoor J, Daminet S, et al. Urinary biomarkers for acute kidney injury in dogs. J Vet Intern Med. 2013;27(5):998–1010.