Pathophysiology and treatment of kidney disease in cats

Kidney failure is one of the most common diseases that affects feline patients. With advances in treatment options and the understanding of kidney disease, cats are living longer and more productive lives after being diagnosed with this condition. This article outlines the physiology of the kidneys, the pathophysiology of acute and chronic renal disease and treatment options available to feline patients.

Physiology

The kidneys filter approximately 20% of the body’s blood (Aspinall and O’Reilly, 2006). They are responsible for a myriad of tasks, including:

• Regulation of water and electrolyte balances
• Excretion of metabolic waste products and foreign chemicals
• Regulation of arterial pressure z Regulation of acid–base balance
• Regulation of calcium excretion z Metabolism of certain minerals
• Production of the active form of vitamin D
• Glucose synthesis
• Erythropoietin production. In a healthy pet, the kidneys account for almost all the erythropoietin that is secreted into circulation; erythropoietin stimulates the production of red blood cells (Aspinall and O’Reilly, 2006).

Each bean-shaped kidney contains millions of functional units called nephrons, which filter blood through the glomerular filtration (GF) process and produce urine. A nephron is a long tubule that consists of five main parts (Nelson and Couto, 1998):

• Glomerular capsule (also called Bowman’s capsule)
• Proximal convoluted tubule
• Loop of Henle
• Distal convoluted tubule
• Collecting duct.

As blood enters into the glomerular capsule, high pressures force fluid and small molecules out while larger particles (blood cells, plasma and protein molecules) are retained in the blood and continue through (Nelson and Couto, 1998). Within the glomerular capsule lies the glomerulus, a cluster of blood vessels through which blood passes for filtra-tion (Aspinall and O’Reilly, 2006); the glomerular filtration rate (GFR) is the rate the fluid is filtered through the kidneys.

Renin is a hormone produced in the glomerular capsule that controls the activation of the hormone angiotensin. Angiotensin is a hormone that causes vasoconstriction and helps to regulate blood pressure; angiotensin also stimulates the release of aldosterone from the adrenal cortex. Aldosterone helps to conserve sodium, secretes potassium, increases water retention and increases blood pressure (Newman et al, 2007).

The reabsorption of water, sodium, chloride and glucose takes place within the proximal convoluted tubule; in healthy animals, glucose is not passed into the urine. Within the proximal convoluted tubule the concentration of nitrogenous waste occurs, and urea is the main waste product. Certain drugs and toxins are secreted into the filtrate and carried into the bladder via urine (Nelson and Couto, 1998).

The loop of Henle helps to regulate the concentration and volume of the urine by removing excessive amounts of water. It maintains a balance with the body’s extracellular fluid, so if an animal is dehydrated then less water will be reabsorbed, and if it is over-hydrated then more water will be reabsorbed (Nelson and Couto, 1998).

The distal convoluted tubule is responsible for making some of the final adjustments to the fluid by reabsorbing even more sodium, secreting potassium and regulating the acid–base balance (Nelson and Couto, 1998).

The collecting duct is responsible for collecting the fluid and making the final adjustments so that it maintains a complete balance with the extracellular fluid; this is where the concentrated urine is collected (Nelson and Couto, 1998).

When a kidney becomes injured, it is important to remember that only one part of the nephron may fail while the remaining four parts may function normally.

Renal disease

Renal disease can be acute or chronic; both forms are hallmarked by an elevated blood urea nitrogen (BUN) and serum creatinine, known as azo-taemia (DiBartola, 2010). The BUN test measures the amount of nitrogen in the patient’s blood that comes from the waste product urea. Urea is made in the liver, passes through the kidneys and is excreted in urine. When kidneys start to fail they are unable to remove the urea normally, thus causing an elevation in BUN. Creatinine is a breakdown product of creatine phosphate in muscle and is constantly produced in the body and filtered out through the kidneys; there is little or no tubular reabsorption of creatinine. If the kidneys are unable to filter normally, creatinine levels start to rise (Newman et al, 2007).

Uraemia is a term used to describe most of the clinical signs and biochemical findings that occur with renal failure. The most common uraemic complications are the appearance of gastrointestinal symptoms, such as nausea, vomiting and diarrhoea (Stokes and Bartes, 2006). Gastrointestinal signs can escalate to include haemorrhage of the gastrointestinal tract and ulcers in the stomach caused by an increase in gastric acid (40% of gas-trin is metabolized within the kidneys) (Stokes and Bartes, 2006); additionally, ulcers in the mouth may occur, and patients may be termed as having ‘uraemic breath’. Other signs of uraemia include polyuria, polydipsia (caused by an impaired ability to concentrate urine) (Figure 1), hypertension and anaemia. The pet may also experience isosthenuria, where urine is excreted that has not been concentrated by the kidneys and has the same osmolality as that of plasma (a specific gravity of 1.008–1.012) (Goljan, 2006).

Acute kidney injury

Many diseases and injuries that cause acute kidney injury (AKI) are potentially reversible pending diagnosis and early initiation of treatment (Nelson and Couto, 1998). AKI results from a dramatic decrease in GFR as a result of pre-renal, intrinsic renal or post-renal causes (Cowgill and Elliott, 2010).

Pre-renal azotaemia is not caused by primary kidney disease, but rather by a decrease in cardiac output resulting in inadequate blood supply to the kidneys (Goljan, 2006).

Intrinsic damage to the kidneys occurs from damage to the renal parenchyma (Cowgill and Elliott, 2010). In cats, damage commonly results from toxins, infectious diseases and ischaemic causes (Stokes and Bartes, 2006).

Some of the most common nephrotoxic substances that affect cats include ethylene glycol, gentamicin (and other antimicrobials) and lilies. While not as common as in dogs, ethylene glycol toxicity in cats is prevalent because ethylene glycol is used in numerous products (Cowgill and Elliott, 2010). In cats, the lethal dose of 95% ethylene glycol is 1.4–4 ml/kg (Stokes and Bartes, 2006); ethylene glycol causes a toxic effect by forming oxalate, which binds to plasma calcium and forms calcium oxalate crystals in the renal tubules (Stokes and Bartes, 2006).

Lilies of the Liliaceae family are a common toxic-ity in cats; although the principal toxic factor is unknown, all parts of the plant are poisonous to cats, including the pollen (Tefend, 2007). After initial ingestion of the plant, cats may exhibit gastrointestinal signs such as nausea and vomiting (Stokes and Bartes, 2006). Signs develop within 12 hours, but the plant may still have effects on the body for 2–5 days after ingestion (Tefend, 2007). Although the exact amount needed to produce a toxic effect is unknown, even a single bite of the plant can cause symptoms; therefore, any cat suffering from exposure to a lily plant should be treated as if it were suffering nephrotoxic effects (Tefend, 2007).

Aminoglycosides such as gentamicin are eliminated through the kidneys. Although the nephrotoxic effects of gentamicin are not completely understood, gentamicin may be more nephrotoxic than other aminoglycosides (Stokes and Bartes, 2006); cats appear more sensitive to these drugs than dogs.

One of the most common diseases that causes AKI in cats is pyelonephritis, which usually occurs secondary to a lower urinary tract infection; the bacterium Escherichia coli is a common cause of urinary tract infection (Tefend, 2007). Treatment should be with antibiotics specific to the organism isolated, as well as treating the symptoms of AKI.

Post-renal causes of AKI occur from obstruction or rupture of the urinary tract system; urethral obstruction (Figure 2) is most commonly seen in young to middle-aged male cats (Kerl, 2008). Cats that have had feline lower urinary tract disease (FLUTD) have an increased risk of becoming obstructed because of the inflammation they experience during the obstruction. When a cat becomes obstructed, the pressure within the urethra and urinary bladder is transmitted up the ureters to the kidneys’ nephrons; eventually, this starts to alter the GF pressure until the GFR is zero (Cooper, 2008). Uroliths, mucous plugs, masses or blood clots are common causes of the obstruction (Cowgill and Elliott, 2010); early detection and treatment is imperative in order to correct the post-renal azotaemia. Approximately 25% of cats that obstruct have a complete resolution in 2–5 days; 40% retain mild azotaemia, but are successfully managed with medical treatment (Stokes and Bartes, 2006).

Chronic renal disease

One of the most difficult challenges with chronic renal disease (CRD) is its relatively slow progression, which enables the cat to compensate so that few or no symptoms are noticed by the owner (Figure 3). CRD can be classified as either congenital, familial or acquired.

Congenital causes are often suspected based on the age of the cat, breed and family history (Polzin et al, 2010). Polycystic kidney disease (PKD) is more common in Persian cats and is inherited as an au-tosomal dominant trait (Polzin et al, 2010). PKD is characterized by the presence of multiple, fluid-flled cysts, which can result in the enlargement of the kidneys. The cysts generally develop at an early age (as early as 7 weeks), but signs of renal failure may not occur until the cat is between 7–8 years (Chew and DiBartola, 2007; Polzin et al, 2010). It is important to note that not all cats with PKD will develop kidney failure; for breeders of at-risk breeds, genetic testing is available for cats older than 8 weeks (Polzin et al, 2010).

Familial diseases include amyloidosis, which is found in Abyssinian, Oriental Shorthair and Siamese species of cats (Chew and DiBartola, 2007). Amyloidosis occurs when protein is lost through an increased permeability of the glomerular membrane, caused by the abnormal deposit of amyloid protein within the glomerular capsule; this can result in kidney failure within a year of diagnosis (Guyton and Hall, 1996). The changes in the capsule cause a loss of protein from blood into the urine. However, in some cases the effects on the kidneys is mild, and cats may live without the disease ever being detected (Polzin et al, 2010).

Acquired CRD can result from any disease process that injures the kidneys to a point where the neph-rons can no longer function properly (Polzin et al, 2010). Some common diseases that lead to CRD include (Brown, 1998):

• Feline infectious peritonitis
• Neoplasia (renal lymphosarcoma)
• Hyperthyroidism
• Chronic tubulointerstitial nephritis.

Feline infectious peritonitis affects the kidneys, liver, mesenteric lymph nodes, central nervous system and eyes; signs include fever, lethargy, anorexia and weight loss (DiBartola, 2004a,b). Fluid build-up can occur in both the chest and abdomen.

Thyroid hormones help support the GFR by increasing renal blood flow; thus hyperthyroidism may cause renal failure if left untreated (Basu and Mohapatra, 2012). Hyperthyroidism generally results in systemic hypertension; this can be transmitted to glomeruli, causing glomerular hypertension and glomerular hyperfiltration (Basu and Mohapatra, 2012). Unfortunately, treating thyroid disease causes the hypertension to dramatically decrease, resulting in a decrease in renal blood flow and GFR (Chew and DiBartola, 2007). Studies have reported that 14% of cats with hyperthyroidism have preexisting renal disease, while approximately 30% become azotaemic after therapy for hyperthyroidism (Daminet, 2006).

Lymphosarcoma is the most common renal neoplasm of the cat, which usually affects both kidneys. Approximately 50% of cats with renal lymphosar-coma are positive for feline leukaemia. Treatment is aimed at dealing with the kidney disease and using conventional chemotherapy; unfortunately, prognosis is poor (DiBartola, 2004a,b).

Chronic tubulointerstitial nephritis continues to be one of the most common findings in cats (Polzin et al, 2010). It occurs gradually over years, and results in renal tubule atrophy, dysfunction and interstitial fibrosis, causing decreased renal function. There are many contributing factors to chronic tubulointersti-tial nephritis, so it is generally difficult to determine the exact cause.

Treatment of kidney disease

In general all kidney disease is treated the same, with the exception of a few additional therapies depending on the disease. There are five main goals when managing renal failure (Boothe, 2001):

• Make a diagnosis
• Treat or minimize underlying disease
• Fluid therapy — diuresis
• Correct electrolyte and acid–base abnormalities
• Manage systemic complications.

Fluid therapy — diuresis

The gold standard of treatment is diuresis. It is important to account for any water deficits in the body (dehydration), as well as any ongoing losses such as vomiting and diarrhoea. Initial hydrating solutions are generally isotonic crystalloids; if a patient has cardiac disease or hypernatremia, low-sodium flu-ids should be used, such as 0.45% sodium chloride (Boothe, 2001). Once a patient is rehydrated, technicians should ensure that the amount of fluid that is being delivered equals the amount of urine that is being excreted. The most accurate way of monitoring urine production is by placing an indwelling urinary catheter; however, in cases where this is not possible, using a non-absorbent litter or catching the urine in a bowl should enable the quantification of urine produced.

In the case of oliguria, additional fluids or treatment may be required. Most commonly, the loop diuretic furosemide is chosen because it helps to increase tubular and renal flow without significantly affecting GF; there is also some evidence that furosemide may protect the cells within the loop of Henle (Boothe, 2001). It is important when using furosemide to account for volume and potassium requirements so that the patient does not become dehydrated.

Correct electrolyte and acid–base abnormalities

Hyperkalaemia is commonly seen in patients with urethral obstruction (Nelson and Couto, 1998). In severely hyperkalaemic patients, bradycardia, peaked T-waves, loss of P-waves and life-threatening cardiac arrhythmias can be seen (Boothe, 2001); in such severe cases, several treatments can be initiated to help deal with the hyperkalaemia. The administration of calcium gluconate may be necessary to help prevent further cardiac toxicity. Calcium only helps to counteract the effects of potassium without lowering serum potassium; bicarbonate will help to lower potassium by facilitating a shift in potassium ions (Boothe, 2001). Both bicarbonate and calcium gluconate must be given slowly, with patients monitored by electrocardiography throughout administration. Another treatment for hyperkalaemia is the administration of insulin, which helps to draw potassium back into the cells. Glucose must be immediately given after the insulin to ensure hypoglycaemia does not occur.

Patients with CRD are more likely to suffer hypoka-laemic effects because the potassium is closely regulated by the kidneys. When serum potassium levels are <2.5 mEq/L, neuromuscular signs can occur, such as a reluctance to move, a stiff gait, ventroflexion of the neck and tremors (Shell, 2008). Intravenous administration of potassium (given as a constant rate infusion) can be used to correct initial hypokalaemia.

Hyperphosphataemia is commonly observed in patients with CRD because the kidneys play an important role in excreting phosphorus (Polzin et al, 2010). Typically, hyperphosphataemia does not produce clinical signs, but it can lead to the progression of secondary hyperparathyroidism, which can lead to death (Polzin et al, 2010). Hyperparathyroidism is an overproduction of the parathyroid hormone, which helps to regulate the levels of calcium and phosphorus in the body; it can lead to muscle weakness and central nervous system disturbances. Typically, calcitriol is used to treat secondary hyperthyroidism because it inhibits growth of the parathyroid glands (Schenck and Chew, 2006).

Another common finding in patients with CRD is hypocalcaemia; intravenous calcium gluconate may initially be administered to help correct any serious hypocalcaemia, and then oral calcium supplements may be used after.

Manage systemic complications

Nutrition

Several studies has shown that feeding patients a ‘renal-friendly’ diet results in longer survival times (16 months compared with 7 months of non-renal diet food; Chew and DiBartola, 2007). Typically, most renal diets restrict phosphate, sodium and protein intake while allowing for adequate potassium, nutrients and calories (Boothe, 2001). It is important that calorie intake is closely monitored, as many patients with CRD are malnourished. As many patients with CRD are nauseous, anti-emetic and appetite-stimulant drugs are generally indicated.

Hypertension

Over 60% of cats develop systemic hypertension from renal disease; this could result from a decrease in GF, inappropriate filtering of sodium and water or impaired production of renal vasodilatory substances (Boothe, 2001). Signs may include blindness, retinal haemorrhage and detachment, glaucoma, cardiac failure or neurologic sequelae (Boothe, 2001). Hypertension is treated with sodium restriction alongside medication; most commonly, a calcium-channel blocker (such as amlodipine) is chosen (Boothe, 2001).

Anaemia

There are a myriad of reasons why patients with CRD suffer anaemia (Figure 4), including gastrointestinal haemorrhage, erythropoietin deficiency (the renal tubules are the major source of erythropoietin synthesis), iron deficiency and shortened red blood cell life (Polzin et al, 2010). When drawing blood from patients with anaemia it is imperative that only the amount needed is drawn, and that pressure bandages are used to avoid haemorrhage after venipuncture.

Red blood cell transfusions are rarely recommended because of the decreased life span of red blood cells. As the patient’s kidney values decrease, the anaemia starts to resolve. Red blood cell transfusion is only recommended for patients undergoing surgery (Polzin et al, 2010).

Recombinant human erythropoietin (r-HuEPO) is commercially available and is used to treat patients with CRD and anaemia. Depending on the dose of r-HuEPO given, it can take 2–8 weeks for the haema-tocrit to rise to low–normal (Polzin et al, 2010). It is a human protein product attached to human albumin, and approximately 30% of dogs and cats develop anti-erythropoietin antibodies (Adams, 2008); as a result of the serious side effects that can occur, many veterinarians do not treat with r-HuEPO until the patient’s haematocrit has fallen below 15–18% (Basu and Mohapatra, 2012). It is important to supplement with iron, since iron deficiency is a relatively common side effect of r-HuEPO administration (Adams, 2008).

Renal transplant/intermittent haemodialysis

The first successful long-term feline kidney transplant took place in 1984 (Polzin et al, 2010); the procedure has good survival rates, with more than 90% of cats surviving past 1 year and most surviving to 3 years (mean survival rate is 613 days) after transplantation (Rosenthal, 2008). Unfortunately, this is not the case in dogs; some large universities report a 40% success rate in dogs, while other universities have discontinued this procedure because of the poor prognosis.

Clients who wish to pursue this treatment option must be prepared for the expensive cost and adopt the pet who donates the kidney (Rosenthal, 2008). The actual renal transplant is long, roughly 4 hours, and complications include bleeding, hypertension, embolism, infection and, ultimately, rejection of the new kidney (Rosenthal, 2008). Complete blood counts, blood chemistries and electrocardiograms should be routinely checked post operatively to look for any signs of complications. A steroid, cyclosporine (for immunosuppressive therapy) and antibiotics are usually started post operatively; vaccinations, especially live or modified live, are not recommended for the rest of the pet’s life (Rosenthal, 2008).

Intermittent haemodialysis has been a successful treatment in managing renal failure in both dogs and cats. Its purpose is to correct the effects associated with uraemia by passing the blood across an ‘artifcial kidney’ membrane outside the patient’s body to enable filtration (Stafford, 2003). As a result of its expensive price tag, complications and limited facilities that offer the treatment, it is commonly reserved for pets suffer-ing from AKI. Intermittent haemodialysis is generally indicated in patients where the BUN is >90 mg/dl and creatinine >8 mg/dl (Polzin et al, 2010). Most common complications include neurologic sequelae (caused by disequilibrium from shifting osmotic gradients), gastrointestinal sequelae (vomiting and nausea) and hypertension during the treatment (Stafford, 2003).

Continuous renal replacement therapy

As the name implies, continuous renal replacement therapy (CRRT) relies on continuous, gradual blood purification; the patient’s blood is filtered until the kidney function returns to normal. CRRT is almost always used for AKI, but can be used when a toxin has been ingested as well for diuresis (Acierno, 2010). The patient’s blood is passed through filtration circuit tubing in a machine to a semipermeable membrane, where waste products and water are removed; replacement fluid is added to the blood, which is returned to the patient (Acierno, 2010).

From human nursing literature, the benefits of CRRT are (Schardin, 2006):

• Its ease of use when treating patients with AKI
• It enables higher doses of therapy to be delivered, consistent with current clinical literature
• It enables 24-hour therapy
• It results in better haemodynamic stability
• It enables volume reduction, allowing for fluids and nutrition
• It facilitates cytokine removal.

Although complications are less than that for intermittent haemodialysis, the technician staff must constantly monitor these patients (Schardin, 2006). Coagulation disorders can occur, so clotting times need to be constantly monitored (Acierno, 2010). Hypotension can be a problem and is likely to occur because of the large amount of blood needed for the CRRT unit (50–84 mL), as well as the reduction in blood volume (Acierno, 2010). Patients weighing as little as 2.4 kg have been successfully treated with CRRT, which indicates that there may be no size restriction (Acierno, 2010). Certainly more research must be done in veterinary medicine, but the limited research available has shown CRRT to be effec-tive and safer than intermittent haemodialysis.

Conclusion

It is important that cats with kidney failure receive a complete diagnostic work-up in order to determine the underlying cause, especially as there are many contributory factors to this condition. Kidney failure is not a death sentence for cats; with advances in treatments, both dogs and cats can live long and productive lives with both AKI and CRD.

Key Points

• Although kidney failure is one of the most common diseases that affects feline patients, increased understanding of the disease and advances in treatments mean that cats are living longer after diagnosis.
• Renal disease can be acute or chronic, hallmarked by an elevated blood urea nitrogen and serum creatinine (azotaemia).
• It is important that cats with renal failure receive a complete diagnostic work-up to determine the underlying cause as there are many contributory factors to this condition.
• Treatment includes fluid therapy (diuresis), correcting electrolyte and acid-base abnormalities, managing systemic complications, renal transplantation, intermittent haemodialysis and continuous renal replacement therapy.