Kidney Diseases in Cats
Article : Halil İbrahim GÖKCE & Habibe ÖZDEMİR
(Prof. Dr.), Burdur Mehmet Akif Ersoy University, Faculty of Veterinary Medicine, Department of Internal Medicine, Burdur, Turkey E-mail: higokce@mehmetakif.edu.tr
ORCID: 0000-0002-4458-6671
(Vet. Dr.), Burdur Mehmet Akif Ersoy University, Institute of Health Sciences, Department of Veterinary Internal Medicine, Burdur, Turkey -E-mail: habibeozdemir2612@gmail.com
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| Kidney Diseases in Cats |
Kidney diseases are of great importance in veterinary medicine due to the difficulty and prolonged nature of their treatment. Particularly in older cats, progressive loss of kidney function leading to chronic kidney failure is predominant, with such kidney diseases observed in nearly 50% of cats over ten years of age. Kidney diseases are often subclinical, referring to any deviation in normal kidney structure and function. Kidney failure is divided into two forms: acute and chronic. Acute kidney failure often results from ischemic or toxic causes, affecting the tubular portion of the kidney and characterized by the sudden onset of oliguria or anuria and azotemia. Chronic kidney failure, on the other hand, results from many chronic kidney diseases or disorders, can affect any part of the kidney, and is characterized by prolonged signs related to uremia. Chronic failure is always irreversible, whereas acute kidney failure is treatable and exhibits reversible characteristics. Therefore, early diagnosis and treatment are crucial in kidney diseases.
Acute Kidney Injury (AKI)
Acute kidney injury occurs in four stages. The first stage begins when pathological damage starts in the kidneys and occurs during and after the injury to the kidneys. The second stage is the extension phase, where ongoing ischemia, hypoxia, inflammation, and cellular damage lead to cellular apoptosis, necrosis, or both. Clinical and laboratory findings may not be prominent in the first two stages. The third stage is characterized by azotemia, uremia, or both, and can last for days or weeks. Although urine production is quite variable, oliguria or anuria may develop in this stage. The fourth stage is recovery, during which azotemia resolves and renal tubules repair. Marked polyuria may occur in this stage due to partial restoration of renal tubular function and the osmotic diuresis of accumulated solutes. Kidney function may return to normal, or the animal may be left with residual kidney dysfunction. Non-azotemic kidney failure characterized by abnormalities similar to those seen in the polyuric recovery phase of acute kidney injury may emerge. The prognosis largely depends on the cause of the disease, and determining the cause as early as possible is important in the management of acute kidney failure.
Etiology
While the exact cause of acute kidney injury cannot be determined in approximately one-third of feline patients, identifying the etiology is important due to its potential impact on treatment and prognosis. Among the various etiological factors known to result in acute kidney failure, toxins are the triggering cause in over 50% of patients. The most commonly encountered toxins include lilies, non-steroidal anti-inflammatory drugs (NSAIDs), ethylene glycol (EG), aminoglycosides, doxorubicin, Vitamin D, and food contaminants like cyanuric acid. Other possible etiologies for acute kidney injury include ischemic injuries, upper urinary tract infections (pyelonephritis), neoplasia, prolonged urethral obstruction, and sepsis.
Toxic Nephropathy
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their therapeutic effects by inhibiting cyclooxygenase enzymes COX-1 and/or COX-2 to halt prostaglandin production. COX-1 is constitutively expressed and involved in producing prostaglandins necessary for normal physiological functions in various organs, including the kidneys. COX-2 expression can be induced by bacterial endotoxins, cytokines, and growth factors. Administration of NSAIDs that inhibit COX-2 can cause kidney damage, especially in dehydrated patients. Kidney damage associated with NSAID use stems from the disruption of this prostaglandin pathway when renal blood flow is reduced, leading to decreased renal perfusion and subsequent ischemic nephrosis. All NSAIDs carry this risk for kidney function, regardless of their reported COX-selectivity.
Ethylene Glycol
Ethylene glycol is a highly nephrotoxic substance found in antifreeze and other industrial solvents. Cats are more susceptible to the toxic effects of ethylene glycol than dogs, and severe, life-threatening kidney damage can be seen in those consuming as little as 1.4 ml/kg. Ethylene glycol is metabolized and broken down in the liver by alcohol dehydrogenase. It is reduced to various toxic metabolites, including glycoaldehyde, glycolate, glyoxylate, and oxalate. Toxicity develops due to the direct effects of these metabolites on the tubular epithelium, as well as the accumulation of calcium oxalate crystals in the renal tubular lumen and interstitium. The main compound is rapidly absorbed in the stomach, and blood concentration peaks within 1 hour of ingestion in cats. It is almost completely metabolized and eliminated within approximately 24 hours. Laboratory findings include increased serum osmolality, increased anion gap, metabolic acidosis; calcium oxalate monohydrate crystalluria; osmotic diuresis, isosthenuria; hypocalcemia, and hyperglycemia. If left untreated, azotemia, hyperphosphatemia, hyperkalemia, and oliguria/anuria develop.
Aminoglycosides
Many drugs have the potential to cause nephrotoxicity, but aminoglycosides are the most well-known. These drugs cause acute kidney failure through direct damage to proximal tubular cells, followed by tubular necrosis. Risk factors for nephrotoxicity include the type of aminoglycoside, high serum levels, cumulative dose, duration and frequency of administration, concurrent use of furosemide or other nephrotoxic drugs, hypoalbuminemia, hypovolemia, and pre-existing kidney disease. To reduce the risk of toxicity, the use of these drugs should be avoided in patients with pre-existing kidney disease, and adequate hydration and volume resuscitation should be ensured before administration. They should be given once daily with fluids and preferably not for more than 5-7 days. Fresh urine sediment should be monitored before and during administration so that the drug can be discontinued if casts are noted.
Ischemic Nephropathy
Another common cause of kidney damage in cats with acute kidney failure is ischemia. Such damage can result from hypotensive events (e.g., general anesthesia), hypovolemia (e.g., shock, bleeding, severe dehydration/volume loss), and thromboembolic diseases. The kidneys normally receive about 20-25% of cardiac output and are therefore highly susceptible to ischemic damage. Autoregulation allows renal perfusion to be maintained even when mean arterial pressure drops to 80 mmHg. This maintenance of perfusion occurs primarily through a prostaglandin-mediated decrease in afferent glomerular arteriolar resistance to sustain glomerular filtration. Angiotensin II also causes constriction of the efferent arteriole, helping to preserve glomerular filtration. If systemic blood pressure continues to drop, endogenous vasoconstrictors will eventually cause an increase in afferent arteriolar resistance, followed by a decrease in GFR and post-glomerular blood flow perfusing the tubules. Ultimately, tubular damage leads to cell sloughing and tubular obstruction, impaired sodium reabsorption, back-leak of luminal contents, cell edema, and cast formation.
Obstructive Nephropathy
Urinary tract obstruction, involving blockage of the urethra, ureters, or renal pelvises, can lead to acute kidney failure. Possible causes of obstruction include stones (most commonly calcium oxalate), dried solidified blood calculi, blood clots, mucus plugs, strictures, or neoplastic masses that block or compress the urinary tract lumen. When urine flow is obstructed, a rapid decrease in glomerular filtration and the development of inflammation and edema occur. If this persists, tubular atrophy, fibrosis, and apoptosis eventually develop. If the obstruction affects only one kidney and the other is functioning normally, the contralateral kidney undergoes hypertrophy to compensate, and this process may go unnoticed.
Neoplastic Nephropathy
Lymphoma and adenocarcinoma are the most common kidney tumors in cats. Other tumors include transitional cell carcinoma, nephroblastoma, hemangiosarcoma, and adenoma.
Infectious Nephropathy
Pyelonephritis is common in acute and chronic kidney diseases in cats. Urine culture should be performed for all patients presenting with acute kidney injury, and antibiotics should be initiated pending results. However, given the possibility of occult infection, a positive response to treatment may be an indication to continue treatment for 6-8 weeks in cases with negative urine culture. While pyelonephritis develops secondary to lower urinary tract infections, hematogenous spread of bacteria can also cause renal colonization. The most frequently isolated bacterial pathogens in feline pyelonephritis cases include Escherichia coli and Enterococcus species. Some viruses, particularly herpesviruses and cytomegalovirus, can also cause infections in the kidneys. Although rare, fungal infections can also cause nephropathy. Recurrent or chronic infections can damage kidney tissue over time and result in infectious nephropathy. Cats with compromised immune systems are more susceptible to infections.
Septic Nephropathy
Sepsis has been identified as a triggering factor in 32% of patients with acute kidney failure. Potential mechanisms contributing to injury in sepsis include intrarenal hemodynamic changes such as decreased glomerular capillary pressure, endothelial dysfunction, coagulopathy, and obstruction of renal tubules.
Clinical Findings
In the early stages of acute kidney failure, clinical signs are minimal and non-specific, while in advanced stages, they are systemic and life-threatening. Azotemia, fluid-electrolyte and acid-base imbalances, metabolic and endocrine disorders, and nutritional deficiencies trigger the manifestation of advanced acute kidney injury. In animals with predisposing or comorbid medical conditions or multiple organ dysfunction, it can be difficult to distinguish whether clinical problems are specifically related to kidney dysfunction or other concurrent conditions. Almost all clinical consequences of acute kidney failure (vomiting, hyperkalemia, metabolic acidosis, bleeding) progress further as the disease stage worsens.
Changes in body fluids are common and significant for all stages of acute kidney injury. Both hydration status and volemia should be assessed. Most causes of acute injury lead to decreased fluid intake or excessive fluid loss through diarrhea, polyuria, or vomiting, causing dehydration, hypovolemia, and potentially hypotension in the first place. Dehydration and hypovolemia exacerbate azotemia by adding hemodynamic contributions to the underlying uremia and making the kidneys prone to additional ischemic damage and decreased urine output. Hypervolemia carries the risk of pulmonary and peripheral edema, pleural effusion, systemic hypertension, and congestive heart failure. Oliguria and anuria are life-threatening features of AKI. Bladder size and urethral patency should be assessed to determine if oliguria or anuria is due to post-renal causes. Approximately 30-60% of animals with parenchymal acute kidney failure initially have oliguria or anuria. If oliguria or anuria is not corrected, overhydration, hyperkalemia, and metabolic acidosis quickly become life-threatening.
Cardiovascular disorders develop as a result of the underlying cause of AKI, uremia itself, or as a consequence of certain treatments. Cardiac arrest is a complication of severe hyperkalemia or the collective metabolic, acid-base, and electrolyte disturbances of acute uremia. Some normokalemic animals develop bradycardia (heart rate <80/min), thought to be due to increased vagal tone associated with uremic gastroenteritis. An acute vomiting episode will lead to further vagal stimulation, worsening bradycardia, and cardiac arrest.
Respiratory findings developing in cats with AKI include pleural effusion, pulmonary edema, aspiration pneumonia, uremic pneumonia, pulmonary artery thromboembolism, and pulmonary hemorrhage.
The brain is one of several distant organs that becomes dysfunctional or damaged due to acute kidney injury. Encephalopathy seen in animals with acute uremia may be due to uremia, hypertension, fluid or electrolyte disorders, drug toxicity, or induced inflammatory responses. Clinical signs of uremic encephalopathy include depression, lethargy, behavior change, confusion, stupor, coma, fatigue, sleep disorders, anorexia, nausea, myoclonus, tremors, cramps, and seizures.
Gastrointestinal disorders seen in AKI include anorexia, nausea, vomiting, odor in breath, stomatitis, oral ulcerations, necrosis on the tip and lateral edges of the tongue, gastritis, gastrointestinal ulcers, gastrointestinal bleeding, enterocolitis, and diarrhea. Gastritis and gastric ulceration exacerbate the anorexia and vomiting associated with acute uremia. Excessive secretion of gastric acid and direct damage to the gastric mucosa, submucosa, and vasculature by uremic toxins cause the severity of gastritis. Anorexia and vomiting, along with concomitant catabolic diseases, uremic toxins, oxidative stress, inflammation, and endocrine abnormalities such as insulin resistance and hyperparathyroidism, cumulatively contribute to nutritional deficiencies. Metabolic acidosis is a significant stimulus for the breakdown of muscle protein in acute uremia and increases ongoing catabolism.
Diagnosis
Although acute kidney failure is defined as a rapid loss of nephron function, precise criteria describing the reduction in kidney function and the duration of loss have not been defined in animals. Unfortunately, since pre-acute kidney failure information on serum creatinine concentration and urine output is often not available in cats, classification as in humans is not possible. Examination of an animal with acute kidney failure should include a clinical estimate of dehydration, assessment of cardiovascular status, evaluation of kidney or abdominal pain, and measurement of arterial blood pressure.
Initial laboratory evaluation should include a complete blood count, serum biochemistry profile, assessment of acid-base status, urinalysis, and urine culture. Leukocytosis may indicate an infectious cause of acute kidney failure. Blood urea nitrogen (BUN) and creatinine may be elevated, but if azotemia is absent, acute kidney failure should not be ruled out. Sodium concentration can be low, normal, or high depending on the disease process, the degree of vomiting and/or diarrhea, and previous treatment. Hyperkalemia occurs primarily in animals in the oliguric or anuric phase of acute kidney failure. Other causes of azotemia and hyperkalemia, such as hypoadrenocorticism (Addison's disease) and postrenal azotemia, must be distinguished from acute kidney failure. Serum calcium levels are usually normal unless there is acute kidney failure due to hypercalcemia; hypocalcemia can occur in animals with ethylene glycol toxicity. Serum phosphorus levels are frequently elevated; however, the degree of elevation depends more on the degree of reduction in GFR than on the duration of the disease. Metabolic acidosis is a significant and frequently encountered finding in AKI cases.
Urinalysis in acute kidney failure shows isosthenuria, while an increased urine specific gravity may suggest a prerenal cause of azotemia. Measurement of urine electrolytes and creatinine can help differentiate prerenal azotemia from primary renal azotemia. Animals with prerenal azotemia but normal kidney function conserve sodium and chloride while excreting creatinine; in patients, urine sodium and chloride levels are increased while creatinine is conserved. With acute tubular damage, mild to moderate glucosuria may appear, and with glomerular or tubular damage, microscopic hematuria may occur. Urine pH is usually acidic but can be alkaline in the presence of some bacterial urinary tract infections. Urine sediment should be carefully examined for the presence of casts, leukocytes, bacteria, and crystals. Serum levels of intact ethylene glycol or its metabolites can be measured by medical laboratories in cases of ethylene glycol toxicosis. In the absence of blood levels, metabolic acidosis with a high anion gap, hypocalcemia, and calcium oxalate crystals in the urine support the diagnosis of ethylene glycol toxicity. In cases suspected of rodenticide or vitamin D toxicosis, serum cholecalciferol levels should be measured in animals with hypercalcemia.
Diagnostic imaging is indicated for the assessment of kidney size and shape and the presence of uroliths. Abdominal radiographs allow assessment of kidney size (normal length measured in ventrodorsal view in cats is 2-3 times the length of the second lumbar vertebra). Identification of radiopaque uroliths and assessment of the amount of urine in the bladder are important. In addition to radiography, ultrasonography can be performed; this allows more precise measurement of kidney size, determination of renal parenchymal echogenicity, and identification of cysts or masses in the kidneys. Intravenous urography is generally not useful in determining the causes of acute kidney failure in cats, except for urethral obstruction caused by uroliths. Computed tomography and magnetic resonance imaging generally do not provide more information than ultrasonography and have the disadvantage of requiring general anesthesia.
Histopathological examination of kidney tissue provides the most accurate information about the chronicity of the disease process but may not identify a specific cause. Also, the benefits of biopsy must be weighed against the risks. Ultrasound-guided biopsy performed under injectable anesthesia may be the safest method for the animal, but biopsies obtained via laparoscopy or laparotomy are also among the options. Kidney aspiration is useful only when lymphosarcoma is suspected, but false-negative results can occur even in the presence of malignancy.
Treatment
Treatment of acute kidney failure consists of supportive care, applied according to the stage of acute kidney failure, developing complications, and the animal's fluid, electrolyte, and acid-base status, in addition to cause-specific therapy.
Specific Treatment: If the cause is known or suspected, specific treatment should be applied to correct or eliminate the cause of kidney damage. In animals with known recent toxin ingestion, such as ethylene glycol or lilies in cats, vomiting should be induced. Those that have ingested ethylene glycol should receive 4-methylpyrazole or ethanol to prevent its conversion to toxic components. The renal excretion of intact ethylene glycol can be increased by intravenous fluid diuresis. Intact ethylene glycol and its metabolite, glycolic acid, can be removed by hemodialysis.
Fluid Therapy: Correcting and maintaining the animal's dehydration, acid-base, and electrolyte imbalances form the basis of acute kidney failure treatment. Intravenous fluid therapy is almost always necessary. Dehydration, including clinical assessment of mucous membrane capillary refill time, heart and respiratory rate, arterial blood pressure, plasma fluids, and serum biochemistry parameters (BUN, creatinine, sodium, potassium, chloride, and phosphorus), should be monitored frequently to make appropriate adjustments in treatment.
Generally, IV fluids are administered at as high a rate as the animal can tolerate to maximize GFR and residual kidney function (RBF) and ensure the elimination of metabolic waste products. However, increased fluid administration does not necessarily mean increased urinary excretion of such substances. Especially since dialysis is not readily available in practice, avoiding fluid overload appears similarly beneficial. The primary cause of fluid overload is the failure to adjust the fluid administration rate in the face of decreased urine production. The initial volume of fluid to be administered should be calculated based on the animal's body weight and degree of dehydration. To return RBF to normal as soon as possible, fluid deficits should be replaced within 4 to 6 hours. In addition to maintenance fluid requirements (44-66 ml/kg/day), estimated fluid losses from causes such as vomiting and diarrhea must also be met. Initially, Lactated Ringer's solution or an isotonic, polyionic fluid can be administered. If hyperkalemia is present and oliguria or anuria is suspected, a potassium-free fluid such as 0.9% sodium chloride may be indicated. After rehydration, the type of fluid should be adjusted according to the animal's fluid and electrolyte status. Continuous administration of high-sodium fluids according to maintenance needs can lead to hypernatremia, especially in cats. Fluids with lower sodium content, such as half-strength LRS or 0.45% sodium chloride in 2.5% dextrose, can be used for longer-term maintenance therapy in these animals.
Assessment of urine output is one of the most important and most neglected aspects of monitoring animals with acute kidney injury. Placement of an indwelling urinary catheter is the most accurate method for monitoring urine volume. Meticulous attention must be paid to sterile catheter placement, maintenance of a closed collection system, and daily cleaning of visible parts of the catheter with disinfectant to reduce the risk of infection. Since the incidence of catheter-related infections increases rapidly after 3 days, the urinary catheter should be changed at 2-3 day intervals.
Oliguria and Anuria Treatment: After the animal's dehydration is treated, urine flow should increase to 2 to 5 ml/kg per hour depending on the IV fluid administration rate. If urine production is inadequate, the animal's hydration status, including arterial blood pressure and central venous pressure, should first be reassessed. Reduced circulating blood volume can cause a decrease in GFR and urine volume. The fluid administration rate should be slowed to prevent further fluid overload and associated adverse effects. An indwelling urinary catheter should be placed if not already present. Specific treatment aimed at increasing urine flow is the next step. The first drug to be applied for this purpose is furosemide. Although furosemide can increase urine output by acting on the renal tubules, it does not increase GFR or improve outcome. Continuing IV fluid administration to correct acid-base and electrolyte imbalances depends on increasing urine output. Generally, furosemide is administered rapidly at an initial dose of 2 mg/kg IV, and if the initial dose fails to increase urine production, doses are increased to 4-6 mg/kg at hourly intervals. If furosemide administration fails to increase urine production, osmotic diuresis can be tried. For this purpose, a 20% mannitol solution can be given at 0.5 to 1.0 g/kg over 15 to 20 minutes. If effective, urine flow increases within an hour. Dosages above 2 to 4 mg/kg/day can actually cause kidney failure and should be avoided. In addition to its diuretic effect, mannitol has an inhibitory effect on renin release due to its hyperosmolar effect on the tubular luminal filtrate. Also, mannitol acts as a free radical scavenger, reduces harmful increases in mitochondrial calcium, and contributes to the beneficial release of atrial natriuretic peptide. Since mannitol is not metabolized, its effects remain in the intravascular space longer than dextrose. Administration of hypertonic solutions is contraindicated in oliguric animals with volume overload because they cause an increase in serum osmolality, circulating blood volume, and blood pressure. Alternatively, a 20% dextrose solution can be given. To prevent dehydration from osmotic diuresis, hypertonic dextrose administration should be alternated with a polyionic solution. Urine should be monitored for glucose to determine the effectiveness of this treatment. If pharmacological measures fail to increase urine output and improve azotemia and uremia, renal replacement therapy is indicated.
Polyuria Treatment: Animals recovering from the oliguric or anuric phase of acute kidney injury or those with milder kidney injury that do not become azotemic often exhibit severe polyuria for days or weeks. In these animals, electrolyte abnormalities, particularly hyponatremia and hypokalemia, may develop and require correction with IV or oral therapy. Frequent monitoring of serum electrolytes and treatment as needed is necessary until urine output decreases and kidney function and serum electrolyte concentrations stabilize.
Correction of Acid-Base Abnormalities: Metabolic acidosis can occur in animals with acute kidney injury. After the fluid deficit is corrected, alkalinization therapy is not recommended unless the blood pH is below 7.2 or the serum bicarbonate level is below 14 mEq/L. Such treatment can cause significant complications, including paradoxical CSF acidosis, decreased ionized serum calcium levels, and hypernatremia. If the animal is oliguric or anuric, moderate or severe, life-threatening hyperkalemia can occur. The first and most important step in treating hyperkalemia is to ensure urine production and excretion. In animals with severe hyperkalemia or persistent oliguria, additional specific treatments such as sodium bicarbonate, regular insulin and glucose, or calcium gluconate in life-threatening situations can be administered.
Treatment of Other Uremic Complications: Vomiting is one of the most common signs of uremia in animals with acute kidney injury. Vomiting occurs due to uremic toxins stimulating the vomiting center and locally due to uremic gastritis. Hypergastrinemia occurs in animals with reduced kidney function, contributing to increased gastric acidity and associated inflammation. The destructive effects of acid on the gastric mucosa can be reduced by using histamine receptor antagonists like famotidine (0.5-1.0 mg/kg every 24 hours) and proton pump inhibitors like omeprazole to inhibit gastric acid production. In some animals, the use of centrally acting antiemetics like maropitant may be necessary. This drug is a neurokinin-1 (NK-1) receptor antagonist with efficacy against peripheral and centrally mediated vomiting. The dose is 1 mg/kg subcutaneously (SC) or 2 mg/kg PO once daily for up to 5 days. Metoclopramide, a dopamine antagonist, can be given as intermittent therapy at 0.2 to 0.5 mg/kg IV every 8 hours or as a constant rate infusion at 1-2 mg/kg/day IV. Other centrally acting drugs include dolasetron and ondansetron. Phenothiazine-derived antiemetics like chlorpromazine can be tried if vomiting persists despite other therapy. Phenothiazines should be used with caution as they cause sedation and hypotension.
Hypertension Treatment: Arterial hypertension is common in animals with AKI and can be exacerbated by overhydration. Treatment involves reducing the IV fluid administration rate, administering diuretics, and dialysis to remove excess fluid if the animal is oliguric or anuric. Pharmacological treatment is limited because most antihypertensive drugs are only available in oral formulations, and vomiting associated with AKI often prevents oral medication. If hypertension is severe, parenteral antihypertensives may be necessary; however, blood pressure must be monitored very closely in this case.
Nutritional Management: Anorexic AKI animals are at risk of malnutrition if food intake is lacking for more than a few days. Adverse outcomes associated with malnutrition include suppression of the immune system, reduced tissue synthesis and repair (including kidney tubular cells), and altered drug metabolism. If the animal is not vomiting, enteral nutrition can be provided using a nasogastric, esophagostomy, or gastrostomy tube; otherwise, parenteral nutrition is indicated.
Supportive and specific treatment should continue until kidney function returns to normal. If dialysis is not an option, euthanasia may be indicated at this point.