Renal Dysfunction in Dogs and Cats

The International Renal Interest Society (IRIS) establishes guidelines for staging of CKD in dogs and cats. CKD is staged after it has been diagnosed. The purpose of staging is to provide therapeutic and monitoring guidelines, as well as prognostic information.

In brief, CKD is classified into four stages defined by blood creatinine concentration and blood SDMA (symmetric dimethylarginine) concentration (see the table Staging of Chronic Kidney Disease), assessed on at least two occasions in a stable, hydrated patient after food withholding. CKD is then substaged on the basis of proteinuria and on the basis of systolic arterial blood pressure.

The SDMA biomarker has the advantage of greater sensitivity to smaller losses of GFR, rising above the reference interval when creatinine concentrations are still normal. Furthermore, compared with creatinine concentration, SDMA concentration is less affected by a decrease in lean muscle mass.

In stage 1 CKD, the kidneys are damaged, but renal azotemia and clinical signs have not developed. Laboratory changes are subtle. Persistently increased SDMA concentration, progressive increases in creatinine concentration that are still within the reference interval, persistent renal proteinuria, and loss of urine-concentrating ability for which nonrenal causes have been ruled out are some indicators of stage 1 CKD. 

In stage 2 CKD, the disease has progressed, and GFR has decreased, as evidenced by persistent mild renal azotemia. Clinical signs are often not yet evident; however, this stage can be associated with impaired urine-concentrating ability and increased urine volume.

In stage 3 CKD, GFR has declined further. Moderate renal azotemia is present, and clinical signs are often evident but can vary in extent and severity.

Stage 4 CKD reflects further progression of the disease. Severe renal azotemia is present, and there is higher risk of systemic clinical signs and uremic crises.

Known causes of CKD include the following:

• diseases of the macrovascular compartment (eg, systemic hypertension, coagulopathies,chronic hypoperfusion)

• diseases of the microvascular compartment (eg, systemic and glomerular hypertension, glomerulonephritis, developmental disorders, congenital collagen defects, amyloidosis)

• diseases of the interstitial compartment (eg, pyelonephritis, neoplasia, obstructive uropathy, allergic and immune-mediated nephritis)

• diseases of the tubular compartment (eg, tubular reabsorptive defects, chronic low-grade nephrotoxicosis, obstructive uropathy)

Many causes of chronic, generalized renal disease are associated with progressive interstitial fibrosis. The severity of interstitial fibrosis is positively correlated with the magnitude of GFR decline and negatively correlated with prognosis.

Glomerular, tubulointerstitial, and vascular lesions in animals with generalized CKD are often similar, regardless of the initiating cause, particularly in stage 4. In stage 4 CKD, renal histological evaluation might show only marked interstitial fibrosis, also called "chronic interstitial nephritis" or "tubulointerstitial fibrosis." These terms describe the morphological appearance of kidneys with end-stage chronic disease of any cause.

Because acute kidney injury can progress to a chronic condition, any cause of acute kidney injury is also a possible cause of CKD.

Generally, no clinical signs that are a direct result of CKD are evident until loss of ≥ 75% of renal functional mass (stages 3 and 4). Exceptions are CKD that develops as part of a systemic disease with clinical signs referable to involvement of other body tissues (eg, systemic lupus erythematosus, systemic hypertension), CKD accompanied by nephrotic syndrome, and CKD associated with marked renal inflammation and capsular swelling leading to flank pain and occasionally to vomiting.

Usually, the earliest clinical signs commonly attributable to renal dysfunction are polydipsia and polyuria, which are not evident until approximately two-thirds of the nephrons are lost (usually CKD stage 1 or 2). Further destruction of renal tissue leads to azotemia without new clinical signs in stage 2, and finally to the clinically apparent uremic syndrome in stage 4.

Initially, uremia is associated with occasional vomiting and lethargy. As the disease progresses in stages 3 and 4 throughout months (dogs) to years (cats), anorexia, weight loss, dehydration, oral ulceration, vomiting, and diarrhea become fully manifested.

Loose teeth, deformable maxilla and mandible, or pathological fractures can occur with renal secondary osteodystrophy. However, these signs are uncommon, generally occurring only in young dogs with end-stage congenital renal disease.

Physical examination and imaging studies of animals in CKD stages 3 and 4 usually reveal small, irregular kidneys; however, animals with neoplasia, hydronephrosis, or glomerulonephritis can have normal-size to large kidneys. Mucous membranes can be pale in late stage 3 and stage 4 if anemia of CKD develops (anemia of CKD is typically nonregenerative, normocytic, and normochromic).

• Clinical signs

• Serial laboratory evaluations

Because CKD is typically not associated with clinical signs until uremia develops or polyuria/polydipsia occurs as a result of loss of urine-concentrating ability, regular monitoring of kidney function laboratory markers is critical for early diagnosis. 

Serial monitoring of creatinine concentrations can reveal persistent increases above the patient’s normal baseline. Even though the creatinine concentration might remain within the reference interval, such a trend should alert the clinician to the development of CKD. Trends in SDMA concentrations can also reveal decreasing GFR well before azotemia develops, so they should be monitored over time, especially in senior dogs and cats.

Loss of urine-concentrating ability is another marker of CKD. For clinically normal individuals, the urine specific gravity can range from 1.001 to 1.060 in dogs and from 1.005 to 1.080 in cats, depending on body needs for water homeostasis.

Dehydrated animals with normal renal function should have a urine specific gravity > 1.030 in dogs and > 1.035 in cats. The inability to produce concentrated urine when challenged by dehydration is an early clinical sign of CKD. Animals (especially cats and dogs with glomerular disease) can become azotemic while retaining the ability to concentrate urine to a specific gravity > 1.035. 

As GFR continues to decline and CKD progresses in stages 2 and beyond, BUN, serum creatinine, and phosphorus concentrations increase. 

Potassium concentration can be low, normal, or mildly increased, depending on nutritional status, comorbid conditions, and medications administered. 

Mild to moderate increases in total calcium concentration are common; however, ionized calcium concentration, rather than total calcium concentration, should be monitored to direct decisions regarding therapy.

CKD must be distinguished from the more readily reversible acute disease. Frequently, differentiation can be accomplished with an appropriate history and physical examination. Evidence of chronic muscle atrophy and palpably small or irregular kidneys, plus a history of clinical signs such as weight loss, polyuria/polydipsia, and loss of appetite—all are indicative of chronicity. 

When possible, animals with CKD should be carefully evaluated for factors that could be contributing to progression or acute exacerbation of disease. Specifically, abdominal imaging (usually a combination of radiography and ultrasonography) can be performed to evaluate for urolithiasis and/or obstructive uropathy. Urinalysis and urine culture, taken in the context of CBC, examination, and imaging findings, could identify ascending bacterial urinary tract infection that can also acutely exacerbate CKD. 

• Nutrition

• Hydration

• Management of complications and sequelae

With appropriate therapy, animals with CKD can survive for long periods with only a small fraction of functional renal tissue, perhaps 5–8% in dogs and cats.

Recommended treatment varies with disease stage. In stages 1 and 2, animals usually have minimal or no clinical signs. Identifying the primary process causing kidney disease, especially in stages 1 and 2, is important to formulating a treatment plan and determining prognosis.

Identification and supportive treatment of developing complications (eg, systemic hypertension, potassium homeostasis disorders, metabolic acidosis, bacterial urinary tract infection, and obstructive uropathy) should be aggressively pursued.

Mild AKI often goes unrecognized; severe initial or repeated bouts can lead to chronic kidney disease. Usually, AKI is recognized in severe cases and in advanced stages. It is characterized clinically by anorexia, depression, dehydration, oral ulceration, vomiting and/or diarrhea, or inappropriate urine volume (polyuria, oliguria, or anuria).

Physical examination findings often reveal dehydration but usually are otherwise unremarkable; however, pain is occasionally elicited on palpation of the kidneys, which can be normal in size to slightly enlarged.

• Laboratory evaluation

• Infectious disease testing

• Diagnostic imaging

An animal with AKI typically has sudden-onset uremia and a history of hypotension, shock, or recent exposure to known nephrotoxins. The presence of poorly concentrated urine (specific gravity 1.007–1.030), despite dehydration and/or azotemia, suggests renal dysfunction.

Differentiating between CKD and AKI (and establishing a specific cause of AKI) is important because the prognosis and specific therapy might differ. Animals with AKI usually have a compatible history and other urinalysis abnormalities; marked cylindruria (cylindrical casts within urine sediment that form in renal tubules) is a common and definitive finding.

Other urinalysis findings could include the presence of a large number of renal epithelial cells and leukocytes in the urine sediment, glucosuria, crystalluria, enzymuria, and/or myoglobinuria/hemoglobinuria. Animals with AKI generally have increased BUN, creatinine, and inorganic phosphorus concentrations, as well as metabolic acidosis.

Oliguria or anuria after rehydration, which is often associated with hyperkalemia, indicates a poor prognosis; in contrast, animals with polyuria have a better prognosis, even though they can become hypokalemic. The kidneys are typically normal in size and shape, and anemia is often, but not always, absent—findings that can help differentiate AKI from CKD.

After injury, the kidney has considerable potential for functional regeneration via compensatory hypertrophy and adaptive hyperfunction. In animals with CKD, most of this regenerative process usually occurs before the initial diagnosis. In contrast, animals with AKI have considerably more potential for improvement of renal function, if they can be sustained through a uremic episode.

As a disease process, AKI is a spectrum, and the International Renal Interest Society recommends that patients with AKI be categorized primarily on the basis of serum creatinine concentration. Animals with grade I AKI have nonazotemic AKI (serum creatinine ≤ 1.6 mg/dL). Animals with grades II–V AKI exhibit varying degrees of azotemia, with the following serum creatinine concentrations:

• Grade II: 1.7–2.5 mg/dL

• Grade III: 2.6–5 mg/dL

• Grade IV: 5.1–10 mg/dL

• Grade V: > 10 mg/dL

• Specific therapy for known or suspected underlying etiology

• Judicious fluid therapy and management of electrolyte derangements

• Supportive care

• Renal replacement therapy

Severe AKI that necessitates medical intervention is a serious condition, with a survival rate of approximately 50%; patients with treatable infectious diseases have the best prognosis and those with toxic etiologies, the worst. If the cause is known, specific therapy should be instituted (antimicrobials for leptospirosis or pyelonephritis, 4-methylpyrazole or ethanol for ethylene glycol toxicosis in dogs, etc).

Fluid therapy is a key component of managing AKI in small animals. The goal of fluid therapy is to correct dehydration and account for any ongoing losses to restore and maintain optimal perfusion of the kidneys.

An arbitrarily high rate of fluid administration should not be selected to promote diuresis with AKI. There is no evidence that a high rate of fluid administration is beneficial; rather, it is more likely to result in overhydration, which is difficult to correct and is associated with worse outcomes.

The choice of fluid type, rate of administration, and additives should be based on hydration, electrolyte, and acid-base status. Vigilant monitoring of hydration (serial physical examinations, body weight measurement) and urine output is imperative in any AKI patient receiving fluid therapy.

Urine output is highly variable in AKI cases but is usually inappropriate, manifesting as polyuria (> 2 mL/kg/hour), oliguria (< 0.5 mL/kg/hour), or anuria. Animals with AKI can shift between AKI phases (from oliguric to polyuric, for example). Polyuric AKIs are associated with a better prognosis and are easier to manage; however, some patients can have severe polyuria, requiring large amounts of IV fluids to maintain euvolemia.

Caution should be taken to avoid overhydration in oliguric or anuric animals. Dehydrated animals should be given fluids for rehydration while urine output is carefully monitored. If urine production is still absent after the patient is hydrated, fluids should be administered to replace insensible losses only (10–20 mL/kg every 24 hours).

In overhydrated anuric/oliguric patients, fluid therapy should be stopped entirely. Administration of excess fluid to an animal in oliguric or anuric renal failure can result in life-threatening pulmonary and cerebral edema and can even exacerbate kidney damage.

Because of the challenges with fluid balance in AKI, severe cases often require careful monitoring of "ins" (IV fluids, IV medications, enteral water) and "outs" (urine output measured via urinary catheter with a closed collection system, ongoing losses from vomiting/diarrhea, insensible losses) and adjustment of fluids to maintain euhydration.

Renal replacement therapy (eg, hemodialysis) is indicated in cases of overhydration, oliguria/anuria, severe uremia, and hyperkalemia; however, this treatment is often not a viable option, because of high cost and limited availability. In oliguric or anuric animals that cannot receive renal replacement therapy, diuretics can be administered to attempt to increase urine output.

Potentially beneficial diuretics include furosemide (2 mg/kg, IV, which can be followed by 0.5–1 mg/kg/hour, CRI, if urine production does not increase above the target of 0.5 mL/kg/hour) and mannitol (0.5–1 g/kg, IV, to effect). Diuretics should not be administered to dehydrated patients.

Effects of uremia should be managed with appropriate antiemetic and antinausea therapy. Although uremic gastropathy is uncommon, patients with signs of GI bleeding should be managed with gastroprotectants such as a proton pump inhibitor and sucralfate. AKI is a highly catabolic disorder, and nutritional support should be implemented with assisted enteral feeding (tube-feeding) in anorectic patients.