Disease of the kidney can be generally classified as acute or chronic. A diseased kidney could be functioning normally leading to no clinical pathologic abnormalities, but the disease can also lead to a loss of ability to concentrate or dilute tubular filtrate (requires 2/3 loss of functional mass), to eliminate nitrogenous wastes (requires loss of 3/4 of functional nephron mass) and to maintain acid-base status (requires functioning tubules). Identification of renal injury continues to evolve with specific guidelines developed for both humans and animals. Human guidelines differ somewhat, but there is increasing recognition of the need to differentiate between “early renal success” and different grades of acute kidney injury (AKI).
Early renal success
Early renal success refers to renal dysfunction, principally an acute azotemia, that is due to prerenal causes. This condition has not been clearly defined, but it is likely associated with an increase in creatinine concentration of >0.3 mg/dL in 48 hours and a lack of anuria. Oliguria can be present in severely dehydrated patients that are trying to conserve water. Correction of prerenal conditions leads to restoration of renal function, e.g. fluid resuscitation. In such patients, there is no evidence of tubular injury or necrosis, as ascertained by tests used in humans, including fractional excretion of sodium <1%, fractional excretion of urea (<35%), no granular or epithelial casts on urinalysis, and normal biomarkers of renal injury, including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalicin (NGAL) (Lima and Macedo 2018, Monari et al 2020). Note, that we do not run many of these tests in animals.
Acute kidney injury
Acute kidney injury (AKI) is characterized by a rapid deterioration in renal function over hours to days (48 hours to 7 days), resulting in a failure of the kidney to excrete nitrogenous waste (azotemia) and maintain fluid, electrolyte and acid-base status. Acute kidney injury can be corrected (transient), however it may be persistent and progress to acute kidney disease (defined as renal dysfunction persisting for 7-90 days) or chronic renal disease (CKD, defined as renal dysfunction persisting for >90 days) as defined by a 2017 consensus statement of the Acute Disease Quality Initiative (ADQI) workgroup (Chawla et al 2017). Of course, AKI can also complicate a pre-existing CKD. A staging system called Kidney Disease: Improving Global Outcome (KDIGO) was developed in 2012 to diagnose AKI and classify it into stages in humans. According to this system, AKI is defined by an increase in serum/plasma creatinine ≥ 0.3 mg/dL within 48 hours, a ≥ 1.9 x increase in serum/plasma creatinine that was present (or assumed to be present) in the last 7 days or oliguria (<0.5 ml/kg/hr in 6 hours). The severity of AKI was differentiated into three stages, based on the severity of increase in serum/plasma creatinine and oliguria. The ADQI workgroup recommended that transient AKI be defined as a “complete and rapid reversal” of AKI within 48 hours on the basis of urine production as well as creatinine concentrations, and one that does not recur within an additional 48 hours, whereas persistent AKI is present for greater than 48 hours (based on KDIGO criteria of creatinine concentrations and urine output, as well as other data supporting AKI, such as imaging findings and biomarkers) and progresses to acute kidney disease (AKD) if present for equal or more than 7 days. Patients with AKD that survive can recover from the disorder or redevelop AKI, depending on the initiating cause of AKI and successful treatment thereof (Chawla et al 2017).
Similar guidelines have developed for animals by the International Renal Interest Society (IRIS), which have also classified 3 stages of AKI.
- This system categorizes stage I AKI as non-azotemic animals but with evidence of renal dysfunction (e.g. increased SDMA concentrations, proteinuria excessive for the urine specific gravity, granular/cellular casts, glucosuria without hyperglycemia), imaging evidence of AKI, and/or oliguria or anuria (<1 ml/kg/hr or no urine produced within 6 hours, respectively). Within this category were included animals with ≥ 0.3 mg/dL in serum/plasma creatinine (remaining within the reference interval) over 48 hours and animals that responded to fluid therapy with a decrease in creatinine over 48 hours and increased urine production (also called volume-responsive AKI). Acute kidney injury that is not volume responsive is called intrinsic AKI.
- IRIS stage 2 AKI differs from stage 1 by including animals with mild azotemia and evidence of renal dysfunction as indicated above. However, similar to stage 1 AKI, the serum/plasma creatinine can be corrected within 48 hours with fluid therapy, as can the oliguria or anuria, i.e. the AKI is volume responsive (which is difficult to differentiate from early renal success) and not intrinsic. Patients with stage 2 AKI can have pre-existing CKD.
- IRIS stage 3-5 AKI includes animals with more severe grades of azotemia (based on serum/plasma creatinine)
The IRIS guidelines do not indicate how to differentiate animals from early renal success (prerenal azotemia) from animals with renal azotemia. It is likely that many animals with moderate to severe prerenal azotemia have transient AKI that we do not recognize as we often do not collect urine from these animals for markers of renal injury (e.g. urinary biomarkers of renal tubular injury as indicated above or fractional excretion of sodium > 0.9% [Troia et al 2018), nor do we always monitor urine output. Thus, it is very difficult to differentiate early renal success from transient AKI, because both can present with oliguria and both will correct with fluid therapy (within 48 hours). Evidence of renal dysfunction, such as proteinuria that is excessive for the urine specific gravity with an inactive sediment, glucosuria without hyperglycemia and cellular or granular casts would support AKI over primary prerenal azotemia alone. Other limitations of these staging systems is that creatinine can be influenced by prerenal factors (e.g. sepsis, decreased muscle mass) and it takes time for creatinine to increase with acute decreases in GFR (Lima and Macedo 2018). It remains to be seen whether SDMA is a more superior marker than creatinine for reduced GFR secondary to AKI.
Acute kidney injury can result from the following causes:
- Decreased renal perfusion from prerenal causes: Hypovolemia due to fluid losses (dehydration), low blood pressure, low effective circulating blood volume (cardiac disease, chronic liver disease)
- Intrinsic renal disease. This can be due to acute tubular necrosis (nephrosis) or inflammation (nephritis).
- Nephrosis: Acute tubular necrosis is usually due to traumatic, ischemic or toxic injury. Ischemia is the most common cause of AKI in animals and can be primarily due to prerenal causes. Most cases of ischemic renal tubule injury are reversible if the underlying cause is corrected, unless there has been extensive necrosis or vessel injury. Examples of nephrotoxins that produce severe AKI are myoglobin (rhabdomyolysis), hemoglobin (intravascular hemolytic anemia), aminoglycosides (all species), acorns (large animals) and ethylene glycol (companion animals).
- Nephritis: This can be glomuleronephritis or interstitial nephritis. Causes include leptospirosis, Lyme disease, Rocky Mountain Spotted Fever, ehrlichiosis and bacteremia.
- Post-renal causes. This is usually due to outflow obstruction or rupture of the urinary tract.
Chronic kidney disease
Chronic kidney disease (CKD) is due to slowly progressive, chronic deterioration of kidney function (>90 days per KDIGO guidelines) and may be preceded by AKI in some (but not all) cases. Chronic kidney disease progresses through four stages. As for AKI, KDIGO and IRIS have guidelines for CKD. With IRIS, staging is based on 2 serum/plasma creatinine concentrations taken on two occasions.
- Stage 1 – Decreased renal reserve
- During this period, there may be an upward trend in urea nitrogen and creatinine concentrations, but are still within reference intervals. SDMA concentrations may be increased. There are no clinical signs, but the kidneys are less able to compensate for dehydration or decreased perfusion. This also pertains to stage I IRIS CKD.
- Stage 2 – Chronic renal insufficiency
- Additional loss of renal function will lead to decreased urine concentrating ability and polyuria, eventually accompanied by azotemia. However, other clinical signs of uremia are not yet present. With IRIS stage 2 CKD, serum/plasma creatinine concentrations are at the upper end of normal or mildly increased and SDMA concentrations are mildly increased.
- Stage 3 – Chronic renal failure
- Clinical signs of uremia accompanied by worsening azotemia develop as the kidney disease progresses. At this stage, the animal is considered to be in stage 3, or chronic renal failure. These animals may also develop additional laboratory abnormalities such as high anion gap or titration metabolic acidosis (from failure to excrete acids produced from amino acid metabolism). Stage 3 IRIS is based on a moderate azotemia, which can be early if the animals lack associated clinical pathologic abnormalities or clinical signs, or late, if they demonstrate the latter.
- Stage 4 – End-stage renal disease
- The kidney can no longer produce much urine and the animal becomes oliguric and severely uremic, with very severe changes on serum chemistry and demonstration of clinical signs. The oliguria and severe laboratory changes can be similar to the presentation of animals with stage 3 AKI, but animals in the end stage of chronic kidney disease will have a longer time course of disease that may have included a period of polyuria. IRIS stage 4 is based on a severe azotemia with a higher risk of clinical signs and clinical pathologic abnormalities.
An acute exacerbation of renal disease may occur in some patients with chronic renal failure (“acute on chronic” renal failure). The most common cause of chronic renal failure in large animals is glomerulonephritis. In small animals, both glomerulonephritis and amyloidosis can produce chronic renal failure. Some breeds are predisposed to amyloidosis, e.g. Sharpei, Beagles, Oriental and Siamese cats. In addition, many breeds suffer from inherited renal dysplasias which result in chronic renal failure, e.g. Samoyeds, Bull Terriers and Soft-coated Wheaten Terriers. Often proteinuria is the first sign of renal disease in breeds with inherited renal disease. Both acute and chronic renal failure have similar laboratory features, including azotemia, hyperphosphatemia, and a titration metabolic acidosis (hyperphosphatemia is not commonly seen in ruminants or horses with chronic renal disease). Differentiation of AKI from chronic renal disease can be difficult but can be accomplished by assessment of clinical signs, laboratory features and history.
| Acute kidney injury | Chronic renal disease | |
| History | Ischemic episode, toxicant exposure, trauma, nephrotoxic drugs | May have had previous episodes of acute renal failure |
| Clinical signs | Good body condition, acute onset of vomiting, diarrhea, lethargy and depression. Anuria or oliguria is usually present. | Long standing signs of polyuria, polydipsia, nocturia, vomiting and diarrhea |
| Kidneys | Normal to large, with smooth contours, may be painful | Small with irregular contours |
| Osteodystrophy | Absent | Present |
| Packed cell volume | Normal or increased | Mild to moderate non-regenerative anemia |
| Urine sediment | Usually abnormal: Glucosuria, mild proteinuria, granular and/or casts | Severe proteinuria, granular and waxy casts may be seen, glucosuria is less common. |
| Serum creatinine | Previously normal | Previously increased |
| Serum potassium | Normal to increased (if anuric or oliguric) | Normal to decreased (cats in particular), unless oliguric or anuric (expect increased) |
| High anion gap or titration metabolic acidosis | Severe | Less severe |
| Histopathology | Acute tubular necrosis or inflammation | Interstitial fibrosis, chronic inflammation, glomerulosclerosis, amyloidosis |
Protein-losing nephropathy
A protein-losing nephropathy (PLN) is caused by glomerular disease, which results in alterations of the glomerular filtration barrier, allowing albumin to escape into the urine (called a selective proteinuria if mostly albumin is getting through the barrier). This results in a proteinuria that is excessive for the urine specific gravity (USG) and, if the proteinuria is severe and/or long-standing, serum/plasma albumin concentrations will decrease. If the albumin concentrations drop low enough, there may be decreased oncotic pressure, resulting in edema or body cavity effusions. We can attribute a low albumin concentration to glomerular loss of albumin when we see excessive proteinuria for the USG and a urine protein to creatinine >2.0 (although it is usually far higher), with no other cause for the proteinuria. Glomerular “leakiness” to protein may progress, allowing even higher MW proteins to leak through, which is called a non-selective proteinuria. Even when this happens, globulin concentrations are typically normal, so a PLN is expected to result in a hypoalbuminemia but not a hypoglobulinemia (i.e. not a panhypoproteinemia). In contrast, with protein-losing enteropathy, both albumin and globulins are lost, so there is a panhypoproteinemia (which is one of our clues as to the source of albumin loss being the intestinal tract). Glomerular leakage of albumin does result in tubular damage and interstitial inflammation, thus tubular defects can be a consequence of a PLN.
The most common cause of a PLN in all species is an immune-complex glomerulonephritis, in which immune complexes deposit in the glomerular basement membrane, causing alterations in the glomerular barrier. Another cause is amyloidosis, with deposition of amyloid in the glomerulus (this is usually a reactive or inflammatory amyloidosis with increases in the acute phase protein, serum amyloid A, which is the source of amyloid deposits). Because animals still have functional nephrons that can still filter nitrogenous waste (urea nitrogen and creatinine are freely filtered through the normal glomerulus), they are not usually azotemic until later in the disease (so glomerulonephritis is a cause of a protein-losing nephropathy and a renal azotemia, which may or may not be concurrent).
Nephrotic syndrome is the name given to a protein-losing nephropathy that is characterized by hypoalbuminemia, proteinuria (due to albuminuria), hypercholesterolemia and edema/ascites (increased fluid accumulation may not be present in all cases). The hypercholesterolemia is due to production of a specific form of lipoprotein that is rich in cholesterol, called “lipoprotein X”. Ascitic fluid is typically a low protein transudate formed secondary to low oncotic pressure (albumin usually needs to be <1-1.5 g/dL to result in ascites) and we have seen it resemble water (particularly in cats). Most animals with nephrotic syndrome are not azotemic, indicating that they still have functional nephron mass.
