Differentiation Between Acute Kidney Injury and Chronic Kidney Disease

Adapted from the IRIS education article by Gilad Segev, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Israel (2018).

Introduction

Acute kidney injury (AKI) and chronic kidney disease (CKD) are relatively common in dogs and cats. In the past, AKI and CKD were considered two completely separate conditions. However, research on novel biomarkers of kidney damage suggests that they share some characteristics. These biomarkers were first intended as early markers of AKI, but they were found to be consistently higher than in healthy animals when measured in animals with apparently stable CKD, indicating ongoing active damage. This suggests that the two seemingly different conditions may be mechanistically linked, and that the main difference between them may be the rate at which the disease progresses.

Differentiating AKI from CKD is often straightforward, but it can be challenging in some cases. Part of the challenge is that the same markers, such as serum creatinine and symmetric dimethylarginine (SDMA), are used to diagnose both conditions. These functional markers are expected to rise with any decrease in kidney function, whatever the underlying disease. Differentiation between AKI and CKD is therefore based mostly on the history, physical examination findings, laboratory data, ultrasound findings, and occasionally on histology.

An acute exacerbation of CKD is even more challenging, because features of AKI and CKD are present at the same time, and animals with acute-on-chronic kidney disease vary widely. Some have advanced CKD with a relatively small acute decompensation, while others have early-stage CKD with a severe acute exacerbation. When an animal is presented with acute azotemia, the clinician has to judge, mainly for prognosis, whether the kidneys were completely normal before the deterioration or whether some kidney dysfunction was already present. Previous serum creatinine or SDMA results are extremely valuable for this, but they are often not available.

History and Physical Examination

The history and physical examination are very important in distinguishing AKI from CKD, and in most cases they make the distinction straightforward. Animals with AKI have no history of chronic illness and are typically presented with a sudden onset of clinical signs, which are often nonspecific and include vomiting, diarrhea, poor appetite, and lethargy. The clinical signs of AKI are often more severe than the azotemia alone would explain, because AKI is frequently accompanied by other conditions and complications, such as pancreatitis, gastroenteritis, and acute lung injury.

Animals with CKD have a slowly progressive disease, with clinical signs that increase over time. Sometimes azotemia is found incidentally on routine blood work, which most likely indicates CKD rather than AKI. Whether clinical signs are present, and how severe they are, depends on the stage of the disease, but it also varies between individuals, because some animals tolerate azotemia better than others, especially dogs with congenital CKD. Typical historical signs of CKD include increased thirst and urination (polyuria and polydipsia, or PU/PD), decreased appetite, weight loss, a low body condition score, and pale mucous membranes caused by anemia. Occasionally, signs of severe proteinuria (such as edema or fluid accumulation in body cavities) or of hypertension (such as sudden blindness) predominate.

Most clinical signs of CKD do not become apparent until IRIS CKD Stage 3, so the absence of clinical signs in the history does not rule out CKD. In theory, most dogs with CKD lose the ability to concentrate their urine before creatinine rises above the upper limit of the reference range, so at least PU/PD would be expected. In reality, owners often overlook PU/PD.

Laboratory Findings

Several blood test results can help distinguish AKI from CKD. None is conclusive on its own, but together they substantially improve the accuracy of the assessment.

  • Severity of azotemia: severe azotemia suggests AKI or an acute decompensation of CKD, because it is unlikely that severe kidney dysfunction was present without any previous clinical signs.
  • Phosphorus: in CKD, blood phosphorus initially stays within the reference range, because compensatory mechanisms increase phosphorus excretion. As the disease progresses, phosphorus rises gradually, in proportion to the decrease in kidney function and so to the increase in serum creatinine. In AKI, these compensatory mechanisms have not had time to act, so phosphorus rises substantially relative to the increase in creatinine. A high phosphorus-to-creatinine ratio therefore suggests AKI.
  • Calcium: blood calcium tends to be normal to low in AKI and normal to high in CKD. There are exceptions. AKI caused by grape or raisin toxicity can be associated with hypercalcemia, and vitamin D toxicity causes both hypercalcemia and AKI (hypercalcemic nephropathy).
  • Anemia: anemia may be present in CKD Stages 3 and 4, and its severity depends on the stage and duration of the disease. Animals with AKI can also be anemic, however, because of inflammation or gastrointestinal bleeding.

A urinalysis can also help. In AKI, active damage to the tubules can cause glucose in the urine despite normal blood glucose (glucosuria) and urinary casts (cylindruria). However, only about 30% of animals with AKI have glucosuria or casts, so both findings have low sensitivity, and their absence does not rule out AKI or an acute exacerbation of CKD.

Ultrasound Examination

Ultrasound is one of the most commonly used tools for distinguishing AKI from CKD, and for identifying underlying CKD in animals with an acute exacerbation. The ultrasound appearance of the kidneys depends on the cause of the disease. Typical changes in CKD include small kidneys with irregular margins, hyperechoic (bright) cortices, and poor distinction between the cortex and the medulla. In AKI, the kidneys usually keep their normal architecture and are often enlarged, with hyperechoic cortices.

There are exceptions. In some causes of CKD, the kidneys may be enlarged, for example with amyloidosis, lymphoma, polycystic kidney disease, or hydronephrosis. In some causes of AKI, the kidneys may look abnormal, for example in ethylene glycol (antifreeze) poisoning. It is also important to remember that ultrasound changes often correlate poorly with both kidney function and histology.

A less commonly used ultrasound method is to examine the parathyroid glands. Secondary renal hyperparathyroidism is an inevitable and early consequence of CKD that enlarges the parathyroid glands, so enlarged glands would be expected, at least in advanced CKD, and not in AKI. Ultrasound of the parathyroid glands has been shown to help distinguish AKI from CKD, but finding the glands requires special skill.

Kidney Biopsy

In some cases, distinguishing AKI from CKD is difficult, and the final diagnosis relies on a kidney biopsy. The benefits of a biopsy must be weighed against the risks and cost of the procedure, and it is indicated mainly when the result is likely to change the treatment.

Response to Treatment

Sometimes, especially when early-stage CKD was present before an acute exacerbation, it is difficult to know whether CKD existed beforehand. In early CKD, clinical signs may be absent or overlooked, and the kidneys may look normal or inconclusive on ultrasound. Without a kidney biopsy, it may be impossible to confirm or rule out CKD before the acute decompensation. This question matters mainly for prognosis, and it becomes less relevant once treatment has started.

If serum creatinine returns to normal and the animal recovers completely, it is likely that either CKD was not present before the decompensation or the animal had IRIS CKD Stage 1, since otherwise kidney function values would not have returned to normal. Either way, animals that recover from AKI should be monitored as IRIS CKD Stage 1 patients, because complete clinical recovery and a normal serum creatinine do not rule out residual chronic kidney damage.

Prognosis

Many studies have evaluated the short-term and long-term prognosis of animals with AKI and with CKD, but there is little veterinary information on the prognosis of acute-on-chronic kidney disease. Owners often ask about both the short-term and the long-term outlook for these animals, assuming the acute component can be treated successfully. Based on human medicine, the prognosis for these patients is more guarded than for patients with AKI alone.

One of the most practical prognostic tools is the animal's quality of life before the decompensation, on the assumption that once the crisis resolves, the animal will return to a similar quality of life, or even a better one once appropriate medical treatment is in place. In animals that were losing weight and appetite before the sudden decline in kidney function, and that have substantial ultrasound changes, successful treatment is less likely and life expectancy is likely to be short.

Two studies, one in dogs and one in cats, found that the short-term outcome of acute-on-chronic kidney disease was not different from that of AKI. This unexpectedly high survival rate may be related to the causes identified and to how reversible the injury was. The most common causes in these studies were inflammation, pyelonephritis, and ischemia, which are considered reversible, while nephrotoxicity, a common cause of AKI, was not reported. In addition, owners who already know their pet has CKD are probably more alert to subtle changes and seek veterinary care earlier, which may improve survival. The short-term prognosis of acute-on-chronic kidney disease therefore appears to be at least as favorable as that of AKI.

Although the short-term outcome appears fair, the long-term prognosis in these studies was guarded. The median survival time was 105 days in dogs and only 66 days in cats, and only 13% of dogs and 8% of cats were still alive 12 months later.

AKI Versus CKD at a Glance

  • History: in AKI, previous compatible clinical signs are absent. In CKD, they are usually present, although they may be absent or overlooked by owners, especially in CKD Stages 1 and 2.
  • Attitude: animals with AKI are typically severely ill. Animals with CKD vary with the stage of the disease, but they are typically less ill than an animal with AKI and the same degree of azotemia. AKI can be subclinical in its early stages, and the severity of signs in CKD varies between individuals, especially with congenital disease.
  • Body condition: normal in AKI. Normal to decreased in CKD, although weight loss is not expected until late Stage 3.
  • Mucous membranes: usually normal in AKI. May be pale in CKD because of anemia.
  • Azotemia: any degree in AKI. In CKD, azotemia is unlikely to be severe if there is no history of clinical signs.
  • Phosphorus: a high phosphorus-to-creatinine ratio suggests AKI. In CKD, phosphorus is initially within the reference range and then rises in proportion to the azotemia.
  • Calcium: normal to decreased in AKI, although grape or raisin toxicity and vitamin D toxicity can cause hypercalcemia. Normal to increased in CKD.
  • Anemia: usually absent in AKI, although inflammation or gastrointestinal bleeding can cause it. Present in the late stages of CKD.
  • Ultrasound: in AKI, the kidneys are often enlarged, with normal architecture. In CKD, the kidneys are usually small, with irregular margins, hyperechoic cortices, and poor corticomedullary distinction, although some causes of CKD enlarge the kidneys, such as neoplastic infiltration, amyloidosis, and hydronephrosis.
  • Kidney biopsy: findings depend on the cause. Fibrosis indicates CKD and is absent in pure AKI.