Differentiation between Acute Kidney Injury and Chronic Kidney Disease (2018)

Gilad Segev, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Israel

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 entities; however, recent research of novel biomarkers of kidney damage suggests that these conditions share some common characteristics. These biomarkers were initially intended to be used as early markers of AKI, however, when measured in animals with stable CKD they were found to be consistently elevated compared with healthy controls, possibly indicating presence of ongoing active damage to nephrons, also in animals with apparently stable CKD.1 This might imply that these seemingly different conditions may be mechanistically linked and interrelated, and the main difference between them is the rate of disease progression.

Differentiation between AKI and CKD may be straightforward in many cases, however may pose a challenge in some cases. This challenge partially arises from the fact that the very same markers (e.g., serum creatinine and symmetric dimethylarginine [SDMA]) are used to diagnose both conditions, and an increase in these functional markers are expected with any decrease in kidney function (reduced glomerular filtration rate), regardless of the underlying situation (AKI or CKD). Therefore, differentiation between AKI and CKD is mostly based on the history, physical examination findings, clinicopathologic data, ultrasonographic findings and occasionally histology.

Acute exacerbation of CKD poses even a bigger challenge because characteristics of AKI and CKD are concurrently present and there is a great deal of variability in the presentation of animals with acute-on-chronic kidney disease, as some animals have advanced CKD and relatively small acute decompensation, whereas others have early stage CKD and severe acute exacerbation. When an animal is presented with acute azotemia, mostly for prognostic projections, the clinician has to assess whether the kidneys had completely normal function before the deterioration, or alternatively, some degree of kidney dysfunction was already present. In that regard historical serum creatinine or SDMA measurements are extremely important however, are not available in the majority of clinical patients.

History and physical examination

History and physical examination findings are very important for the differentiation of AKI and CKD. In most cases, differentiation between these two conditions is straightforward. Animals with AKI do not have history of chronic illness and typically are presented with acute onset of clinical signs (although nonspecific), including, but not limited to, vomiting, diarrhea, inappetence, and lethargy. The intensity of clinical signs in AKI is often more severe than can be attributed to the azotemia per se, since the disease is frequently accompanied by concurrent comorbidities and complications, such as pancreatitis, gastroenteritis, and acute lung injury.

Animals, especially cats, with CKD have slowly progressive disease with increasing intensity of clinical signs. Occasionally, azotemia is found as an incidental finding upon routine blood work, which likely indicates presence of CKD rather than AKI. Presence and intensity of historical clinical signs depend on the disease stage, but also vary among individual patients, as some animals are more resilient to the azotemia compared to others (especially dogs with congenital CKD). Historical clinical signs of CKD include polyuria and polydipsia (PU/PD), decreased appetite, vomiting, weight loss, low body condition score, and pale mucous membranes (due to anemia). Occasionally, clinical signs associated with severe proteinuria (e.g., edema, effusion) or hypertension (e.g., acute blindness) could predominate. Presence and intensity of clinical signs depend on the stage of the disease and possibly rate of progression prior to presentation, thus are not always present, and most do not become apparent until IRIS CKD stage 3. Therefore, absence of clinical signs in the history does not completely rule out the presence of CKD. In theory, most dogs with CKD lose their ability to concentrate urine before creatinine exceeds the upper limit of the reference range; therefore, at least PU/PD is to be expected, unfortunately PU/PD is often overlooked by the owners.2

Clinicopathologic parameters

Some serum biochemistry parameters may aid in the assessment and differentiation between AKI and CKD. None of these is conclusive, yet the combination of all, substantially improve the ability to accurately assess the condition. Presence of severe azotemia attests for AKI or acute decompensation of CKD, as it is unlikely that severe kidney dysfunction was present in the absence of historical clinical signs. Hyperphosphatemia is another biochemical measure that can be used as part of the overall assessment. In CKD, phosphorous concentration initially remains within the reference range due to the activation of secondary compensatory mechanisms promoting phosphorus excretion.3,4 As the disease progresses, phosphorous concentration increases gradually and proportionally to the decrease in kidney function (i.e., to the increase in serum creatinine concentration). Conversely, in AKI, since compensatory mechanisms are inactive, phosphorus concentration increases substantially compared with the increase in serum creatinine concentration. Thus, high phosphorous to creatinine ratio is more suggestive of AKI. Total calcium concentration tends to be normal to low in animals with AKI, while in animals with CKD, calcium concentration tends to be normal to high. However, these trends are not consistent enough to make them useful in differentiating AKI and CKD and there are some exceptions to these trends. For example, grapes and raisins intoxication leading to AKI might be associated with total hypercalcemia.5 Finally, anemia may be present in animals with late Stage 3 or Stage 4 CKD, and its severity depends on the disease stage and its chronicity. Yet, animals with AKI may show anemia due to inflammation or gastrointestinal bleeding.

Urinalysis can also aid in differentiating AKI vs. CKD. In AKI, active tubular damage might result in glucosuria (in face of normoglycemia) and cylindruria (urinary casts). Yet, only 30% of animals with AKI have evidence of glucosuria or cylinruria,6 thus both markers suffer from low sensitivity, and their absence does not rule out AKI or acute exacerbation of CKD.

Ultrasonographic evaluation

Ultrasonographic examination is one of the most common diagnostic modalities utilized to differentiate AKI vs. CKD as well as to identify the presence of CKD in animals with acute exacerbation of CKD. The ultrasonographic appearance of the kidneys is affected by the etiology; however, typical ultrasonographic changes characterizing CKD include small kidneys with irregular margins, hyperechoic cortices and poor corticomedullary differentiation, whereas in AKI, the kidneys maintain normal architecture and often are enlarged with hyperechoic cortices. However, exceptions occur and in some etiologies of CKD the kidneys may be enlarged (e.g., amyloidosis, lymphoma, polycystic kidney disease, hydronephrosis) whereas in AKI the kidneys may have abnormal appearance (e.g., ethylene glycol intoxication). One always has to bear in mind that the association between the ultrasonographic changes and kidney function as well as histology is often poor.7 A less utilized ultrasonographic method to differentiate AKI from CKD is to evaluate the parathyroid hormone and parathyroid gland size. Secondary renal hyperparathyroidism is an inevitable and relatively early consequence of CKD, resulting in elevation of PTH and later on hypertrophy of the parathyroid glands, therefore should be present in CKD and absent in AKI. PTH is labile in plasma or serum and should be collected into tube containing protease for accurate analysis. It has been shown that ultrasonographic examination of the parathyroid glands is helpful in differentiating AKI from CKD,8 yet identifying the parathyroid glands requires special skills.

Kidney biopsy

In some cases, differentiation between AKI and CKD is challenging and the final diagnosis has to relay on kidney biopsy. The advantages of kidney biopsy should be weighed against the risk and cost associated with the procedure, and is indicated mostly when the results are likely to change the treatment.

Response to treatment

In some cases, especially when early stage CKD was present before the acute exacerbation of the disease, it is difficult to assess whether CKD was present or not. In early stages of CKD, clinical signs may be completely absent or overlooked by the owners, and the ultrasonographic appearance of the kidneys may be normal or inconclusive. In the absence of kidney biopsy, it may be impossible to rule in or rule out CKD prior to the acute decompensation. This question may be important mostly for prognostic projections, however, becomes irrelevant once therapy is initiated. If serum creatinine normalizes and there is complete clinical recovery, it is likely that either CKD was not present prior to the decompensation, or CKD stage 1 was present (otherwise, parameters of renal function would not have been normalized). Regardless, animals that recover from AKI have to be monitored prospectively as CKD Stage 1 patients, since complete clinical recovery, as well as normalization of serum creatinine concentration, do not rule out residual chronic kidney damage.

Prognosis

There are many studies evaluating the short and long-term prognosis of animals with AKI and CKD.6,9-16 Unfortunately, the veterinary literature provides little information informing the prognosis of acute-on-chronic kidney disease. Yet, owners often inquire regarding the short and long-term prognosis of animals with acute-on-chronic kidney disease, providing a successful intervention and recovery of the acute component of the disease. Based on human literature, the prognosis for these patients is more guarded compared with the prognosis for AKI patients.17 With the lack of relevant veterinary literature, the most clinically applicable and straightforward prognostic tool is assessing the animal's quality of life before the decompensation, with the assumption that after resolution of the crises the animal will regain the same quality of life as before the crisis, or even better, once appropriate medical therapy is applied. In animals experiencing progressive weight and appetite loss before the abrupt reduction in kidney function and with supportive evidence of substantial ultrasonographic changes, the likelihood of successful treatment is lower and the life expectancy is likely shorter.

Table 1: Differentiation between acute kidney injury and chronic kidney disease

Parameter AKI CKD Comments
History
Historical
compatible clinical signs
Absent Present Clinical signs may be absent or overlooked by owners, especially in CKD Stage 1-2
Physical Examination
Attitude Typically, severly sick Vary with the disease
stage, but typically less
sick compared to AKI
for the same degree of
azotemia
AKI might be subclinical in early stages.
The intensity of clinical signs in animals
with CKD vary among individuals
(especially in congenital disease)
Body condition
score
Body condition
score
Normal -decreased Weight loss is not expected in CKD until
late stage 3
Mucous
membranes
Normal Might be pale Anemia develops only in late stages of
CKD
Clinicopathologic data
Azotemia Any degree Unlikely to be severe in
the absence of historical
clinical signs
Phosphorous High phosphorus to
creatinine ratio
Initially within range,
proportionally increase
with azotemia
The differentiation of AKI and CKD on
this basis alone is unlikely to be reliable
Calcium Normal to decreased Normal to increased Grapes and raisin intoxication might be
associated with hypercalcemia
Anemia Absent Present in late stages of
the disease
Animals with AKI may show anemia due
to inflammation of gastrointestinal
bleeding
Imaging
U/S findings Large kidneys with
normal architecture
Small kidneys with
irregular margins,
hyperechoic cortices and
poor corticomedullary
differentiation
Exceptions:
CKD: some etiologies results in enlarged
kidney (e.g., neoplastic infiltration,
amyloidosis, hydronephrosis)
Pathology
Kidney biopsy Depends on the etiology,
fibrosis in absent
Depends on the etiology:
fibrosis is indicative of
CKD

References

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