Differentiation between Acute kidney injury and chronic kidney disease (updated 2022)

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 completely two 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, were found to be consistently elevated compared with healthy controls when measured in animals with apparently stable CKD, indicating presence of ongoing active damage.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, although it 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; an increase in these functional markers is expected with any decrease in kidney function, regardless of the underlying disease (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 low 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, often are not available.

History and physical examination

History and physical examination are very important for the differentiation of AKI vs. 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 by the azotemia per se, since the disease is frequently accompanied by concurrent comorbidities and complications, such as pancreatitis, gastroenteritis, acute lung injury and others.

Animals 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 (PUPD), decreased appetite, 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) predominate. Presence and intensity of clinical signs depend on the stage of the disease 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 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 PUPD is to be expected, however, in reality, PUPD 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 assess the condition accurately. Presence of severe azotemia attest 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. 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. Yet, there are some exceptions to these trends. For example, grapes and raisins intoxication leading to AKI might be associated with hypercalcemia,⁵ and vitamin D intoxication results in hypercalcemia and AKI (i.e., hypercalcemic nephropathy). Finally, anemia may be present in animals with Stage 3 and 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 commonly utilized modalities 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 cortexes. 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 glands. Secondary renal hyperparathyroidism is an inevitable and early consequence of CKD, resulting in hypertrophy of the parathyroid glands, therefore should be present, at least in animals with advanced CKD, and absent in AKI. 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 IRIS CKD stage 1 was present (otherwise, kidney function parameters would not have been normalized). Regardless, animals that recover from AKI has to be monitored prospectively as IRIS 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 is scarce with information regarding 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 of these patients is more guarded compared with the prognosis of AKI patients.¹⁷

One of the most clinically applicable and straightforward prognostic tools is assessing the animal's quality of life before the decompensation, with the assumption that after resolution of the crisis the animal will gain to the same quality of life as before the crisis, or even better, once appropriate medical therapy is to be 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 to be short.

Recently, two studies have evaluated the prognosis of dogs and cats demonstrating that the short-term outcome of both dogs and cats with acute on chronic kidney disease is not different compared with animals with AKI.^{18, 19} This unexpected high survival rate possibly related to their particular identified etiologies, and the potential reversibility of the injury. The common etiologies identified in these studies included inflammation, pyelonephritis and ischemia which are considered reversible injuries, while nephrotoxicity, commonly reported as a cause for AKI were not reported in these studies. Additionally, as owners are aware of the presence of CKD, they are likely more sensitive to occurrence of subtle clinical abnormalities, thereby seeking early medical intervention, which potentially improves the survival rate. It therefore seems that the short-term prognosis for dogs with ACKD is at least as favorable as that of those sustaining AKI. Although the short-term outcome is apparently fair, the long-term prognosis in this study was guarded, with median survival time of 105 days in dogs and only 66 days in cats. In dogs only 57% and 13% survived to 6 and 12 months, respectively, and in cats 81% and 8% survived to 6 and 12 months, respectively.^18,19

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

References

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18. Chen H, Dunaevich A, Apfelbaum N, et al. Acute on chronic kidney disease in cats: Etiology, clinical and clinicopathologic findings, prognostic markers, and outcome. J Vet Intern Med 2020;34:1496-1506.

19. Dunaevich A, Chen H, Musseri D, et al. Acute on chronic kidney disease in dogs: Etiology, clinical and clinicopathologic findings, prognostic markers, and survival. J Vet Intern Med 2020;34:2507-2515.