Differentiating between acute and chronic kidney disease
Here are some diagnostics test that can help with this complicated task.
Differentiating between acute and chronic kidney disease can be a complicated task. The recommended tests, treatments, and short- and long-term prognoses differ depending on whether the patient has acute or chronic disease.
Illustration by Kip Carter
In this article, we review important components of the diagnostic process that aid in differentiating acute kidney injury (AKI) and chronic kidney disease (CKD). We discuss historical, physical examination, laboratory, and histologic findings and diagnostic imaging results. Common clinical findings and diagnostic test results in cases of AKI or CKD are summarized in Table 1. We also briefly discuss a few less common diagnostic techniques.
Table 1: Common Clinical Findings and Diagnostic Test Results in Cases of Acute Kidney Injury or Chronic Kidney Disease*
OVERVIEW OF AKI VS. CKD
Multiple definitions of AKI are used in the human medical and veterinary literature. Specific criteria for the severity of damage range from an increase in creatinine concentration of 0.3 mg/dl (compared with a previous reading) to the need for renal replacement therapy.1-5 The time frame for increased creatinine concentrations varies from hours to weeks.6 The term acute kidney injury has been adopted in lieu of acute renal failure to accentuate that damage to the kidney is a continuum—even mild decreases in glomerular filtration rate, even if they do not lead to overt azotemia, are associated with adverse clinical outcomes.6,7 AKI may be reversible.
Most definitions of CKD specify that renal disease has been present for at least three months,8,9 although some sources suggest that four to eight weeks may be sufficient time for stabilization after an acute insult to allow accurate categorization.10 After an acute insult to the kidney, compensatory hypertrophy may gradually improve renal function, but this adaptation is generally maximal within three months. Renal dysfunction that persists after three months is typically not reversible. The term chronic kidney disease is preferred to chronic renal failure to accentuate the concept that renal disease may be present in the absence of azotemia. For azotemia to develop, over 75% of the nephrons must be lost.11
In this article, AKI and CKD are used to include pre-azotemic (disease) and azotemic (failure) conditions. Dogs and, especially, cats may have compensated CKD in which they exhibit no clinical signs until an acute uremic crisis is superimposed. This "acute-on-chronic" kidney disease may have clinical features of both AKI and CKD.
The diagnostic and therapeutic approach to AKI differs from the approach to CKD. With AKI, an aggressive diagnostic plan is recommended to uncover any ongoing process that requires a specific treatment in addition to supportive therapy. AKI frequently requires aggressive treatment in the hospital, whereas CKD may be treated on an outpatient basis in many cases.
Prognosis varies considerably between acute, chronic, and acute-on-chronic kidney disease. Giving clients prognostic information allows them to make informed decisions about their pets' care. In one study, 53% of cats survived an episode of AKI.12 Of these surviving patients, 47% were discharged from the hospital with a normal serum creatinine concentration, whereas the remaining 53% of surviving cats had persistent azotemia.12 Therefore, 25% of the total study population were discharged without azotemia.12 A similar study in dogs with AKI revealed comparable results in dogs, with 44% of the study population surviving to be discharged from the hospital.13 Nineteen percent of the total study population had creatinine concentrations that returned to normal.13 Although cure is impossible with CKD, long-term survival (i.e. years) is possible in many patients. Patients with acute-on-chronic disease may require aggressive treatment in the hospital but will have residual CKD requiring some degree of long-term management.
Obtaining a thorough clinical history is useful in determining the chronicity of a patient's kidney disease. Polydipsia and polyuria are classic signs of kidney disease but are not present in all cases. Their presence does not differentiate AKI from CKD, but their duration may help distinguish between the two. In one study, 70% of cats with CKD presented with an owner complaint of polydipsia and 31% with polyuria.14 The discrepancy in owners' reporting of polydipsia more frequently than polyuria is likely because owners are better able to detect abnormalities in water consumption than abnormalities in urination volume or frequency. About half of dogs and cats with AKI are oliguric or anuric.12,13,15
Decreased appetite, vomiting, or other gastrointestinal signs can be associated with both AKI and CKD, but these signs would be of recent onset with AKI. In one study, decreased appetite was present in 33% and vomiting in 22% of cats with CKD.14 Often these signs were waxing and waning for months. In addition to complete refusal of food, other common signs include taking longer to eat or showing interest in food without actually eating. Historical weight loss suggests chronic disease, although owners frequently do not recognize weight loss when it is slowly progressive and subtle. Compensatory mechanisms can mask a great degree of the patient's clinical signs at home, leading owners to miss subtle changes. The history should also include questions about exposure to medications (administered or accidental) or possible toxins.
A thorough physical examination can help differentiate between AKI and CKD. Initially, most patients with AKI without concurrent disease processes have a normal body condition. However, because kidney disease is a highly catabolic disease, muscle loss can occur rapidly. Although weight loss and poor body condition are not specific for kidney disease, a poor body condition with diffuse muscle wasting and an unkempt coat are often some of the first characteristics noted on physical examination of a patient with CKD (Figure 1). Palpation of the epaxial muscles often reveals subtle but marked muscle loss. Small, irregular kidneys on abdominal palpation support a diagnosis of CKD, while normal or large kidneys can be associated with either AKI or CKD.
Figure 1. A cat with poor body condition secondary to CKD. Note the generalized severe muscle wasting, including the epaxial muscles.
The prevalence of hypertension is 9% to 93% in dogs with CKD16-21 and 19% to 65% in cats with CKD.22-24 With AKI, 87% of dogs25 and 30% of cats are hypertensive (Worwag S, Langston CE, Unpublished data, 2009). Thus, the presence of hypertension does not distinguish between AKI and CKD. Because the eyes are a target of hypertensive damage, retinal examination is indicated in any patient with renal disease and is quick and easy to do with an indirect lens. The most common ocular manifestation of systemic hypertension is exudative retinal detachment.26 Retinal edema can be seen as an early manifestation of systemic hypertension and appears as "pseudonarrowing" of retinal arterioles. Dilation and tortuosity of retinal vessels, retinal hemorrhage, retinal detachment, and retinal degeneration are seen more commonly with chronic hypertension.26,27 Identification of any of these ocular signs should prompt blood pressure measurement. Ocular lesions are identified in between 48% and 100% of cats and 20% and 62% of dogs with hypertension.24,28-32 Hypertensive retinopathy tends to gradually progress with chronic hypertension, but an acute rise in blood pressure may precipitate an acute exudative retinal detachment or hyphema.27
Clinical signs of CKD may be less pronounced when compared with those of AKI with the same level of azotemia,33 although we have observed that some patients with early AKI have minimal clinical signs, which worsen over the subsequent several days if recovery is not prompt. As with the patient history, the physical examination is just one of multiple pieces in this clinical puzzle.
Although initial laboratory testing (a serum chemistry profile, complete blood count [CBC], and urinalysis) is essential to diagnosing kidney disease, these tests cannot, by themselves, differentiate between AKI and CKD. These two disease processes often have similar initial laboratory findings. But patients with results consistent with renal failure may have additional findings that support further characterization of the disease process as acute or chronic, such as an elevated parathyroid hormone (PTH) concentration.
Serum chemistry profile
Calcium concentrations. Hypercalcemia has traditionally been associated with CKD. It can develop in the presence of renal tertiary hyperparathyroidism, if the hyperplastic parathyroid gland autonomously starts secreting PTH despite normal to high serum ionized calcium concentrations. This only occurs with CKD. However, because ionized hypercalcemia can cause AKI and because hypercalcemia can also be secondary to either AKI or CKD, it is not useful in distinguishing between acute and chronic disease. No cats in one study of 32 cats with AKI were hypercalcemic (Worwag S, Langston CE, Unpublished data, 2009), although total hypercalcemia was present in 62.5% of dogs with AKI from grape or raisin intoxication and in 30% of dogs with AKI in another study.34,35 With CKD, 9% to 22% of dogs and cats have total hypercalcemia,17,35-39 whereas 0% to 30% have ionized hypercalcemia.14,35-37,40
Total hypocalcemia occurs in 7% to 23% of dogs with CKD,17,35,41,42 compared with 10% to 15% of dogs with AKI.37-39 In cats with CKD, 8% to 15% have total hypocalcemia, compared with 30% of cats with AKI (Worwag S, Langston CE, Unpublished data, 2009). Given these similar ranges for both AKI and CKD, total hypocalcemia cannot be used to differentiate acute from chronic kidney disease.
In the presence of CKD, the total calcium concentration is poorly predictive of ionized calcium, the metabolically active fraction.37 Thirty to forty percent of dogs and 10% to 26% of cats with CKD have ionized hypocalcemia.35,37,40,41,43 Data on ionized calcium concentrations in AKI are not available.
Unfortunately, because of the prevalence of both hypercalcemia and hypocalcemia with both acute and chronic kidney disease, the value of calcium concentrations in differentiating between acute and chronic kidney disease is quite low.
Evidence of a nonregenerative anemia on a CBC should trigger suspicion that the azotemia is long-standing. Seventy percent of dogs with CKD in one study presented with a nonregenerative, normocytic, normochromic anemia,44 compared with 25% of dogs with AKI presenting with anemia in another study.13 Erythropoietin is an important factor in replacing senescent red blood cells, and erythropoietin production decreases in the face of CKD. A relative or absolute erythropoietin deficiency leads to chronic, nonregenerative anemia. With severe AKI, erythropoietin production may be decreased, but anemia would not be expected to occur unless there is accelerated red blood cell loss (bleeding or hemolysis).
Conditions that contribute to anemia include low-grade hemolysis secondary to uremic toxin accumulation causing increased erythrocyte fragility; blood loss associated with platelet dysfunction, especially from gastrointestinal ulcers; and increased PTH concentrations inhibiting hematopoiesis.44 Patients with renal disease may have less severe clinical signs from anemia compared with patients with anemia associated with other disease processes, since concurrent increases in serum phosphate concentrations and erythrocyte 2,3-diphosphoglycerate concentrations may improve tissue oxygenation in the face of a lower hematocrit.44
Similar to the serum chemistry profile and CBC, urinalysis is indispensable in diagnosing kidney disease. However, it often does not shed enough light on whether the kidney disease is acute or chronic. An active urine sediment with evidence of pyuria, hematuria, bacteriuria, and proteinuria can be seen with either form of kidney disease. Renal epithelial cells may be present in a urine sample in a patient with AKI. However, it is not possible to definitively distinguish whether the cells originated in the kidney or lower in the urinary tract unless they are formed into casts.45 Occasional renal epithelial cells may be normal. However, larger numbers may indicate acute inflammation, infection, or neoplasia of the renal pelvis.45
Casts may be evident in both AKI and CKD and indicate active damage. Casts rapidly disintegrate, frequently precluding identification at the laboratory.46 Hyaline casts are present with acute or chronic proteinuria and may not represent marked renal pathology.43 Cellular casts are more common in AKI.43 White blood cell casts are usually associated with acute nephritis, pyelonephritis, or toxins that damage the renal tubular epithelium, and red blood cell casts often support a diagnosis of glomerulonephritis or renal hematuria,47 although both types of casts are uncommon in cats and dogs. Casts with kidney tubular epithelial cells signal tubular damage.48 Granular casts can be present in cases of AKI and are composed of cells that have degenerated such that the cell type cannot be distinguished.47 Fatty casts are course granular casts with lipid granules that are seen with glomerular disease or diabetes mellitus.47 Waxy casts indicate chronic renal tubular degeneration47 as they are the final stage of granular cast degeneration.46
Additional laboratory testing: PTH assay
An increased serum phosphorus concentration decreases the serum ionized calcium concentration, which stimulates secretion of PTH to return the ionized calcium concentration to normal. With progressive CKD, PTH concentrations tend to increase. In one study, 47% of asymptomatic cats with CKD had elevated PTH concentrations, compared with 100% of cats with severe end-stage CKD.14 In another study, 100% of dogs with CKD or AKI had elevated PTH concentrations.35 Although the mean PTH concentration was higher in the dogs with CKD compared with those with AKI, this difference was not significant.35
Radiography and ultrasonography can be useful tests in differentiating AKI from CKD as well.
An abdominal radiographic examination allows evaluation of renal size and shape. Normal canine kidneys should measure 2.5 to 3.5 times the length of the second lumbar vertebra in a ventrodorsal view.49 The kidneys of neutered cats should measure 1.9 to 2.6 times and the kidneys of intact male and female cats 2.1 to 3.2 times the length of the second lumbar vertebra on a ventrodorsal view.50
Small kidneys in comparison to the patient's size suggest CKD (Figure 2). One study showed 33% of cats with CKD had small kidneys, 40% had normal-sized kidneys, and 27% had enlarged kidneys.51 Renal asymmetry can be caused by chronic damage to one kidney leading to scarring, fibrosis, and small size with hypertrophy of the contralateral side. Acute obstruction of one kidney could lead to enlargement of that side with a normal-sized contralateral kidney, but azotemia would not be expected if the normal-sized kidney were functioning normally. An irregular renal contour can be caused by an acute or chronic infarction, cystic diseases, or, rarely, renal masses. Symmetrically enlarged kidneys suggest acute disease. Uroliths in the kidney or ureters indicate a chronic disease process but may have caused acute uremia from acute obstruction or pyelonephritis.
Figure 2. Radiographic examination can allow efficient evaluation of kidney size. In this ventrodorsal radiograph of a neutered male cat, the length of the L2 vertebra measures about 2.2 cm. The length of the right kidney measures about 4 cm, and the length of the left kidney measures 6.6 cm. The right kidney is slightly smaller than normal, and the left kidney is enlarged. This radiograph also reveals bilateral nephroliths (arrows) and an irregular margin to the right kidney. Bilateral ureteral obstructions secondary to proximal ureteroliths were diagnosed in this cat. Severe hydronephrosis of the left kidney and mild pelvic dilation were identified with ultrasonography. Evaluation of bone density throughout the radiograph is important in diagnosing any concurrent renal osteodystrophy secondary to renal secondary hyperparathyroidism. Radiography alone is 60% sensitive and 100% specific for detecting nephroliths or ureteroliths in cats.52 Ultrasonography alone is 77% to 100%53,54 sensitive and 33% specific,52 and the combination of radiography and ultrasonography is 90% sensitive.55
An abdominal ultrasonographic examination allows for the evaluation of kidney size, shape, and architecture. A normal feline kidney is about 3.8 to 4.4 cm in length and has no pelvic dilation.56 Ultrasonographic determination of renal volume (by measuring renal length, width, and depth) and the ratio of renal length to aortic diameter have been evaluated to determine normal renal size parameters in dogs.57 Although both the renal volume and the ratio methods provide some utility, the amount of normal variation is large, especially in very small or very large dogs, and these techniques are not commonly used.54,57
During an ultrasonographic examination, CKD will frequently appear as small irregular kidneys with hyperechoic cortices and decreased corticomedullary distinction (Figure 3). Pelvic dilation, renal mineralization (nephrocalcinosis), or nephroliths may also be present. Renal asymmetry, with one small and one normal or large kidney, suggests chronic disease of the small kidney, but the contralateral kidney may have chronic disease (e.g. compensatory hypertrophy, hydronephrosis from obstruction) or acute disease (acute obstruction, pyelonephritis, ischemic or toxic insult). Renal cysts typically denote chronic disease.58 The kidneys may appear structurally normal in the presence of CKD.
Figure 3. Ultrasonographic images of cats with diseased kidneys. Panel A: Normal renal shape and internal architecture with good corticomedullary distinction in a cat with AKI. Panels B and C: Reduced corticomedullary distinction (arrowheads), renal asymmetry (right larger than the left), irregular renal contour bilaterally, and a caudal infarct on the left kidney (flattened caudal pole, arrow) in a cat with CKD.
In the presence of AKI, the kidneys may appear normal or may be enlarged, hydronephrotic, and hyperechoic on ultrasonographic examination. Perinephric fluid generally is associated with acute disease.59 Enhanced corticomedullary distinction does not distinguish between acute or chronic disease, nor does the presence of a medullary rim sign (a hyperechoic band at the corticomedullary junction), which has also been seen in normal animals.56 Decreased cortical echogenicity can be seen in both acute and chronic renal disease.56 Varying degrees of renal pelvic dilation or ureteral dilation occur with partial or complete obstruction, which can be acute or chronic.
Ultrasonographic examination can also be used to evaluate the size and echogenicity of the parathyroid glands. In CKD, chronically increased phosphorus and decreased calcium concentrations stimulate chronic increases in PTH production. This renal secondary hyperparathyroidism leads to parathyroid gland hyperplasia. In one study, parathyroid glands in dogs with CKD were larger (2.8 to 7.1 mm) than parathyroid glands in healthy control dogs or dogs with AKI (1 to 3.5 mm).60 Parathyroid gland size varies with patient size. Although ultrasonographic examination of the parathyroid gland is not part of the routine evaluation of patients with kidney disease in most practices, it is helpful to determine chronicity in experienced hands.
Fibrosis, sclerosis, and atrophy are histologic indicators of chronicity of injury.61 Because these changes are irreversible, renal biopsy rarely affects the management or outcome of CKD.62 Biopsy is typically reserved for suspected cases of AKI when a diagnosis cannot be confirmed by less invasive testing, and it is used to attempt to definitively diagnose histologic lesions causing protein-losing nephropathy, providing appropriate technique is used. Fibrosis and other evidence of chronicity may not be uniformly distributed throughout the kidney, so biopsies may miss the lesion. It is prudent to inspect a core biopsy with a dissecting microscope to ensure that at least 10 glomeruli have been collected. If the sample is insufficient, additional tissue should be collected.
Good-quality kidney biopsy samples are more likely to be obtained in anesthetized patients compared with those that are only sedated.63 A complication rate of 13.4% in dogs and 18.5% of cats was noted in one large study.62 Ten percent of dogs and 17% of cats required transfusion because of post-biopsy hemorrhage, and 2.5 % of dogs and 3% of cats died.62 Renal function does not decrease in healthy dogs and cats after unilateral renal biopsy.64,65
Various other tests have been investigated to help distinguish between AKI and CKD but are not commonly used in veterinary medicine. An elevated urea concentration causes hemoglobin to become carbamylated, and this abnormal hemoglobin accumulates over time within red blood cells. The carbamylated hemoglobin concentration can be correlated to the duration of azotemia. In one study, CKD was accurately diagnosed in dogs with a carbamylated hemoglobin concentration exceeding 108 µg of valine hydantoin per gram of hemoglobin with a positive predictive value of 71.2%.66 If the blood urea nitrogen concentration is not elevated, this test will not be predictive.
The creatinine concentration at the distal end of the fingernails is another method for differentiating AKI and CKD in people. Nails do not change in their chemical makeup after they leave the cuticle.67 Fingernail growth from proximal to distal end takes about three months.67 Therefore, the creatinine concentration at the distal tip indicates the creatinine concentration three months before, with a false positive result rate of 6.12% with no false negative test results.67 To our knowledge, no veterinary study has evaluated toenail creatinine concentrations.
Identifying whether a patient's kidney disease is acute or chronic in origin is not always easy. All the clinical evidence must be evaluated. In our experience, a long-standing history of clinical signs consistent with kidney disease, poor body condition, and identification of small, irregular kidneys are the most useful in confirming that kidney disease is chronic. In the absence of these findings, evaluation of other parameters such as PTH concentration or parathyroid gland size, presence of anemia, presence of urinary casts, presence of uroliths, renal ultrasonographic architecture, and renal biopsy may be used to further characterize the disease and may, in aggregate, help differentiate acute from chronic disease. Differentiating between AKI and CKD in each patient will ensure that the patient is getting optimal care and that clients are well-informed about their pets' condition to make optimal decisions.
Meghan Myott, DVM
Cathy Langston, DVM, DACVIM
The Animal Medical Center
510 East 62nd St.
New York, NY 10065
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