Accurate clinical evaluation of renal function can be accomplished by a series of diagnostic procedures.
Physical examination and a complete history of the patient are important in the diagnosis of renal failure, most signs are relatively non-specific. Important in differentiating acute from chronic disease.
Examination of urine and blood samples is therefore essential in the diagnostic process.
Normal urine production is the total effect of glomerular and tubular function.
Function tests will be discussed under glomerular and tubular function although there is some overlap since disease in one unit of this closely linked system ultimately affects the other.
This approach is a guide to the investigation of renal disease and, although examples of tests are quoted, the lists are by no means complete.
At present there is no specific or repeatable test that can quantify the effects of renal ageing.
Seizures (uremic encephalopathy in advanced renal failure).
Ascites (rare).
Dyspnea (uremic pneumonitis (rare)).
Clinical examination
Palpation of kidney size and shape:
Small kidneys may indicate chronic renal failure .
Large kidneys may indicate acute inflammation , hydronephrosis , cystic renal disease , amyloidosis or neoplasia .
Renal pain is associated with acute inflammation.
Lingual ulceration.
Muscle wastage.
Evidence of:
Hypertension.
Retinopathy.
Heart murmur.
Laboratory Investigation
Where history and clinical signs are suggestive of renal disease, or in a particular breed with a predisposition to congenital renal disease, or a general health screen suggests renal involvement, further evaluation of renal function is necessary.
Try to answer the following questions:
Is there evidence of early renal damage?
Is the damage affecting primarily the glomerular or tubular system?
Is there evidence of renal failure?
If so is it acute renal failure or chronic renal failure ? (Important as acute renal failure is potentially reversible).
What is the prognosis?
Is there evidence of renal failure?
Initial measurement of urea or creatinine may be sufficient to identify gross renal failure.
Examining urine for presence of protein, cells and casts. Protein, cells and casts are also influenced by integrity of tubules.
Glomerular disease may occur in absence of isosthenuria and azotemia.
Clearance tests
Renal clearance of a substance is the volume of plasma that contains the amount of substance excreted in the urine in one minute.
Compounds used in this determination must be excreted entirely by the kidney and undergo no appreciable tubular resorption.
Suitable compounds include: insulin, mannitol, calcium EDTA, creatinine, iohexol and technetium DTPA - see renal clearance component for details . The use of the first three is limited, due to practical and technical difficulties.
Blood urea and creatinine
Urea and creatinine are normal constituents of plasma that enter the urine by glomerular filtration.
Increased levels of these substances in the blood are generally indicative of a reduced GFR.
Disadvantages:
Levels may be misleading in acute renal failure as blood levels rise slowly in first few days despite severe reduction in GFR.
Poor sensitivity - only useful in detecting reduced GFR if 75% of renal function is lost.
Broad ranges of normal values, ie BUN and creatinine in upper half of normal range can reflect normal renal function in one animal and markedly decreased function in another.
Blood urea can be influenced by extrarenal factors:
False increase: any process inducing protein catabolism, eg fever, burns, infection, starvation.
False decrease: reduced protein metabolism, eg anabolic steroid administration.
Creatinine is less influenced by extrarenal parameters but can be altered:
False decrease: can be the result of a reduced muscle mass.
False increase: ageing of postal samples.
Advantages: clinicians usually familiar with these parameters, and they are easy to measure.
Creatinine clearance test
Creatinine clearance may be used as an endogenous test but has inherent errors and has been superceded by exogenous creatinine clearance test.
Advantages:
Provides more accurate information about renal function, particularly in early stages, than serum, or plasma urea, or creatinine.
Disadvantages:
Not able to distinguish between prerenal and renal disease.
Not as practical to carry out in small animal medicine as in human medicine due to the laborious timed task of urine collection.
Fractional electrolyte excretion
Electrolyte excretion (sodium, potassium and phosphate) gives measure of GFR.
Proteinuria
Proteinuria may be the result of glomerular loss or reduced tubular absorption.
Non-renal causes of proteinuria must be excluded by clinical assessment of likelihood of cystitis, etc.
Laboratory tests for assessing proteinuria include:
Dipstick .
Sulfosalicylic acid.
Trichloracetic acid.
Ponceau S and Coomassie blue.
Each test has a different sensitivity and specificity for detecting various types of urine protein.
In practice the dipstick colorimetric tests for protein is inexpensive, but is only a semiquantative analysis.
Dipstick testing is more sensitive to albumin, and false positives occur with highly alkaline urine or if dipstick left in urine for too long.
False negatives occur with Bence Jones proteinuria, or very dilute, or acidic urine.
Clinical relevance of proteinuria is often difficult to judge and requires the evaluation of several parameters including:
Urine specific gravity .
Urine pH .
Urine sediment examination.
Urine protein/creatinine ratio
This is a quantitative test that has superceded 24 hour urinary protein determination, since the latter procedure is cumbersome in small animal practice.
In advanced proteinuria the protein:creatinine ratio is of less diagnostic value because of progressive hypoalbuminemia.
The magnitude of protein:creatinine ratio may be used as a rough guide to suggest the origin of protein loss:
SDS polyacrylamide gel electrophoresis may be useful to detect and localize renal lesions in cats with proteinuria.
Electrophoretic patterns are classified as typical for glomerular, tubular or mixed, based on appropriate molecular weight and number of silver stained protein bands.
Urinary fibrin degradation products
Where the main lesion is in the glomerulus, ie in other forms of juvenile nephropathy, glomerulonephritis and renal glomerular amyloidosis in older animals, this test may also prove useful.
In the absence of any disturbance to normal water intake, the measurement of specific gravity of urine will give a general indication of the concentrating ability of the tubules.
Urine SG is a useful indicator when taken in conjunction with clinical evidence of the presence/absence of oliguria/anuria or polyuria.
Urine osmolality operates on similar principle to SG, except SG is influenced by additional factors including molecular size and weight. Inadequate urine concentrating ability indicates renal function has been reduced.
Urine SG is determined by refractometry using only a small amount of urine.
Advantages:
Simple and cheap.
Disadvantages:
Interpretation is hindered by broad physiological ranges.
Insensitive - no changes in urine SG until significant amounts of renal function lost.
Puppies and kittens cannot concentrate urine to same extent as adults.
Electrolytes and other blood parameters
Fractional excretion of sodium can be used as a sensitive indicator of tubular function which is probably under-utilized in veterinary medicine.
Solutes, including hydrogen, potassium, phosphate, and magnesium, rise significantly in acute renal failure.
With chronic renal failure the generally insidious nature of this condition permits the development of compensatory mechanisms, and biochemical changes often tend to be relatively unspectacular except in terminal stages.
Water deprivation/vasopressin tests
Water deprivation test is used to rule out non-renal causes of hyposthenuria.
Antidiuretic hormone (ADH), from the neurohypophysis, targets renal collecting ducts, results in water reabsorption, ie concentrates urine.
The neurohypophysis, renal collecting tubules, and hypertonic renal medulla must all be functional for this to occur.
Used to differentiate diabetes insipidus and apparent psychogenic polydipsia in conjunction with water deprivation test.
It is of paramount importance that this test must only be used in absence of confirmed primary renal pathology, ie no azotemia.
A reduction in urine concentrating ability occurs when 66% of renal nephrons are non-functional.
Patients with glomerular disease can be azotemic and yet retain ability to concentrate urine if glomerular involvement is more severe than tubular involvement.
Urine sediment
Sediment analysis allows identification of components essential to diagnosis of urogenital system disease, which might not otherwise be detected:
Protein:creatinine ratio has to be interpreted in context of urine sediment as this may elevate the ratio, particularly if there is hematuria or inflammatory sediment.
Urine dipstick analysis - if blood present check sediment for blood cells.
Quantitative enzymuria
Damaged renal tubular epithelium releases various enzymes into the urine.
Levels are normally low and elevation occurs before other signs of renal disease are evident, either by clinical examination, or routine urine analysis including BUN/creatinine.
Enzymes include:
Aspartate aminotransferase (AST).
Isocitric dehydrogenase (ICHD).
Lactate dehydrogenase (LDH).
N-Acetyl B-D-glucosaminidase (NAG), which is the most stable and useful when samples have to be posted to laboratory.
Fresh uncontaminated urine is essential.
The NAG is localized predominantly in the lysozymes.
The NAG:creatinine ratio is used to eliminate the variance in urine volume production.
Advantages: detect renal injury before azotemia or isosthenuria develop.
Para-amino-hippuric acid (PAH)
Sensitive test to measure renal tubular function but not commonly used in small animal medicine.
Supportive biochemical tests
Hyperglycemia :
Mild, due to insulin antagonism by urea.
Marked, with diabetes mellitus and secondary renal disease.
Hepatic enzymes:
Mild increases of ALP and ALT , secondary to circulatory changes.
Increased ALP can be present in renal secondary hyperparathyroidism .
Total plasma protein :albumin :
May have hypoalbuminemia .
Globulin : normal or hyperglobulinemia.
Cholesterol :
Increased: in nephrotic syndrome .
Calcium: usually low in renal failure but may increase terminally.
Hypercalcemia may be a cause of renal failure.
Lipase and amylase : may be increased due to reduced renal excretion in renal failure.
Electrolyte concentrations, particularly potassium , should be monitored in animals with suspected renal dysfunction as polyuria and reduced renal resorption from tubules may result in 'washout' of solutes.
Hematology
Anemia may be present.
Normally normocytic, normochromic, non-regenerative anemia in CRF.
Lymphopenia may be present in renal disease.
Endocrine assay
PTH measurement is particularly important in hypercalcemic patients to establish etiology of hypercalcemia.
Erythropoietin is produced by kidneys, and concentrations may be reduced in patients with significant renal dysfunction.
Other laboratory tests
FeLV and FIV status should be ascertained in all cases.
Investigation for FIP may be appropriate if there is clinical evidence to support this diagnosis.
Cytopathology
Fine needle aspirate cytology from the kidney may prove diagnostic in cases of lymphoma .
Imaging
Radiography
Useful to determine size of kidney:
Small suggests chronic renal failure.
Large suggests neoplasia , polycystic renal disease , or hydronephrosis .
Intravenous urography
Contrast uptake in the nephrogram phase is reduced in animals with renal dysfunction.
Intravenous urography (IVU) should not be routinely performed in animals with known renal dysfunction.
It may be necessary to perform an IVU to identify the etiology of renal disease, although this has largely been superceded by renal ultrasonography.
Ultrasonography
Used to examine renal architecture, and may give indication of function, ie resistive index of arcuate arteries.
Scintigraphy
Can provide accurate assessment of the GFR but is only available at specialist centers.
Renal biopsy
May provide information about pathogenesis of disease and etiology, except in cases of 'end stage' renal failure.
Is the failure acute or chronic?
What is the prognosis?
At present renal biopsy may not be able to answer these questions but increasing the exposure of pathologists to renal biopsies, and providing them with long-term follow-up, can only increase our understanding of the diseases involved.
Blood pressure monitoring
Cats with renal disease are frequently hypertensive .
Blood pressure monitoring is now a relatively routine procedure.
Cats should be examined for other evidence of hypertension, eg retinal vessel hemorrhage or hypertrophic cardiomyopathy.
Analysis of the reciprocal of the serum creatinine concentrations versus age can provide a forecast of the course and termination of renal disease or improvement.
Projection of the regression line to the abscissa predicts the patients age at time of death attributable to renal failure.
This assumes that renal disease is necessarily progressive, which is controversial.
Proteinuria:
Protein:creatinine ratio alongside serum albumin are useful in advanced cases with progressive hypoalbuminemia.
Important in differentiating acute from chronic disease.
The use of the first three is limited, due to practical and technical difficulties.