Renal disease is a common problem in small animal practice and one of the challenges for the practitioner is to diagnose the presence of renal dysfunction at an early stage. Early diagnosis of renal dysfunction in our patients would allow practitioners:
To protect their patients from treatments that may damage further nephrons and tip them into the clinical stages of renal failure
To instigate renoprotective management regimens at an early stage
To advise owners on familial renal conditions
The reason early diagnosis is a challenge is because the kidney has considerable functional reserve so that standard laboratory tests for renal function can only detect abnormalities once more than 66% of functioning renal tissue has been lost. Precise evaluation of renal function would also allow more effective monitoring of the rate of decline of renal function over time and help determine the efficacy of a therapeutic intervention.
Routine biochemical tests of renal function
Traditionally, plasma biochemical markers of renal dysfunction have been used in the diagnosis of renal disease. These markers accumulate when glomerular filtration rate (GFR) falls. Plasma creatinine is the most reliable. Its production is determined by the muscle mass of the animal. Its rate of excretion depends primarily on GFR since it is freely filtered, not reabsorbed from the filtrate and not secreted to any great extent into the tubule. Non-renal routes of excretion are minor.
Unfortunately, the plasma creatinine concentration is not linearly related to GFR. As the plasma concentration increases so does the rate of passive excretion hence the relationship is an exponential one. Until GFR has fallen below 30% of normal, the plasma concentration of creatinine may remain in the laboratory reference range. Part of the reason for this is that the laboratory reference range has to be broad because we deal with animals within a given species with very variable muscle mass. Ideally, for dogs, reference ranges for creatinine should be established for different breeds. Cats often lose muscle mass with age and a plasma creatinine concentration at the top end of the reference range in an old cat with a low body condition score may well indicate quite severe renal dysfunction.
Serial plasma creatinine measurements over time in the same animal provide more information about the renal function than a single, one-off measurement. This would be particularly true if, each time the plasma creatinine concentration is measured, body weight and body condition score was measured so that muscle mass can be factored into this assessment. More precise methods of measuring body composition will become available in the future and could make serial measurement plasma creatinine concentration a more sensitive marker of changes in renal function over time.
Assessment of renal concentrating ability
In addition to excretion of waste products, one of the important functions of the kidney is to balance water intake with water losses from the body. A normal dog, when deprived of water, should be able to concentrate its urine to a specific gravity (USG) of around 1.060 whereas cats, which are even more adapted to conserve water, can maximally concentrate up to 1.080. It is often said that one of the earliest functions that is lost by the kidney in the face of significant renal disease is the ability to concentrate the urine. If other diseases or the use of drugs which compromise renal concentrating ability have been ruled out, and a urine sample is obtained from a dog after an overnight fast has a USG of <1.025 it is highly likely that its renal function is abnormal. In the cat the equivalent figure often quoted is <1.030. However, it has been shown experimentally that cats retain urine concentrating ability after removal of substantial amounts of renal tissue. Nevertheless, in mild naturally occurring feline renal disease, most animals have USGs of <1.030.
Assessment of tubular function
In the early stages of renal disease when the number of tubules has declined, there are compensatory changes that go on to mask the fall in GFR. These adaptations result in hyperfiltration and hypertrophy of the remaining functioning nephrons. In addition, in order to maintain balance of minerals and electrolytes, the excretion of substances, such as phosphate and potassium increase per remaining nephron so that the body remains in balance.
If creatinine excretion is used as a marker for GFR, the rate of excretion of a mineral or electrolyte relative to creatinine can be used to assess the way the tubule is handling that substance. Thus, if the fractional excretion of phosphate was 30%, this means that 30% of the filtered load of phosphate was excreted (and 70% reabsorbed). Some commercial laboratories have offered measurement of fractional excretion of phosphate as a test, which they claim, will act as an indicator of early renal dysfunction. If plasma and urine samples are taken at the same time and phosphate and creatinine measured in both, calculation of the fractional excretion of phosphate is simple. However, there are two problems associated with this test. Firstly, the fractional excretion of phosphate is highly variable depending on the diet. Thus, the laboratory reference range for the cat varies from 10 to 70%. Secondly, measurement of this parameter on a spot urine sample is much less accurate that making a 24 hour urine collection. This is because excretion varies over time throughout the day depending on whether the animal has just eaten or is in a fasted state. Studies in the dog have suggested that fractional excretion of phosphate is actually a less sensitive marker of renal dysfunction than measurement of plasma creatinine alone.
Assessment of proteinuria
When a disease has resulted in loss of functioning nephrons and the remainder hypertrophy and hyperfiltrate, loss of increasing amounts of albumin across the glomerular membrane may occur as a result. Some renal diseases lead to damage to the glomerulus and damaged nephrons will leak more proteins leading to proteinuria. The former situation is likely to give rise to loss of very small amounts of protein in the urine and require a very sensitive assay to detect it accurately. The latter will give rise to gross proteinuria and will be detectable with conventional dip-stick methodologies.
Measurement of the urine protein to creatinine ratio (UPC) is one method of assessing loss of protein in the urine. On a spot sample, it has been shown to give a reasonable reflection of the 24 h urine protein excretion rate. If the urine protein is less than 0.65 g/l on a dipstick test, regardless of the USG, it is probably not worthwhile measuring the UPC because it is likely to be in the reference range. However, if the protein concentration is >0.65 g/l it is worthwhile investigating by measuring a UPC. In the absence of evidence of urinary tract inflammation, a UPC of >1 is abnormal for the dog and >0.5 is abnormal for the cat. Gross proteinuria indicating glomerular disease can occur in the absence of azotaemia and will give rise to UPCs often >5. Most cats with chronic renal disease have very mild urinary protein loss until the very severe end stages of the disease when UPCs are often above 1. The prevalence of significant glomerular disease is higher in the dog.
Sensitive methods of measuring albumin in urine allow detection of microalbuminuria. This level of proteinuria would remain undetectable by standard dip-stick methods. Albumin is immunologically distinct between species and ELISA assays have to be developed for each species. Measurement of microalbuminuria is an indicator of glomerular hypertension and hyperfiltration and is also a reflection of tubular capacity to reabsorb the filtered albumin. Tests have been developed for the dog and cat but their value as markers for sub-clinical renal disease remains to be determined.
Measurement of glomerular filtration rate
The gold standard method of assessing renal function is to measure GFR by exogenous administration of a marker. Initially such tests relied on measuring the rate of excretion of the marker in the urine during an infusion of the test substance which maintained the plasma concentration at a stable concentration. As such, this test was not applicable to small animal practice as timed urine collections were cumbersome and invasive. These methods have now been adapted to enable a single bolus dose of the marker to be administered and, provided the marker distributes rapidly into extracellular fluid and glomerular filtration determines its rate excretion, measuring the rate of disappearance of the marker from the plasma can be used to determine the GFR. A number of suitable markers have been proposed (e.g., iohexol, inulin or creatinine). The one most likely to be available for the general practitioner is inulin. If a source of sterile inulin of medical grade can be found, a standard dose can be injected, a minimum of three blood samples taken up to 1 to 3 hours following the injection and submitted to a laboratory by mail for analysis. GFR can be calculated from the dose administered and the rate of decline of inulin concentrations. The accuracy of the dose administered, the timing and number of the blood samples taken and the method used for measuring inulin will all influence the accuracy of the result.
This type of assessment of renal function could be used for early diagnosis of renal disease and in the monitoring of renal function in an azotaemic animal where long-term treatment is being administered. Such a test would not be indicated for an acutely sick animal that had suddenly become azotaemic or acutely decompensated from a previously stable but chronically azotaemic state. The value of such methods over serial measurements of plasma creatinine concentrations for monitoring the progression of chronic renal disease remains to be determined in clinical cases although direct measurement of GFR, if applied appropriately, should be a more effective monitoring tool. If consistent protocols can be agreed, a true assessment of the rate of progression of chronic renal disease and the effects of various interventions on this progression could be assessed in multi-centre clinical trials.