Diagnosing and Measuring Kidney Failure

How can kidney failure be diagnosed?

Kidney disease can be detected by imaging techniques, such as X rays of the abdomen, sonograms of the kidneys, or intravenous pyelograms. But with the exception of X rays, which might show small kidneys (indicating the presence of renal failure), imaging techniques are ordered only if kidney disease is already suspected. Thus these techniques are not generally a means of detecting kidney disease, even though they can be definitive if kidney failure is already suspected. The best screening test for chronic renal impairment is on a sample of blood. Let's find out why blood constituents change in concentration in early kidney failure.

Urine contains hundreds of known constituents. A few of these are produced in the kidney, but the vast majority are derived from the blood. Day after day, each of these constituents is being added to the bloodstream continuously, either derived from the diet or produced by the metabolic activity of one organ or another, and is then removed by the kidney at the same rate (on average). Thus the concentration in the blood of each constituent fluctuates around some average value. Long term, the rate at which each of these urinary constituents appears in the bloodstream is the same as the rate at which it is being excreted. So even if there are short-term fluctuations in the level in the blood, the average concentration, over time, tends to be constant.

Consider now what would happen if one kidney were removed. The remaining kidney would excrete any given constituent at a rate half as great as did two kidneys before. The constituent would therefore accumulate in the body, causing a progressive rise in its concentration in the blood and in its rate of excretion. Eventually, a new steady state would be reached, such that the rate of production of the substance by the body (or rate of its addition to the body by the diet) would again be equal to its rate of excretion, at least on a daily basis. We would find that its concentration in the blood is twice normal, and we therefore could infer that kidney function was one-half of normal. If its measured concentration in the blood were four times normal, we would infer that kidney function was one-quarter of normal. If the measured concentration were five times normal, we could infer that kidney function was one-fifth of normal, and so forth.

This reciprocal relationship is very useful in the evaluation of kidney disease. Measurement of some such constituent in the blood is essential to assessing how well the kidneys are working. Unfortunately, no ideal substance for this purpose has been identified yet, and all such measurements are subject to some error.

For the results to come out as predicted by the reciprocal relationship described earlier, two conditions must be met:

1. The rate at which the constituent is entering the bloodstream

(from diet or from metabolism) would have to be constant from day to day, and fluctuations in its production rate would have to be minor.

2. Exact proportionality would have to exist between the concentration of the constituent in the blood and its rate of excretion by the kidney. More precisely, the ratio of the excretion to blood concentration (known as clearance) would have to be a constant at any level of kidney function.

No known constituent meets these requirements. However, a few come close.

The substances that come closest are not naturally occurring constituents but they can be injected. Obviously they also must be nontoxic. It is hoped that their only fate in the body is removal by the kidney; that is, no other organ metabolizes them to any significant extent. (This last condition turns out to be the hardest to meet.)

Inulin, a sugar polymer obtained from the Jerusalem artichoke, was the first such substance identified. The earliest quantitative studies of kidney function, 75 years ago, were made with the aid of inulin. Several other substances subsequently have been identified that meet the required conditions for this use, some radioactive and some nonradioactive. They are known as glomerular filtration markers. These other substances are usually employed in place of inulin, because inulin is difficult to obtain, difficult to work with, and difficult to measure. When one of these glomerular filtration markers is infused intravenously at a constant rate, its concentration in the blood and its rate of excretion in the urine gradually increase until a steady state is reached. At that point the rate of filtration by the glomeruli and rate of excretion in the urine are exactly equal to the marker's rate of infusion. The more glomeruli are operative, the lower the final concentration. If total kidney function is halved, the final concentration in the blood is doubled, and so forth.

The time required for the final concentration to be achieved depends on the amount of kidney function. In a healthy person, it takes several hours; in someone with severe kidney failure, it may take as long as two days. Because the marker substance must be infused continuously throughout this time, the patient must wear a constant infusion pump on a belt, attached to an intravenous line.

How can we use the known rate of infusion of this substance and its final steady-state concentration to determine the rate of glomerular filtration? Since the concentration of the marker in the filtrate is the same as its concentration in blood plasma, the amount of filtrate formed per unit of time, in ml per minute, is simply the excretion rate (or infusion rate) of the marker divided by this final concentration. This quotient is the volume of fluid having a concentration the same as this final plasma concentration. This volume of fluid is being formed in each unit of time. Called the glomerular filtration rate (GFR), it is the only good measure of the amount of kidney function remaining.

Normally GFR is about 100 ml per minute. In kidney failure, GFR decreases progressively; when it gets below 5 to 10 ml per minute, dialysis or transplantation is necessary for survival.

We have also described the principle of renal clearance: The rate of excretion of any substance divided by its plasma concentration is its plasma clearance. The clearance of glomerular filtration markers is the glomerular filtration rate. If a substance is also added to the tubular fluid by tubular secretion, its clearance will be greater than the GFR. If a substance is partially reabsorbed by the tubules, its clearance will be less than the GFR. Some of the substances recommended for measuring various aspects of kidney function have clearances that are greater or less than the GFR.

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