Renal function: which parameter to choose?
If the nature of kidney function were to be defined, it would probably be considered that the main role of the kidney is to maintain homeostasis of the inner environment. However, there is no obvious parameter that directly quantifies this role. In addition, the kidney also has a distinct metabolic role (eg, secretion of erythropoietin or hydroxylation of (OH) -vitamin D. Despite this complexity, it has been shown, in particular due to the nephron theory that the glomerular filtration rate is a parameter that reflects well the renal function and it is therefore the glomerular filtration rate (GFR) that is conventionally accepted as the operational parameter of this function Although there are some cases of decoupling, most renal diseases affect both glomeruli and tubules, and glomerular function and tubular function are linked by the double mechanism of glomerulotubular (positive) balance and Since it is much easier to measure the glomerular function reliably, it is the latter that is considered as the ference.
Some authors have suggested using other parameters such as renal plasma flow (DPR) or renal plasma flow (RPF).There are two problems with this. On the one hand, it is not easily measurable, for lack of a purely secreted tracer with a constant extraction coefficient; the fraction of filtration of the tracers used is subject to considerable intra- and inter-individual variations, both under pathological circumstances and even within a physiological framework. On the other hand, and even more fundamental, the DPR itself is subject to large physiological fluctuations. Moreover, since the kidney adapts to a large extent to the variations of the DPR by maintaining the DFG constant, it is the latter that is recommended to be measured.
Absolute function, relative function:
In most cases, it is useful to measure the absolute global renal function, that is, the GFR of both kidneys in a grouped manner. In routine, this absolute function is roughly estimated by the plasma creatinine assay; as soon as a more accurate and accurate measurement is useful, a radioisotope clearance measure must be performed.
Sometimes it is useful to measure the separate function of the kidneys, that is, the respective share of each of them in the overall function. If the technique of reference is to catheterize the ureters to make a separate collection of urine, it is virtually never practiced because of its invasiveness and is in practice replaced by a scintigraphic measurement.The relative proportion of the kidneys can be determined by scintigraphy.
It is only the combination of the two examinations (clearance and scintigraphy) that reliably measure the absolute individual function of each of the kidneys. Note that the measurement of an individual function makes sense not only to distinguish the right kidney part and the left kidney part, but also to distinguish between transplanted kidneys and native kidneys when the latter retain a function part.
This part therefore deals with the isotopic techniques of measurement of the total (or absolute) renal function by the techniques of clearance, plasma or urinary. This document is consistent with international consensus on the subject, which dates from 1996 and 1999, but is still relevant.
The association of a clearance with a renal scintigraphy (which allows the determination of the relative function, ie the respective percentage of function of each of the kidneys) makes it possible to know the individual value of the function of each kidneys.
One of the main roles of the kidney is to keep the volume of extracellular fluids constant. To achieve this function, fine regulation of several physiological processes occurs in the different regions of the nephron and in particular in the glomerular filtration, reabsorption and secretion of electrolytes and small molecules in the tubule, and finally in the process of concentration-dilution of the final urine.
The precise knowledge of the pharmacokinetics of radiotracers used for the radioisotopic measurement of renal function is essential for the interpretation of the results as well as knowledge of the limits of the techniques used.
Let us recall first of all that the glomerular ultrafiltration of a molecule, and therefore of a radiopharmaceutical, depends essentially on four factors:
• the hydrostatic pressure difference between the glomerular capillaries and that of the Bowman space;
• the effective surface area of filtration, reduced in chronic kidney disease;
• the intrinsic physicochemical characteristics of the molecule studied (molecular mass, size, surface electric charges);
And the binding of the latter to plasma proteins, and in particular to albumin.
Passive or active transport mechanisms perform the functions of reabsorption or secretion of electrolytes and small solutes in the various segments of the renal tubule.
If secretion phenomena play a major role in the elimination of certain tracers, such as organic anions (PAH, MAG3, IOH, LL-EC, etc.), reabsorption systems for available radiotracers. Proximal secretion is provided by an antiport located on the basolateral side of the proximal tubular cell which allows the entry of the organic anion in exchange for a dicarboxylate, alpha-ketoglutarate. The coupling of this anion exchanger with an Na + / dicarboxylate cotransporter and the Na + K + adenosine triphosphatase (ATPase) pump provides the energy required to maintain the process. At the apical pole, the organic anions diffuse passively according to their concentration gradient in the tubular lumen (anion exchanger and / or facilitated diffusion). This secretion is therefore relatively stereospecific, saturable and above all can be inhibited by competitive agents such as probenicide.
Like all other radiopharmaceuticals (medicines with marketing authorization [AMM]), the tracers used clinically for the evaluation of renal function are composed of a carrier molecule and a gamma-emitting radionuclide allowing its external detection. The three main radionuclides used are 99m Tc, iodine 123, 125 or 131 and chromium 51. From a pragmatic point of view, diagnostic radiopharmaceuticals can be classified into four groups:
• those for the evaluation of renal plasma flow, for example in the monitoring of renal transplants;
• those that allow the measurement of the glomerular filtration rate;
• those who rate “renal function”;
• and those which allow the diagnosis of kidney damage during infectious or tumoral processes.
Tracers for the measurement of the glomerular filtration rate:
The characteristics of the ideal plotter for this measurement are:
• purity and radiochemical stability;
• no pharmacodynamic or toxic, renal or systemic effects;
• freely filtered molecule without reabsorption or renal tubular secretion;
• lack of plasma protein binding; ease of dosage in plasma and urine.
The radiotracers used are thus small molecules (PM <5,000), hydrophilic, having a very low affinity for plasma proteins. Inulin has long been the benchmark for this measure, but the occurrence of anaphylactic reactions has led to its withdrawal, limiting its use to animal testing. Two tracers, with an extraction coefficient close to 20% at the first passage and a very small dosimetry, are currently available:
• Technetium 99m or 99m Tc-DTPA labeled diethylene pentaacetic acid, used both for scintigraphy and for functional explorations;
• Chromium 51 or 51 Cr-EDTA-labeled ethylene diamine tetraacetate, reserved for functional explorations.
The results reported in the literature concerning the binding to plasma proteins are discordant because they are based on different methods (ultrafiltration, gel filtration, in vitro or in vivo plasma measurement) but this fixation remains low.For ultrafiltration methods, correction of the Donnan effect must be taken into account since the labeled EDTA and DTPA are charged at physiological pH.
Diethylene-penta-acetate ( 99m Tc-DTPA):
DTPA, an octahedral complex insoluble in lipids and carrying two negative charges at pH 7, was initially used as a chelating agent for heavy metals before being used in nuclear medicine from 1970. DTPA is essentially eliminated by glomerular filtration without reabsorption nor tubular secretion, as demonstrated by the microponent and microperfusion work in vivo in the rat. A very small extrarenal excretion (<5%) has been reported by some authors.The main limitations to its use are a variable plasma protein binding (up to 10%) – hence a tendency to underestimate GFR – and the need for rigorous adherence to kid preparation conditions (low stability 99m Tc-DTPA complex, reduction of complex formation in the case of traces of other competitive heavy metals, delay between preparation and injection). The latest kits sold have improved stabilities. These limitations are, however, offset by ease of preparation of the kit, low cost and good reproducibility of GFR measurements.
The 99m Tc-DTPA clearance has an excellent linear correlation with other GFR reference methods, with a ratio of 0.92 to 0.97 in the literature.
Ethylenediaminetetraacetate ( 51 Cr-EDTA):
Used since 1966, this hydrophilic chelator, stable in vivo and in vitro, has a high radiochemical purity and low binding to plasma proteins; it is only filtered without capturing by the tubular cells. Its extrarenal clearance is very low and at 24 hours, we find only less than 1% of the radioactivity injected. Its low dosimetry justifies its use in both adults and children.
Urinary clearance of 51 Cr-EDTA is approximately 5% lower than that of inulin but due to the existence of an extrarenal excretion, plasma clearance of 51 Cr-EDTA is very close to clearance of inulin. Although readily available in Europe, this tracer is not marketed in the United States.
We shall only mention iothalamate, a contrast agent for radiographic examinations, the labeling of which with iodine 125 or 131 allows the use as a tracer for the study of glomerular function. Unfortunately, a variable and non-negligible fixation of plasma proteins (up to 15%), variable tubular secretion with renal insufficiency, and an extrarenal elimination make it difficult to interpret results for this agent, marketed as North America.
Tracers for the evaluation of renal plasma flow:
The leader of these products is amino-hippuric acid (PAH), an organic anion that undergoes a very large first-pass extraction in the kidney by glomerular filtration ( ≈ 25%) and by proximal tubular secretion ( ≈ 75%). This very high renal clearance is therefore an excellent indicator of “effective” renal plasma flow.
Ortho-iodo-hippurate or hippuran ( 123 I-OIH):
Analogue of PAH, ortho-iodo-hippurate or hippuran (OIH) labeled with iodine 123 or 125 has been widely used as a reference tracer. Its use is nevertheless limited by considerations related to radiochemistry (risk of radiolysis, cost and availability of iodine 123). Above all, the process of secretion of OIH and PAH is a secondary active transport dependent on Na + reabsorption; this explains the competitive inhibition of this transport observed with probenecid, but also with antibiotics, antimitotics or nonsteroidal antiinflammatory drugs (NSAIDs). Finally, if hippuran, labeled with iodine-131, which is more irradiating, is available, the hippuran, marked with iodine 123, currently has no MA in France.
Mercapto-acetyl-triglycine ( 99 Tc-MAG3):
Mercapto-acetyl triglycine (MAG3) is a lipophilic polar complex which contains a carboxyl group of pKa 4.27, hence its anionic form at blood pH. The hippuran and the MAG3 share a group of close spatial configuration. This explains why MAG3 is also secreted via the organic anion transport (OAT) in the tubular cells of the distal part of the proximal tube, as demonstrated by the microponent work in the rat. Very highly bound to plasma proteins, this radiotracer has a coefficient of renal extraction of approximately 60%, mostly by tubular secretion (90% of extraction in rats and 95% in humans) and very weakly by glomerular filtration (5 to 10%). Note that the renal tubule has a higher secretory capacity for the OIH than for the MAG3.
Hepatobiliary elimination is responsible for the majority of the extrarenal excretion, of the order of 10%, which can sometimes induce visualization of the liver and the gallbladder during MAG3 renal scintigraphies in humans. The preparation of this radiopharmaceutical from the commercial kit requires a fresh technetium 99m eluate and heating at 100 ° C for 10 minutes; poor compliance with the procedure may lead to a higher level of impurities, resulting in increased hepatobiliary excretion.
The limits to its use are variability in the level of impurities during the preparation of the kit and the great variability of the extraction coefficient, which is lower than that observed with the OIH. Nevertheless, the advantages of MAG3 are its 99m Tc labeling, which means ease of supply, and images of the renal parenchyma and the excretory tree of higher quality than those obtained with the OIH, allowing a satisfactory study ureteral drainage and possible reflux.
Ethylenedicystine ( 99 Tc-L, L-EC):
This polar metabolite of ECD, a tracer used for cerebral perfusion, has been the subject of numerous preclinical and clinical studies but has no MA in Europe or the United States. It is likely that EC is secreted by the same tubular transporter as MAG3 and OIH.
Tracers for the evaluation of “renal functional mass”:
Dimercaptosuccinic acid ( 99 Tc-DMSA):
The chemical structure of the technetium DMSA is not completely elucidated. The complex is composed of several isomeric forms, the meso form for 90% and the enantiomers (d, l) for 10%. Technetium is at the degree of oxidation T (III) in the renal complex formed at acid pH. In the case of partial reduction, the complex formed of type T (V) will have an essentially osseous and not renal tropism.
The precise intrarenal fixation of DMSA is still under discussion, despite numerous biodistribution, microponent and autoradiographic studies. DMSA accumulates in the renal cortex with negligible activity in the medulla and papilla (cortex / medullary ratio of about 22). The radiotracer is found in the cytoplasm of the proximal tubular cells.Glomerular filtration of DMSA is very low. Capture of 99 Tc-DMSA is saturable and dependent on urinary pH; it is altered in pathologies of the proximal tubule (Fanconi’s syndrome) and in renal toxicities induced by gentamicin, cis-platinum or ifosfamide. This suggested tubular reabsorption of DMSA but was never directly measurable, particularly during in vivo microperfusions in rats. The majority of the experimental work favors the extraction of DMSA from the peritubular fluids as the main mechanism of capture. DMSA is extracted very little extrarenally, especially in the liver. It can be increased in patients with renal insufficiency, urine acidification or impurities in the preparation.
Because of its residence time, DMSA is a radiopharmaceutical of choice for obtaining images of the renal cortex with high resolution. Indeed, although the rate of transfer of blood to the renal parenchyma is relatively low, the uptake reaches a plateau of approximately 50% of the dose administered 2 hours after the injection.
Measurement of the absolute function:
To measure the glomerular filtration rate (GFR), a freely filtered substance (ie relatively small molecular weight), non-secreted and non-reabsorbed, must be available. It must also be non-toxic and readily determinable.
The most commonly used substance is an endogenous substance: creatinine. Unfortunately, it does not ideally meet the above criteria: it can be excreted by tubular secretion, its dosage is neither standardized nor precise and its endogenous production variable, both between individuals and over time in a given individual. It therefore raises serious methodological problems in order to derive a reliable value from GFR.
In clinical routine, the estimate of renal function is usually provided by the plasma creatinine dosage.
Formulas estimating GFR from serum creatinine (Cockcroft and Gault and more recently MDRD for adult, Schwartz and Counahan and Barratt for the child) are considered to be more reliable than simple serum creatinine, and even the urinary clearance of creatinine, little reproducible.
Due to the limited availability of GFR measurement techniques, the French Consensus Conference routinely recommends the use of GFR estimation methods. However, the same consensus conference states that “20 to 35% of patients admitted to dialysis are referred to nephrologists less than 6 months before the dialysis …
This late nephrological management has negative consequences for the patient. The results given by the Cockcroft and Gault estimate are both biased (from 9 ml min -1 on average) and imprecise (with a standard deviation of 16 ml min -1 ): the rendered value therefore has an interval confidence at 95% of 64 ml min -1 of width, which corresponds to the normal function of a kidney! It should also be noted that after nephrectomy in a patient without renal insufficiency, it is usual to observe that creatinine levels do not increase or little (and therefore GFR estimated by the Cockcroft and Gault formula or by the formula MDRD, does not diminish or little …). It must therefore be noted that this simple dosage does not allow early detection or reliable monitoring of renal insufficiency. Finally, the Cockcroft and Gault formula is inadequate for obese or elderly subjects. It should also be noted that there are many techniques for the determination of serum creatinine, the results of which are not always consistent. A recent French study concludes that, in the present state, the variability between the different assay techniques makes it impossible to estimate GFR from serum creatinine. Similarly, the validity of the MDRD approach is still very much discussed in the United States.
Exogenous tracers: Is the isotopes still useful for the measurement of renal function?
Among the exogenous substances, one can distinguish the “cold” tracers: mainly inulin and iohexol and the radioactive tracers. The historical reference technique (inulin clearance) is no longer feasible in France, as inulin is no longer marketed as a human drug, unlike glomerular radiopharmaceuticals ( 51 Cr-EDTA and 99m Tc-DTPA) . The injected activities for the determination of GFR are minimal and result in negligible irradiation (of the order of that induced by a chest x-ray). They have no toxicity (unlike iodinated contrast media such as iohexol).
Their dosage is extremely sensitive and therefore allows accurate measurements. Isotopic techniques, on the other hand, have the disadvantage that they are currently limited to specialized centers. However, they remain the only current way to measure (and not simply to estimate) a parameter as important as renal function. We therefore believe that they have a role to play, including in routine practice.
Among the radiotracers, the reference substance is 51 Cr-EDTA. This tracer has great stability both in vivo and in vitro.It is readily available in Europe, but this is not the case in all parts of the world (not marketed in the United States).This tracer has a slightly lower urinary clearance (about 5%) than that of inulin (probably due to its negative charge); it also has a low extrarenal clearance (of the order of 4 ml min -1 ). These two imperfections compensate and, finally, the plasma clearance of 51 Cr-EDTA is very close to the inulin clearance.
The typical activity injected for an examination is 7 MBq.
99m Tc-DTPA is also an excellent tracer provided that it has verified the absence of binding to the proteins of the preparation used. Indeed, the published studies diverge on the rate of binding to proteins. The activity usually injected for a clearance is of the order of 10 MBq. If more is injected, a dynamic renal scintigraphy can be performed at the same time.
Diatrizoate is not used in France. Some iodinated contrast media are sometimes used: iohexol is in particular a non-radioactive glomerular tracer whose clearance can provide an accurate measurement of GFR provided that it is assayed by high performance liquid chromatography (HPLC), heavy technique, assay by fluorescence being simpler but not providing the necessary precision.
A clearance can be determined either by the disappearance of the plasma substance (plasma clearance) or by renal uptake (scintigraphy) or finally by the appearance of the substance in the urine (urinary clearance).
Urinary clearance is sometimes referred to as renal clearance (although it should be noted that although renal and urinary clearances are synonymous with glomerular tracers, this is not the general case: for example, DMSA is partially filtered and partly captured, without secretion, by the tubular cells: its renal clearance thus exceeds its urinary clearance). Clearance is defined as the imaginary flow of totally purified plasma of a substance. This can be expressed as the urinary output corrected for the ratio of urinary to plasma concentrations:
Cl = UP
Where V is the urine flow and U and P the respective concentrations of the tracer in urine and plasma. For example, if the substance is twice as concentrated in the urine as in the plasma, each liter of urine corresponds to the purification of 2 l of plasma. If renal blood flow is rated F, the extracted tracer flow rate is:
UV = FP A – P V (2) where P A and P V are the arterial and venous concentrations of the tracer. The extraction coefficient, defined as the ratio of arteriovenous difference to arterial concentration,
E = P A – P V P A (3) characterizes the propensity of an organ to extract a substance.
From equations (1), (2) and (3), it can be concluded that the clearance is given by:
Cl = EF (4)
The clearance is therefore the product of renal plasma flow and its extraction coefficient (which characterizes its own effectiveness).
This is the reason why clearance is a good parameter to characterize the function of the kidneys in their actual infusion state. It is as if the role of the kidney was to extract the creatinine (or any other glomerular tracer) from the plasma. Of course, it should be kept in mind that this is only a way of quantifying function and that the role of the kidney is to preserve homeostasis. The plasma flow rate varies much more than the clearance and control phenomena compensate for variations in flow rate by opposite variations of the extraction coefficient so as to maintain, to a large extent, the constant DFG.
According to equation (1), for a correct measurement, the clearance C and the plasma concentration P must be constant during the measurement. Although there are nycthemeral variations of DFG, they are of low amplitude and generally slow compared to the durations of the urinary collection periods. In order not to increase the variation of GFR, the subject must avoid significant efforts or absorption of animal proteins during or just before the measurement.To limit the variation of P, two protocols are possible:
• either a direct intravenous injection (IVD) followed by urinary collections with blood sampling for short periods (during which P is assumed to be relatively constant);
• Continuous perfusion to reach a plateau for P.
It is even possible to use a subcutaneous injection (a technique used in the United States with iothalamate).
The interest of these urinary techniques is that only kidney excretion is taken into account (the possible capture by another organ not introducing bias): these techniques are therefore very just. Their disadvantage is the need for urinary collection, which induces large fluctuations due to non-negligible bladder residues, even for normal subjects (the reference technique for reliable urinary collection requires urethral catheterization and bladder washing with air insufflation to empty the bladder, this is obviously never used in practice!).
In order to limit the fluctuations, it is essential to carry out the measurement on several consecutive urinary collections which are then averaged. Urinary flow should also be sufficient (in principle above 3 ml min -1 , any value less than 1 ml min -1 invalidating the measurement). It has also been proposed, in the case of DTPA, to monitor gamma-camera urination in order to estimate the bladder residue. Finally, it should be noted that urinary techniques do not take intrarenal and ureteral transit time into account (this is of little practical importance except during the first few minutes following the injection of the tracer).
Urine clearance after single injection:
After injection of the tracer, the DFG is calculated over several successive periods according to the formula (1) with urinary collections and plasma samplings. The final result is given by the average of the values obtained over each period. The dispersion of the values (standard deviation) indicates the precision obtained. In practice :
• the patient must remain relatively at rest without significant effort;
• the patient should not absorb animal protein just before or during measurement;
• Correct hydration is desirable (eg 7 ml kg -1 per os at the start of the test with subsequent compensation of volume-to-volume losses);
• urine output should be controlled and ideally greater than 3 ml min -1 . Any period for which the flow rate is less than 1 ml min -1 shall not be taken into account in the final calculation;
• the injection is conventionally made in IVD as an embolus; however, any other type of injection remains valid; in particular, extravasation of tracer does not invalidate the technique;
• at least three urinary collections must be performed with strict timing (typically 30 to 60 minutes);
• collections typically begin 1 hour after injection and continue for several hours;
• Plasma samples should be collected approximately in the middle of the urinary collection periods.
Continuous perfusion urinary clearance:
For this technique, the plasma concentration is virtually stable, in the plateau, once the steady state is reached.
The principle is the same as for the urinary technique in single injection, except for the mode of injection: an infusion is carried out at constant rate. This technique, which is slightly heavier, has the advantage that the assumption of stability of P during the collection periods becomes more realistic, which improves the accuracy of the measurement. In addition, dynamic tests (basic measurement and after stimulation), detailed below, are made possible by this technique. Details of the injection are given in the box opposite.
Under the assumption that the disappearance of the plasma tracer and its appearance in the urine are equal, a technique of plasma clearance can be used instead of a technique of urinary clearance. We gain in simplicity and precision but we lose in accuracy since there can exist an extrarenal clearance of the tracer. In practice, if the kidney function is not collapsed and apart from the cases of ascites, edema or third sector, the bias due to the extrarenal clearance remains negligible. Plasma techniques are therefore widely used.
Plasma clearance in continuous infusion:
The principle of this technique is similar to that of urinary clearance. Simply, instead of determining the urine flow of tracer U Å ~ V, we consider the perfused flow of tracer noted R. This approach becomes valid as soon as the tracer reaches a steady state, that is to say when one reaches a plateau of plasma concentration of the tracer. The inputs (R) are then equal to the outputs (U Å ~ V). The clearance is then simply:
Cl = RP (5)
In practice, it is therefore necessary to carry out plasma sampling until a plateau of concentration P is obtained. The infusion pump must be correctly calibrated and, above all, have a constant flow rate. The specific activity of the perfused solution can be obtained by “infusing” count tubes under identical conditions. In order to speed up the preparation of the tray, it is advisable to start the test by injecting a loading activity.
Example: assuming that the standard 3 ml tubes contain 450,000 cpm, the specific activity of the perfused solution is 150,000 cpm ml -1 . If the perfused flow rate is 40 ml h -1 , ie 2/3 ml min -1 , the value of R is 100,000 cpm min -1 . A plasma plateau at 2000 cpm ml -1 then corresponds to a clearance of:
Cl = R
P = 100,000 cpm / min
2,000 cpm / ml = 50 ml / min (6)
This technique is extremely robust and greatly limits the risk of significant error. It also has the advantage of allowing dynamic tests: after the determination of a first base tray, a second tray can be measured under test conditions.
The disadvantage of the technique is that it requires perfusion to the patient for 4 to 5 hours. Furthermore, the accumulation of tracer impurities in the plasma can moderately bias the results. Finally, due to the presence of slow-release compartments, plasma clearance may overestimate urinary clearance. This technique is often presented as cumbersome and difficult to implement. However, the specific equipment required (a continuous flow pump) is available in many clinical departments; moreover, after a few months of adaptation, the nurses who realize this technique do not consider it more burdensome to implement than the techniques in single injection.
Dynamic tests (measurement of the basic glomerular filtration rate and after stimulation):
Measurement of the glomerular filtration reserve involves a basic measurement of DFG followed by a second measurement under dopamine stimulation and / or neoglycogenic amino acids: arginine, glycine, histidine, methionine, proline, serine. Similarly, it may be useful to determine if there is a decrease in DFG under ACE inhibitor.
For these dynamic techniques imposing the measurement of GFR under two different conditions, it is necessary to use a continuous infusion method.
External detection methods:
The methods of external detection, whether in dynamic scintigraphy or static scintigraphy, are reserved for the determination of the relative function. Attempts to use scintigraphy to measure absolute renal function have not led to the development of a reliable method.
An external detection technique can also be used to determine relative changes in short-term GFR. This technique makes it possible to record the variations in the slope of decrease of plasma concentration of the tracer. It does not provide a DFG value, but allows the study of the influence of various factors (eg perfusion of sympathomimetics) on renal function.
The normal DFG depends on the corpulence of the subject. It is therefore conventionally related to body surface area (SC). In 1916, with eight adults and two children, Dubois and Dubois published a formula for estimating the surface area of the skin. Other formulas have since been published without a real consensus emerging for one formula over another. Curiously, and without any real physiological justification, this parameter, combining size and body mass, has become a reference both to normalize parameters like DFG and to adapt the doses of certain drugs. This normalization is done in the following way:
Normalized DFG = crude DFG Å ~ 1.73m 2 SC (27)
Alternatively, it has been proposed to normalize GFR with respect to VEC. For this purpose, it was proposed to use an uncorrected monoexponential technique, in which the VEC was given by Q / B and the DFG by Q b / B; the DFG related to the VEC then simply corresponds to the factor b of the exponential, which is the inverse of a time constant.This approach has the advantage of simultaneously getting rid of the need for a determination of injected activity and standardization.
However, it does not take into account the fact that the monoexponential model is only an approximation: the GFR reported to the VEC is therefore not simply given by b but by:
VEC = b B + b A 2 B + b 2 A (28)
In addition, it incorrectly suggests that GFR would regulate the VEC alone or that the GFR would adjust to the VEC.Finally, in certain circumstances, the VEC may vary quite rapidly; for example, the effect of diuretics in a water-overloaded patient is a significant decrease in VEC, without the need for sustained change in GFR; the DFG / VEC ratio increases without improvement in renal function; the effect is much less pronounced when normalized in relation to body surface area which is much less subject to variation (in a medium-sized adult, a loss of 4 l results in a decrease of about 25% in the VEC but only 2% of SC).
A similar approach has been proposed using fractional uptake rate (FUR). Another uses only the slope of plasma decay determined during clearance, without the need to determine the activity injected. To our knowledge, no publication reports an evaluation of this method by other teams, but our experience is not convincing. Finally, we recommend that the CS standardization approach be maintained despite its imperfections.
For such a review, it is quite difficult for a laboratory to build up a base of normal subjects. Although it has been used for several decades, relatively few original publications provide normal values for 51 Cr-EDTA clearance: normal values are around 105 ml / min / 1.73 m 2 with a difference -type of the order of 15 ml / min / 1.73 m 2 . There does not appear to be a sex-related difference when GFR is related to body surface area. On the other hand, there is a marked increase in GFR relative to body surface area between 0 and 2 years. The senile evolution of the GFD is manifested in one third of the cases by a stability, in a third of the cases by a modest decrease and in a third of the cases by a frank decrease. The normal values measured by inulin clearance can also be used.
Choice of method:
In summary, techniques by external detection alone (such as the Gates method) are even less precise than the creatinine-derived formulas; they should not be used. The only valid approach is the tracking of DFG variations by external probe, but this technique gives only relative variations without any absolute value of function. Of course, scintigraphic studies remain essential for the measurement of relative function. Urinary clearances are accurate but somewhat imprecise. Plasma clearances are accurate, although less accurate than urinary clearances. Among the plasma clearances, biexponential techniques are cumbersome to implement and must be reserved for research studies; in practice, one can thus choose a monoexponential method or a single, simpler but less robust method of sampling; these methods have a precision and accuracy of about 5 ml min -1 . Continuous perfusion techniques are useful when robustness or dynamic study is preferred.
In all other cases, a single injection plasma method is sufficient. The choice is then to make a single sampling method (which is advised by the international consensus with the Christensen and Groth formula) or to improve the robustness by choosing a monoexponential method (with the Brochner-Mortensen formula, which is recommended by the British consensus). In case of hyperfiltration, it is preferable to use the formula of Chantler rather than that of Brochner-Mortensen. In all cases, sampling times should be adjusted to the predictable value of GFR.
Absolute renal function:
In daily practice, renal function estimation is performed by measuring serum creatinine. Using a formula such as Cockcroft and Gault or the MDRD study improves the estimate. However, this calculation does not lead to a fair measurement of GFR; in particular, it is difficult to demonstrate early renal insufficiency using creatinine. Once greater reliability is desired, the only technique that can be used is the measurement of an isotopic clearance.
Relative renal function:
Two main situations can be distinguished in which the determination of relative renal function is useful:
• when a condition is unilateral or asymmetrical, the existence of a functional asymmetry to the detriment of the affected side is a sign of functional impairment, hence severity of the attack; this is particularly the case in obstructive or refluxing uropathies as well as in the sequelae of pyelonephritis;
• when nephrectomy is considered, accurate assessment of the function of the remaining kidney may be required.
In the case of unilateral severe involvement (pyelonephritis, obstructive uropathy, renascascular disease, etc.), the question of preserving or sacrificing the affected kidney may arise; the individual GFR value above which the kidney is preserved is between 10 and 20 ml / min / 1.73 m 2 .
In the case of kidney cancer, it may be useful to predict the functional consequences of nephrectomy, especially in the case of bilateral or renal failure. The precise knowledge of the functional distribution can guide the choice of the intervention and in particular push to realize a partial nephrectomy.
The determination of absolute renal function, a fundamental parameter in human pathophysiology, can only be roughly evaluated by current, non-isotopic biological techniques. An illustration of this point is that serum creatinine generally increases only very shortly after nephrectomy. Since the disappearance of inulin for in vivo use in humans, isotopic clearance techniques ( 51 Cr-EDTA or 99m Tc-DTPA) have become the reference techniques.
Although they are not available in all centers, they remain quite simple, rapid (a few hours) and are very little irradiating. They can be coupled to a dynamic renal scintigraphy ( 99m Tc-DTPA or 99m Tc-MAG3) or static ( 99m Tc-DMSA) to determine the relative functional role of the two kidneys.