**7.1 Physiological and analytical data**

Iothalamate is an ionic contrast product which was particularly used for urography. Iothalamate is derived from the tri-iodobenzoic acid. Its molecular weight is 637 Da (Schwartz et al., 2006) and it is freely distributed into the extracellular volume (Visser et al., 2008). From a historical point of view, iothalamate was not the first contrast agent used to measure GFR. Other derivates from tri-iodobenzoic acid had been tested at the end of the fifties. Diatrizoate (Hypaque) was proposed by some authors as a potential GFR marker because it is fully excreted by the kidneys (Meschan et al., 1963; Burbank et al., 1963; Stokes et al., 1962; Mcchesney & Hoppe, 1957). However, other authors suggested that

2001; Russell et al., 1983; Jeghers et al., 1990). For example, Rehling found a binding to protein of 10-13% but this author was also the only one who found a significant and comparable binding to protein for 51Cr-EDTA and iothalamate (Rehling et al., 2001). The subject is finally still debated (Jeghers et al., 1990). Another potential critic about 99Tc-DTPA is the very poor available data on its physiological handling. A study in a dog model argued

There are hopefully much more clinical studies comparing 99Tc-DTPA with other markers. After the preliminary study published by Hauser (Hauser et al., 1970), the performances of 99Tc-DTPA clearance was studied from the seventies. Klopper may be considered as one of the pioneers with this markers (Klopper et al., 1972). The first studies were however comparing 99Tc-DTPA with iothalamate and the samples were limited (Table 6)(Klopper et al., 1972; Rootwelt et al., 1980). The first study comparing 99Tc-DTPA with inulin was published in 1984 (Rehling et al., 1984). In table 3, we resumed the results of studies comparing 99Tc-DTPA with the gold standard method in adults. Two studies have compared with good statistical methods the urinary clearance of 99Tc-DTPA and inulin. In the study published by Lewis in 1989, the bias was excellent bias (near to 0) but the precision was not satisfying (± 18 mL/min)(Lewis et al., 1989). One year later, Perrone showed excellent concordance between urinary clearances of 99Tc-DTPA and inulin in 13 chronic kidney disease (CKD) patients. However, the results were less impressive in the 4 healthy subject where 99Tc-DTPA clearances overestimate (+12 mL/min) inulin clearances. Definitive conclusion about the performance of 99Tc-DTPA plasmatic clearance is difficult to

99Tc-DTPA presents the advantages and inconvenient of other isotopic methods (see 51Cr-EDTA paragraph). The dosage of the marker is relatively cheap and precise. His short halftime makes it a few less practicable than 51Cr-EDTA. Among the most important advantages of 99Tc-DTPA, we underline the fact that it is the only marker that can be coupled with nephrogram to give separated function between the two kidneys (Durand et al., 2006). Physiological data to confirm its role as a reference marker are however clearly lacking. We also think that global performance of 99Tc-DTPA compared to inulin is probably a few less than the 51Cr-EDTA, especially with plasma clearances (at least in part because 99Tc-DTPA is

Iothalamate is an ionic contrast product which was particularly used for urography. Iothalamate is derived from the tri-iodobenzoic acid. Its molecular weight is 637 Da (Schwartz et al., 2006) and it is freely distributed into the extracellular volume (Visser et al., 2008). From a historical point of view, iothalamate was not the first contrast agent used to measure GFR. Other derivates from tri-iodobenzoic acid had been tested at the end of the fifties. Diatrizoate (Hypaque) was proposed by some authors as a potential GFR marker because it is fully excreted by the kidneys (Meschan et al., 1963; Burbank et al., 1963; Stokes et al., 1962; Mcchesney & Hoppe, 1957). However, other authors suggested that

for the absence of tubular secretion and reabsorption (Klopper et al., 1972).

draw and we clearly need additional studies on this topic.

**6.3 Strengths and limitations**

binding to proteins).

**7.1 Physiological and analytical data** 

**7. Iothalamate** 

**6.2 Clinical data** 


How Measuring Glomerular Filtration Rate? Comparison of Reference Methods 33

Sigman et al., 1965b). For this author, the binding of iothalamate to protein is less than 3% (Sigman et al., 1965b). Such result was confirmed by most of the authors thereafter (Anderson et al., 1968; Gagnon et al., 1971; Blaufox & Cohen, 1970; Prueksaritanont et al., 1986; Back et al., 1988b), except for Maher and Rehling (see 99Tc-DTPA chapter)(Rehling et al., 2001; Maher & Tauxe, 1969). Rapidly, Sigman has proposed to move from labeling with I131 to labeling with I125. I125 is actually more stable (Elwood & Sigman, 1967; Maher et al., 1971). I125-Iothalamate is thus an isotopic method which is precise and safe. The half-life of 125I is 60 days (Perrone et al., 1990). Physiological data on iothalamate have been published after the first clinical studies by Sigman. Iothalamate was then studied in aglomerular fishes and only 3% of injected iothalamate was found in urine. The absence of tubular secretion and reabsorption was confirmed in a dog model (Griep & Nelp, 1969). However, these reassuring results were not confirmed by Odlind in 1985. This author actually observed in rats a tubular secretion of iothalamate (comparing with 51Cr-EDTA and using inhibitors of tubular secretion). In the same view, Odlind described, in 6 healthy subjects, that iothalamate clearance overestimates inulin clearance and that this overestimation is reversible after inhibition of tubular secretion by probenecid (Odlind et al., 1985). In anephric patients, Cangiano described an extra-renal excretion of iothalamate that reached 4 to 8 mL/min. This extra-renal excretion fall to 0 after thyroid saturation by iodine (Cangiano et al., 1971). A potential limited extra-renal clearance of iothalamate was thus suggested in the thyroid. Evans described a clearance of iothalamate of 3.1±1.8 mL/min in 7 dialysis patients (among these, 5 were anuric). In animal models, a limited biliary excretion is suggested by some authors (Owman & Olin, 1978; Prueksaritanont et al., 1986). Comparing the total (i.e. plasma) and the renal clearance of iothalamate in healthy subjects, Back calculated the extra-renal clearance at 6 mL/min (Back et al., 1988b). In the same experience, Dowling calculated extra-renal clearance at 10 ml/ml, which was constant for all the GFR levels (sample of 26 patients)(Dowling et al., 1999). In this last study, the plasma clearance was measured until 180 min, which may be considered as too short (Dowling et al., 1999). Visser has also calculated the urinary excretion of iothalamate on 24 h and estimated the extra-renal excretion at 14±12% (Visser et al., 2008). Such values of extra-renal clearances are thus not so negligible, especially when it is considered in patients with severe CKD. Actually, the relative importance of this extra-renal clearance will be higher when the GFR is yet low

Iothalamate is a safe product but, of course, it will be not used in subjects presenting a known "true" allergy to contrast products (Heron et al., 1984). Regarding the isotopic method, the radioactive dose got by the patient is also very low (lower than the dose got for

Because its relatively low molecular weight, iothalamate is a good marker (just like 51Cr-EDTA) to be used in simplified protocols. Cohen was the first to use the bolus method instead of the constant rate infusing method in 1969 (Cohen et al., 1969). Several authors have showed that iothalamate could be used in plasma clearance (LaFrance et al., 1988; Welling et al., 1976; Back et al., 1988b; Gaspari et al., 1992) even if results are not fully comparable to urinary clearances (Agarwal et al., 2009). It must also be underlined that iothalamate is the only one marker which is frequently used with subcutaneous injection (Israelit et al., 1973). It had actually been shown that plasma iothalamate concentrations remain constant 60 to 90 min after a subcutaneous injection (so, equivalent to the constant

thorax radiography)(Hall & Rolin, 1995; Bajaj et al., 1996).

(Visser et al., 2008).


Table 3. Studies comparing 99Tc-DTPA with inulin. NA: not available, CKD: chronic kidney disease subjects, BA: Bland and Altman analysis, BAr: Bland and Altman analysis recalculated by us, BM: Brochner-Mortensen.

diatrizoate (as other derivates from tri-iodobenzoic acid) was secreted by renal tubules (Woodruff & Malvin, 1960; Harrow, 1956; Winter & Taplin, 1958). In 1961, Denneberg is the first to compare diatrizoate labeled with l131 and inulin in human (Denneberg et al., 1961). This author described a higher renal excretion and then confirmed that diatrizoate is secreted by renal tubules (Denneberg et al., 1961). Diatrizoate was still studied by some authors in the next years but the interest has definitively moved from diatrizoate to iothalamate (Burbank et al., 1963; Morris et al., 1965; Dalmeida & Suki, 1988; Owman & Olin, 1978; Donaldson, 1968).

As we will describe in the next paragraph, interest in iothalamate as a GFR marker has grown from the mid-sixties with the studies proposed by Sigman (Sigman et al., 1965a;

±5 to 130 Inulin:

2 to 69 Inulin:

15 NA ±25 to 160 Bolus and

Table 3. Studies comparing 99Tc-DTPA with inulin. NA: not available, CKD: chronic kidney disease subjects, BA: Bland and Altman analysis, BAr: Bland and Altman analysis re-

diatrizoate (as other derivates from tri-iodobenzoic acid) was secreted by renal tubules (Woodruff & Malvin, 1960; Harrow, 1956; Winter & Taplin, 1958). In 1961, Denneberg is the first to compare diatrizoate labeled with l131 and inulin in human (Denneberg et al., 1961). This author described a higher renal excretion and then confirmed that diatrizoate is secreted by renal tubules (Denneberg et al., 1961). Diatrizoate was still studied by some authors in the next years but the interest has definitively moved from diatrizoate to iothalamate (Burbank et al., 1963; Morris et al., 1965; Dalmeida & Suki, 1988; Owman &

As we will describe in the next paragraph, interest in iothalamate as a GFR marker has grown from the mid-sixties with the studies proposed by Sigman (Sigman et al., 1965a;

urinary clearance and constant infused rate 99Tc-DTPA urinary clearance with bolus

plasma clearance for inulin and 99Tc-DTPA: 6 samples within the first hours, 3 or 4 samples between 2 and 4 h

urinary clearance and constant infused rate 99Tc-DTPA urinary clearance with bolus

Wilcoxon or t-test Correlation

P<0.001

from 0.93 to 0.98 Day 1 +0.5±3 Day 2 -2±3

Inulin (day 1 and 2): 108±14 96±8 99Tc-DTPA (day 1 and 2) 122±24 108±17

> 0.85 =1.12x

=0.98x-0.4 0.98

BA

Correlation Regression

Correlation Regression

 (Perrone et al., 1990)

(Wharton, III et al., 1992)

(Gunasekera et al., 1996)

13

CKD

Healthy

2 successive days

18 Intensive care and CKD

calculated by us, BM: Brochner-Mortensen.

Olin, 1978; Donaldson, 1968).

4

Sigman et al., 1965b). For this author, the binding of iothalamate to protein is less than 3% (Sigman et al., 1965b). Such result was confirmed by most of the authors thereafter (Anderson et al., 1968; Gagnon et al., 1971; Blaufox & Cohen, 1970; Prueksaritanont et al., 1986; Back et al., 1988b), except for Maher and Rehling (see 99Tc-DTPA chapter)(Rehling et al., 2001; Maher & Tauxe, 1969). Rapidly, Sigman has proposed to move from labeling with I131 to labeling with I125. I125 is actually more stable (Elwood & Sigman, 1967; Maher et al., 1971). I125-Iothalamate is thus an isotopic method which is precise and safe. The half-life of 125I is 60 days (Perrone et al., 1990). Physiological data on iothalamate have been published after the first clinical studies by Sigman. Iothalamate was then studied in aglomerular fishes and only 3% of injected iothalamate was found in urine. The absence of tubular secretion and reabsorption was confirmed in a dog model (Griep & Nelp, 1969). However, these reassuring results were not confirmed by Odlind in 1985. This author actually observed in rats a tubular secretion of iothalamate (comparing with 51Cr-EDTA and using inhibitors of tubular secretion). In the same view, Odlind described, in 6 healthy subjects, that iothalamate clearance overestimates inulin clearance and that this overestimation is reversible after inhibition of tubular secretion by probenecid (Odlind et al., 1985). In anephric patients, Cangiano described an extra-renal excretion of iothalamate that reached 4 to 8 mL/min. This extra-renal excretion fall to 0 after thyroid saturation by iodine (Cangiano et al., 1971). A potential limited extra-renal clearance of iothalamate was thus suggested in the thyroid. Evans described a clearance of iothalamate of 3.1±1.8 mL/min in 7 dialysis patients (among these, 5 were anuric). In animal models, a limited biliary excretion is suggested by some authors (Owman & Olin, 1978; Prueksaritanont et al., 1986). Comparing the total (i.e. plasma) and the renal clearance of iothalamate in healthy subjects, Back calculated the extra-renal clearance at 6 mL/min (Back et al., 1988b). In the same experience, Dowling calculated extra-renal clearance at 10 ml/ml, which was constant for all the GFR levels (sample of 26 patients)(Dowling et al., 1999). In this last study, the plasma clearance was measured until 180 min, which may be considered as too short (Dowling et al., 1999). Visser has also calculated the urinary excretion of iothalamate on 24 h and estimated the extra-renal excretion at 14±12% (Visser et al., 2008). Such values of extra-renal clearances are thus not so negligible, especially when it is considered in patients with severe CKD. Actually, the relative importance of this extra-renal clearance will be higher when the GFR is yet low (Visser et al., 2008).

Iothalamate is a safe product but, of course, it will be not used in subjects presenting a known "true" allergy to contrast products (Heron et al., 1984). Regarding the isotopic method, the radioactive dose got by the patient is also very low (lower than the dose got for thorax radiography)(Hall & Rolin, 1995; Bajaj et al., 1996).

Because its relatively low molecular weight, iothalamate is a good marker (just like 51Cr-EDTA) to be used in simplified protocols. Cohen was the first to use the bolus method instead of the constant rate infusing method in 1969 (Cohen et al., 1969). Several authors have showed that iothalamate could be used in plasma clearance (LaFrance et al., 1988; Welling et al., 1976; Back et al., 1988b; Gaspari et al., 1992) even if results are not fully comparable to urinary clearances (Agarwal et al., 2009). It must also be underlined that iothalamate is the only one marker which is frequently used with subcutaneous injection (Israelit et al., 1973). It had actually been shown that plasma iothalamate concentrations remain constant 60 to 90 min after a subcutaneous injection (so, equivalent to the constant

How Measuring Glomerular Filtration Rate? Comparison of Reference Methods 35

**GFR methods** 

urinary clearance and constant infused rate 131iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 131iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

3 to 139 Inulin:

**Statistics Results** 

1.06 (0.74 to 1.23) 6±13

NS 1.005 (from 0.937 to 1.138) 0.7±4

1 (from 0.93 to 1.09) 1±3

1.01±0.19

0.979

It=1.09inulin-0.65

=0.9x+6.7 -0.7±13

Ratio It/inulin BAr

t-test Ratio It/inulin BAr

Ratio It/inulin BAr

Ratio It/inulin Correlation (urinary) Regression

Regression BAr

**(mL/min/1.73 m²)**

NA 2 to 167 Inulin:

NA 27 to 136 Inulin:

19 Healthy and CKD NA Inulin:

18 11 CKD and 8 healthy

10 NA 70 to 108 Inulin:

**References Sample Population GFR range** 

(Sigman et al., 1965a)

(Sigman et al., 1965b)

(Elwood & Sigman, 1967)

(Malamos et al., 1967)

(Anderson et al., 1968)

24 clearances in 16 subjects

26 clearances in 21 subjects

infusion rate method but much easier) (Israelit et al., 1973; Adefuin et al., 1976; Tessitore et al., 1979; Sharma et al., 1997).

Iothalamate can yet be measured by "cold" non-isotopic methods. The first "cold" dosage of iothalamate was proposed in 1975 by Guesry (Guesry et al., 1975). This author used fluorescent excitation analysis or X ray fluorescence (XRF), which will be also used for iohexol measurement (see below). In this technique, iodine atoms are ionized by americanum. When the iodine atom comes back to neutral status, it will emit X ray that will be then quantified (Guesry et al., 1975). Guesry found an excellent correlation between isotopic and XRF iothalamate measurement. Iothalamate concentration can also be determined by electrophoresis but, to the best of our knowledge, this technique is only used in the Mayo Clinic (Wilson et al., 1997). The most used methods to measure iothalamate are HPLC methods (Boschi & Marchesini, 1981). The HPLC method seems specific, sensible and reproducible (CV intra-day lower than 2% and CV inter-day lower than 6%) (Boschi & Marchesini, 1981; Prueksaritanont et al., 1984; Weber et al., 1985; Reidenberg et al., 1988; Back et al., 1988b; Gaspari et al., 1991; Dowling et al., 1998; Agarwal, 1998; Kos et al., 2000; Agarwal et al., 2003; Farthing et al., 2005; Bi et al., 2007). A new technique based on mass spectrometry has recently been proposed to measure iothalamate (Seegmiller et al., 2010). These authors have compared 51 GFR results given by this new technique and by electrophoresis. The results are excellent in term of correlation and bias (0.8%). The SD around the bias, namely the precision, is however less negligible at 13.7%. That means that 95% of the results measures in the same patient may vary from ± 28% according the way iothalamate has been measured. Iothalamate measurement remain very stable (for two months at room temperature and at –4 and -20°C and for 1 year at -80°C) (Weber et al., 1985; Seegmiller et al., 2010).

#### **7.2 Clinical data**

Iothalamate (Conray°) was used as GFR marker for the first time by Sigman from the New York University in 1965 (Sigman et al., 1965a; Sigman et al., 1965b). In these articles, Sigman used iothalamate labeled with 131I and compared its clearance with inulin clearance in 10 patients in the first publication (Sigman et al., 1965a) and in 16 in the second one (Sigman et al., 1965b). On this limited sample, Sigman described a ratio iothalamate/inulin near to 1, even though the ranges of this ratio are from 0.74 à 1 in the first study (Sigman et al., 1965a) and from 0.937 à 1.138 in the second one (Sigman et al., 1965b). These first interesting results were then confirmed by the same authors with 125I-iothalamate (Elwood & Sigman, 1967). Other authors published thereafter their own data comparing performance of inulin and iothalamate clearances. We resumed the results obtained in adults in Table 4. It is probably right to write that iothalamate has been the most studied GFR marker and the marker for which several comparisons to inulin exist. Other authors have confirmed the good performance of iothalamate urinary clearances, especially in CKD patients (Maher et al., 1971; Perrone et al., 1990; Skov, 1970). In healthy subjects, the results are however more questionable and iothalamate seems to overestimate inulin (+20 mL/min)(Perrone et al., 1990) although precision is not optimal ±11 mL/min, as illustrated in the study by Botev (Botev et al., 2011). Data regarding the performance of the iothalamate plasma clearance are less numerous but is seems that bias is acceptable. However, precision is not optimal, especially in higher GFR levels. Additional studies could be of interest for the plasmatic method (Agarwal, 2003; Mirouze et al., 1972).

infusion rate method but much easier) (Israelit et al., 1973; Adefuin et al., 1976; Tessitore et

Iothalamate can yet be measured by "cold" non-isotopic methods. The first "cold" dosage of iothalamate was proposed in 1975 by Guesry (Guesry et al., 1975). This author used fluorescent excitation analysis or X ray fluorescence (XRF), which will be also used for iohexol measurement (see below). In this technique, iodine atoms are ionized by americanum. When the iodine atom comes back to neutral status, it will emit X ray that will be then quantified (Guesry et al., 1975). Guesry found an excellent correlation between isotopic and XRF iothalamate measurement. Iothalamate concentration can also be determined by electrophoresis but, to the best of our knowledge, this technique is only used in the Mayo Clinic (Wilson et al., 1997). The most used methods to measure iothalamate are HPLC methods (Boschi & Marchesini, 1981). The HPLC method seems specific, sensible and reproducible (CV intra-day lower than 2% and CV inter-day lower than 6%) (Boschi & Marchesini, 1981; Prueksaritanont et al., 1984; Weber et al., 1985; Reidenberg et al., 1988; Back et al., 1988b; Gaspari et al., 1991; Dowling et al., 1998; Agarwal, 1998; Kos et al., 2000; Agarwal et al., 2003; Farthing et al., 2005; Bi et al., 2007). A new technique based on mass spectrometry has recently been proposed to measure iothalamate (Seegmiller et al., 2010). These authors have compared 51 GFR results given by this new technique and by electrophoresis. The results are excellent in term of correlation and bias (0.8%). The SD around the bias, namely the precision, is however less negligible at 13.7%. That means that 95% of the results measures in the same patient may vary from ± 28% according the way iothalamate has been measured. Iothalamate measurement remain very stable (for two months at room temperature and at –4 and -20°C and for 1 year at -80°C) (Weber et al., 1985;

Iothalamate (Conray°) was used as GFR marker for the first time by Sigman from the New York University in 1965 (Sigman et al., 1965a; Sigman et al., 1965b). In these articles, Sigman used iothalamate labeled with 131I and compared its clearance with inulin clearance in 10 patients in the first publication (Sigman et al., 1965a) and in 16 in the second one (Sigman et al., 1965b). On this limited sample, Sigman described a ratio iothalamate/inulin near to 1, even though the ranges of this ratio are from 0.74 à 1 in the first study (Sigman et al., 1965a) and from 0.937 à 1.138 in the second one (Sigman et al., 1965b). These first interesting results were then confirmed by the same authors with 125I-iothalamate (Elwood & Sigman, 1967). Other authors published thereafter their own data comparing performance of inulin and iothalamate clearances. We resumed the results obtained in adults in Table 4. It is probably right to write that iothalamate has been the most studied GFR marker and the marker for which several comparisons to inulin exist. Other authors have confirmed the good performance of iothalamate urinary clearances, especially in CKD patients (Maher et al., 1971; Perrone et al., 1990; Skov, 1970). In healthy subjects, the results are however more questionable and iothalamate seems to overestimate inulin (+20 mL/min)(Perrone et al., 1990) although precision is not optimal ±11 mL/min, as illustrated in the study by Botev (Botev et al., 2011). Data regarding the performance of the iothalamate plasma clearance are less numerous but is seems that bias is acceptable. However, precision is not optimal, especially in higher GFR levels. Additional studies could be of interest for the plasmatic

al., 1979; Sharma et al., 1997).

Seegmiller et al., 2010).

method (Agarwal, 2003; Mirouze et al., 1972).

**7.2 Clinical data** 


How Measuring Glomerular Filtration Rate? Comparison of Reference Methods 37

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : plasma clearance: samples at 5, 10, 15, 20, 40, 60, 80, 100 et 120 min + correction

urinary clearance and constant infused rate 125iothalamate : bolus SC and urinary clearance

Inulin: urinary clearance and constant infused rate 125iothalamate : bolus and urinary clearance

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

6 to 125 Inulin:

96 to 147 35 to 87 42 to 98

Ratio It/inulin Correlation Regression

Ratio It/inulin Correlation Regression

Ratio It/inulin Correlation Regression

> Ratio It/inulin

> > BAr

Correlation Regression

1.44±0.13

0.96 =1.18+8.43

1.23±0.16

0.77 =1.06+1.18

1.05±0.04

0.97 =1.054-3.069

> 1.02±0.04 1.43±0.08 1.23±0.04 -1±13 -7±14 -4±13

0.932 =1.04+2.11

hypertensive ±5 to 120 Inulin:

15 hypertensive ±80 to 140 Inulin:

(Mirouze et al., 1972)

(Mirouze et al., 1972)

(Israelit et al., 1973)

(Rosenbaum et al., 1979)

7 healthy 9 renal grafted 8 donors after donation

22 20 CKD

2 healthy

(Ott, 1975) 84 CKD and donors ±10 to 150 Inulin:

36 clearances in 23 subjects


NA ±10 to 180 Inulin:

NA ±30 to 150 Inulin:

198 NA ±5 to 150 Inulin:

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

Inulin: urinary clearance and constant infused rate 125iothalamate : bolus and urinary clearance

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

urinary clearance and constant infused rate 125iothalamate : urinary clearance and constant infused rate

Ratio It/inulin Regression

Ratio It/inulin Correlation Regression BAr

> Ratio It/inulin

Ratio It/inulin Correlation Regression

Bias Regression

0.92 (0.81 to 1.04) Inulin=1.08It

Group 1 0.98±0.06 0.999 =0.972+0.01 0±0 Group 2 1 0±1 Group 3 0.92±0.071 0.968 =1.083+3.46 -2±1

1.01

1.07 0.94 =1.06+1.17


15 hypertensive ±55 to 120 Inulin:

(Maher & Tauxe, 1969)

(Skov, 1970) 43

(Gagnon et al., 1971)

(Cangiano et al., 1971)

(Maher et al., 1971)

65 clearances in 22 subjects 38 clearances in 13 subjects

CKD GFR<5 ml/

GFR between 5 et 15 mL/min GFR between 15 et 25 mL/min

24 clearances in 8 subjects

78 clearances in 24 subjects

49 clearances in 18 subjects


How Measuring Glomerular Filtration Rate? Comparison of Reference Methods 39

CKD ± 20 to 110 Inulin:

94 See above ± 5 to 140 See above Correlation

Table 4. Studies comparing iothalamate with inulin. NA: not available, CKD: chronic kidney

Iothalamate can be measured either by HPLC or XRF methods or by isotopic methods. This is the only one marker where this choice is possible. However, there is no evidence that all the techniques of measurement are fully equivalent. Iothalamate is certainly the marker that has been the most deeply studied from a physiological point of view (with inulin). Unhopefully, there are strong reasons to believe that iothalamate is secreted by renal tubules. Moreover, extra-renal clearance of iothalamate is not so negligible. These limitations are confirmed by most of the clinical studies showing that iothalamate slightly overestimates inulin clearance, especially in the high levels of GFR. A clinical limitation concerns the patients who are allergic to contrast product. This marker remains however

disease subjects, BA: Bland and Altman analysis, BAr: Bland and Altman analysis recalculated by us, BM: Brochner-Mortensen, HPLC: high pressure liquid chromatography,

It: iothalamate, SC: subcutaneous, XRF: X ray fluorescence.

**7.3 Strengths and limitations** 

urinary clearance and constant infused rate Iothalamate (HPLC): bolus and urinary clearance

urinary clearance and constant infused rate Iothalamate (HPLC): plasma clearance on long time with insulin pomp

Correlation Slope with 0 intercept

Bias (Inulin-It) CV

Regression BA (It-Inulin)

0.98 1.05±0.01

> 0.8 19.9%

0.97 =1.04+2.334 +4.6±11

23 CKD 10 to 130 Inulin:

(Isaka et al., 1992)

> (Agarwal, 2003)

(Botev et al., 2011) Data from 5 studies (Anderson et al., 1968; Elwood & Sigman, 1967; Perrone et al., 1990; Rosenbaum et al., 1979; Skov, 1970)

12 clearances in 3 subjects


Healthy and CKD ±10 to 180 Inulin:

NA Lupus 23 to 123 Inulin:

5 healthy 120 to 165 Inulin:

CKD

Healthy Two successive days

urinary clearance and constant infused rate 125iothalamate : bolus SC and urinary clearance

urinary clearance and constant infused rate 125iothalamate : bolus SC and urinary clearance

urinary clearance and constant infused rate 125iothalamate : bolus SC and urinary clearance

urinary clearance and constant infused rate Iothalamate (XRF): bolus and urinary clearance

urinary clearance and constant infused rate 125iothalamate : bolus SC and urinary clearance

urinary clearance and constant infused rate Iothalamate (HPLC): bolus and urinary clearance

±5 to 130 Inulin:

NA Inulin:

Correlation Regression

Ratio It/inulin Correlation

Correlation Regression

Correlation Regression r²

Wilcoxon or t-test Correlation

Means

0.982 =1.02-0.61

1.07±0.05

0.96

0.86 =0.8x+19.5

0.99 =0.9x-2.1 0.99

P<0.001

from 0.93 to 0.98

Inulin : 108±14 day 1 96±8 day 2 125iothalamate 127±12 day 1 120±7 day 2

ratio 1.00±0.06

(Ott, 1975) 100 CKD and donors ±5 to 150 Inulin:

30 15 creatinine<1 mg/dL 15 creatinine<20 mg/dL

(Tessitore et al., 1979)

(Notghi et al., 1986)

(Petri et al., 1988)

(Perrone et al., 1990)

(al Uzri et al., 1992)

76 clearances in 40 subjects

13

4


Table 4. Studies comparing iothalamate with inulin. NA: not available, CKD: chronic kidney disease subjects, BA: Bland and Altman analysis, BAr: Bland and Altman analysis recalculated by us, BM: Brochner-Mortensen, HPLC: high pressure liquid chromatography, It: iothalamate, SC: subcutaneous, XRF: X ray fluorescence.
