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From the Clinical Research Centers |
Departments of Medicine (E.M.K., M.G., M.A.) and Nuclear Medicine (H.L., M.E.S.), University of Southern California, Los Angeles, California 90033
Address all correspondence and requests for reprints to: Elaine M. Kaptein, M.D., University of Southern California, Room 4250 GNH, 1200 North State Street, Los Angeles, California 90033.
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Abstract |
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In CAPD patients, serum radioiodine half-times were 5 times longer, and radioiodine clearance rates by urine plus dialysate were 20% of those in patients with normal renal function. Na131I dosages for the two CAPD patients with thyroid cancer were reduced from 150 mCi [5.6 gigabecquerels (GBq)] to 26.6 mCi (0.98 GBq) and 29.9 mCi (1.11 GBq), respectively, resulting in radiation doses to red marrow and total body comparable to those in patients with normal renal function who received a mean of 148 mCi (5.5 GBq) Na131I. Thus, in patients receiving continuous ambulatory peritoneal dialysis therapy, 5-fold reductions in radioiodine clearance rates require 5-fold decreases in Na131I dosages to avoid excessive radiation doses to total body and red marrow.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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With impaired renal function, reductions in urinary
Na131I excretion rates parallel decreases in
creatinine clearance (8, 9). In ESRD patients, radioiodine excretion is
primarily by dialysis, as residual renal function is minimal or absent
(1, 2, 9, 10, 11). Weekly radioiodine and creatinine clearance rates depend
upon type and duration of dialysis therapy (4, 5, 6, 7, 11, 12). Radioiodine
clearance rates during intermittent peritoneal dialysis therapy (
30
2-L exchanges over 36 h/week) approximate normal renal clearance rates
(2), but are 5-fold higher during hemodialysis therapy (1, 4, 5, 6, 7, 8, 9, 10, 12, 13). However, hemodialysis is only provided for 5–7% of each week,
with creatinine clearance rates averaging 129 ± 18 L/week
(mean ± SD), which is only 10–12% of normal renal
clearance rates (9, 11, 12). Between dialysis treatments, radioiodine
and creatinine clearance rates are minimal or absent (3, 5, 7, 11).
Thus, radioiodine clearance rates were 25% of normal (7), and whole
body half-times were 2.5 times normal (3) when hemodialysis was resumed
24 h after radioiodine administration, whereas whole body
half-times were 4.5 times normal with hemodialysis starting 48 h
after the dosage (3). Radioiodine clearance rates should be reduced in
ESRD patients receiving CAPD therapy (3–5 2-L exchanges/day), because
creatinine clearance rates average 72 ± 14 L/week (mean ±
SD), which is only 5–7% of normal (11).
Bone marrow depression can occur if larger than recommended doses of radioiodine are administered to red marrow for treatment of thyroid cancer (14). Radiation doses to red marrow primarily depend upon rates of radioiodine elimination from the body. In our ESRD patients, quantitation of radioiodine clearance by CAPD and residual renal function was required to adjust dosages of Na131I so that red marrow and total body radiation doses did not exceed those in patients with normal renal function (3, 7, 14).
Thus, objectives of our studies were to determine 1) the rate of radioiodine removal by dialysate plus residual renal function in ESRD patients receiving CAPD therapy compared to that in thyroid cancer patients with normal renal function, and 2) radioiodine dosage adjustments for thyroid remnant ablation in our two CAPD thyroid cancer patients to deliver radiation doses to red marrow similar to those of thyroid cancer patients with normal renal function.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Iodine kinetic studies were performed in 10 patients with
papillary/follicular thyroid carcinomas (2 with ESRD maintained on CAPD
therapy and 8 with normal renal function), and in 8 ESRD patients
receiving CAPD therapy with intact thyroid glands (Table 1
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). All CAPD patients had
urinary creatinine clearance rates below 5 mL/min (three were anuric)
and were performing three to five 2-L exchanges daily (11). All eight
thyroid cancer patients with normal renal function had total
thyroidectomies, three had previous radioiodine ablation, and seven had
5-mCi (185-MBq) Na131I scans before current
ablative dosages (Table 1). Five were hypothyroid after thyroid hormone
withdrawal. Three were clinically euthyroid with suppressed TSH levels;
one was taking L-T4 (0.15 mg/day),
and two had functioning metastases. All eight had normal urinalyses and
normal range serum creatinine values (15). Iodide kinetic studies
The human study protocol was approved by the institutional
review board for human subject research of the Los Angeles
County/University of Southern California Medical Center. Written
informed consents were obtained. All patients had routine chemistry
panels, complete blood counts, and thyroid hormone and TSH levels.
Pregnancy tests were negative in all premenopausal women.
Na123I capsules or Na131I
liquid was administered orally after an overnight fast, followed by
serial blood, urine, and in CAPD patients, dialysate sampling, for
24–70 h. All CAPD patients and one thyroid cancer patient with normal
renal function on L-T4 suppression
received 100 µCi (3.70 MBq) of Na123I, with the
other 100 µCi (3.70 MBq) dosage used as standard. Thyroidal uptake of
Na123I was minimized by an oral saturated
solution of potassium iodide (250 mg/day for 3 days before study) in
the eight CAPD patients with intact thyroid glands (16). For both CAPD
patients with thyroid cancer, Na123I data were
used to estimate Na131I ablative dosages
equivalent to 150 mCi (5.6 GBq) using the MIRDOSE3 program (17).
Studies were repeated after the Na131I ablative
dosage in one CAPD patient and combined with
Na123I data because results were similar. The
other seven patients with thyroid cancer and normal renal function were
studied after therapeutic dosages of oral Na131I
(Table 1). Preparation, Na131I scanning, and
therapy of thyroid cancer patients were under the direction of the
treating thyroidologist and nuclear medicine physicians. Radiation
safety precautions and waste treatment followed established radiation
safety procedures.
After oral Na123I or
Na131I, blood samples were obtained at 0, 0.25,
0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h. After
Na131I therapy, additional blood samples were
obtained for up to 70 h (Fig. 2). Patients voided before oral
radioiodine and collected all urine thereafter. An early urine specimen
was discarded in one thyroid cancer patient with normal renal function,
making cumulative urinary Na131I data unusable.
For CAPD patients, dialysate was collected for 32–66 h after oral
radioiodine. Urine and dialysate total volumes were determined
gravimetrically. Radioactivity of thyroid and standard were determined
24 h after Na123I and 10–15 days after
Na131I treatment using a thyroid uptake probe
(model 62 with a standard straight bore collimator, Nuclear Data, Inc.,
Schaumburg, IL). Thigh counts were used to assess neck tissue
background.
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-counter with reference standards to 10,000 cpm.
Samples from Na131I studies were counted in a
radioisotope dose calibrator (Capintec, Ramsey, NJ), with a
read-out in microcuries. All samples containing 2 µCi (0.074 MBq) or
less of 131I were recounted in a scintillation
well counter (Ortec, Oak Ridge, TN) to validate
131I activity. All samples were counted in
duplicate, averaged, corrected for radioactive decay, and expressed as
a percentage of the ingested dosage. The majority of radioactivity was
assumed to be inorganic iodine with the relatively short duration of
serum sampling and low thyroidal radioiodine uptake (18, 19). Measurements
Creatinine concentrations were measured in serum, urine, and dialysate using the modified Folin-Wu method, with 1.3% picric acid and 3% sodium hydroxide. Interassay coefficients of variation were 6.2% at 11.9 mg/dL (1052 µmol/L), 3.7% at 41 mg/dL (3624 µmol/L), and 3.3% at 80 mg/dL (7072 µmol/L). As high glucose concentrations interfere with this creatinine assay, creatinine levels were measured in unused dialysate and were 1.0 mg/dL (88.4 µmol/L) for the 1.5% dextrose solution, 1.5 mg/dL (132.6 µmol/L) for the 2.5% dextrose solution, and 2.9 mg/dL (256.4 µmol/L) for the 4.25% dextrose solution (20). Glucose and creatinine levels were determined in all dialysate samples, and creatinine values corrected for glucose concentrations using linear regression analysis [corrected creatinine (mg/dL) = 0.0007 x glucose concentration (mg/dL) - 0.134] (20).
Dosimetry calculations
Radiation dosimetry calculations were performed using MIRDOSE3 program for the medical internal radiation dose (MIRD) approach to internal dosimetry (17, 21) with guidance from Dr. Michael G. Stabin (Oak Ridge Institute for Science and Education, Oak Ridge, TN). Source organs for radioiodine were assumed to be thyroid and total body in our patients, because uptakes by other tissues are minimal in comparison (22). Residence time, defined as area under the source organ’s time activity curve divided by administered activity (14, 17, 21), was estimated for thyroid and total body. Residence time equals 1.443 x fractional uptake of dosage administered x effective half-time (14, 21). As radionuclides disappear from the body by radioactive decay as well as by biological excretion, effective half-time = [(biological half-time x physical half-time)/(biological half-time + physical half-time)] (14, 21). The physical half-time for Na131I is 192 h (22). Fractional radioiodine uptake by the body was assumed to be (1 - fractional thyroid uptake) (14).
As thyroid radioiodine uptakes were less than 5% in all patients, a biological half-time for radioiodine of 52.1 days was used, as reported for thyroids with uptakes less than 5% (22). Thus, thyroid effective half-time for Na131I was estimated at 166.44 h for our patients, which is within the upper range of 15–180 h (average, 95 h) for thyroid remnants (mean uptake, 8%) in 30 hypothyroid thyroid cancer patients 72 h after therapeutic radioiodine (23), as well as within the upper range of 10–192 h (average, 58 h) in 87 patients with mean uptakes of 18% (24). Fractional radioiodine uptakes were extrapolated to 24 h, assuming the half-time of 52.1 days (22), as thyroid radioactivity decreases gradually and is relatively linear for up to 12 days after a therapeutic dosage of radioiodine (18). If effective thyroid half-times of Na131I were overestimated, dosimetry values for extrathyroidal tissues would be minimally affected due to the very low thyroid uptake values.
The effective total body Na131I half-time was approximated by effective serum half-time (14) for the following reasons. Radioiodine uptake by thyroid remnants and metastases are relatively low (23). Biological half-times of radioiodine in tissues such as stomach, intestine, and liver are similar to those in blood (22). Disappearance rates of radioactivity in blood and whole body, from external counting data, are parallel in patients with and without metastases or residual thyroid tissue (14). Ratios of radioiodine activity in blood and whole body are similar in patients with metastases or only residual thyroid tissue (14). Finally, Na131I activity of blood parallels external whole body counts in ESRD patients with thyroid cancer, with or without metastases (5, 7). We verified these findings in our patients as follows.
The slope of the linear terminal portion of the serum radioiodine
disappearance curve for each patient was determined using least squares
fit of logarithmically transformed data (Fig. 2 and Table 1). The
relationship of serum radioiodine levels to time is indicated by
correlation coefficients (Table 1). The serum radioiodine half-time was
calculated as (ln 2)/slope (21). External total body counts were
estimated for radiation safety purposes after the administration of
therapeutic dosages of Na131I, using an
ionization chamber at approximately 1 m from the anterior cervical
region. Counts per min were plotted vs. time on a
semilogarithmic plot. Five patients had at least three terminal linear
points, allowing an estimate of effective total body half-time of
Na131I. The effective serum half-time of
Na131I from four patients with normal renal
function correlated with the estimated total body half-time (r =
0.914). The mean effective half-time for serum was 10.4 ±
2.8 h, and that for total body was 13.0 ± 4.3 h (±1
SD), similar to whole body effective half-lives
for other hypothyroid patients with normal renal function (11 ±
2 h without metastases, 14 ± 3 h with metastases) (25).
For one of the thyroid cancer patients with ESRD given
Na131I, the effective half-time was 43.6 h
for serum and 46.8 h for total body. Somewhat longer total body
than serum effective half-times may relate to a slowly exchanging
compartment for iodine and/or residual thyroid or functioning
metastases (14, 26).
Absorbed doses were estimated for Na131I for tissues and whole body using the MIRDOSE3 program (17, 21, 22) and are expressed as rads per mCi (1 rad/mCi = 1 cGy/37 MBq) and rads per total dosage (1 rad = 1 cGy). Models for a 70- or a 57-kg adult human body, designed to account for size, shape, and positions of organs, were used depending upon body weight (17). Values are presented for total body and red marrow. Thomas et al. (14) showed that dosimetry estimates using the MIRD schema are consistent with those of other methods. Renal doses may be lower than predicted in ESRD patients due to minimal blood flow and filtration by residual renal function. Bladder doses may be lower due to low or absent urinary radioiodine. Other organ doses may also be altered due to minimal or absent urine and the presence of intraabdominal dialysate.
Iodine and creatinine clearance calculations
Clearance rates of creatinine and radioiodine by urine and dialysate were calculated as UV/P or DV/P, respectively, where U is urine and D is dialysate concentration, V is volume per unit time, and P is serum concentration (1). Serum radioiodine levels decreased progressively throughout each study period. Consequently, radioiodine clearance rates from urine and dialysate were estimated for each collection period using a mean serum radioiodine value for that time period, as recommended for creatinine and other solutes for peritoneal equilibration tests (20). As radioiodine clearance values varied randomly as serum radioiodine levels decreased, a mean value for the entire period was calculated for each patient, as described for creatinine clearance. Peritoneal transfer rates of creatinine, urea, protein, and sodium vary with duration of preceding and current dialysate exchanges, dialysate glucose concentration, as well as peritoneal membrane characteristics for each individual (20). Transfer rates of urea, sodium, and potassium parallel those of creatinine (20). Radioiodine clearance rates correlated with creatinine clearance rates in dialysate and urine in our patients (data not shown). Ratios of radioiodine to creatinine clearance rates (fractional excretion of radioiodine) (9) account for variations in dialysate glucose concentrations and dwell times and were calculated for all dialysate and urine collections.
Statistics
Values are expressed as the mean ± 1 SD or as the median and ranges for non-Gaussian distributions. Values were compared by Wilcoxon unpaired rank sum tests or by unpaired Student’s t tests.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Values
were not significantly different between hypothyroid and euthyroid CAPD
patients or between hypothyroid and TSH- suppressed patients with
normal renal function. In CAPD patients, cumulative urinary radioiodine
loss at 24 h was 3.3 ± 3.3% (range, 0–10.5%) of
administered dosages, and that from dialysate was 26.9 ± 4.4%
(range, 20.0–33.0%). Urinary loss of 72.4 ± 3.1% (range,
68.4–76.5%) in thyroid cancer patients with normal renal function was
similar to the 76.1% previously reported (22). The radioiodine
clearance rate from urine plus dialysate in CAPD patients was 21%,
whereas the creatinine clearance rate was 5% of values in patients
with normal renal function (Table 2).
The mean urinary radioiodine clearance rate averaged 38% of the
creatinine clearance rate (fractional excretion of radioiodine) in CAPD
patients, compared to 25% in patients with normal renal function
(P > 0.05; Table 2). Fractional excretion of
radioiodine in dialysate (124%) was significantly higher
(P < 0.01) than that in urine from either CAPD
patients (38%) or patients with normal renal function (25%; Table 2).
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and Fig. 2). Values were not
significantly difference between hypothyroid and euthyroid CAPD
patients or between hypothyroid and TSH- suppressed patients with
normal renal function. In CAPD patients, the mean serum radioiodine
half-time was 5 times longer (mean ± SD, 51.4 ±
13.2 h) than that in patients with normal renal function
(10.2 ± 2.4 h; Table 1). The latter were within the mean
range of 6–11 h previously reported with normal renal function (7, 19).
Thyroidal Na123I uptake at 24 h ranged from
0–3.5% (median, 1.3%) in the CAPD group. In the two hypothyroid
thyroid cancer patients, values were 3.5% and 2.9%, respectively,
whereas thyroid intact CAPD patients had values of 2.7% or less after
exogenous stable iodine (Fig. 3). Uptake
values ranged from 0–0.7% (median, 0.007%) in thyroid cancer
patients with normal renal function who had prior 5-mCi (185-MBq)
Na131I scans or ablative therapy (Table 1) and
were lower than in CAPD patients (P < 0.01; Fig. 3).
Thyroid residence times ranged from 0–8.41 h (median, 2.55 h) in
the CAPD group, with highest values in the two hypothyroid patients
with thyroid cancer (8.41 and 6.97 h, respectively), and from
0–1.71 h (median, 0.034 h; P < 0.01) in patients with
normal renal function.
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].
Based on dosimetry calculations, the two thyroid cancer patients
receiving CAPD therapy were given 29.9 mCi (1.11 GBq) and 26.6 mCi
(0.98 GBq), respectively, of Na131I, estimated to
be a dosage equivalent to 150 mCi (5.6 GBq) (3) if renal function were
normal. Patients with normal renal function received 142 mCi (5.3 GBq)
to 153 mCi (5.7 GBq; Fig. 4). In the CAPD
patients, estimated total absorbed radiation doses to red marrow [26.9
and 17.8 rads (cGy), respectively] and total body [27.4 and 18.7 rads
(cGy), respectively] were similar to those in subjects with normal
renal function [red marrow, 23.1 ± 4.7 rads (cGy); total body,
22.2 ± 4 rads (cGy); Fig. 4]. Radiation doses to thyroid
remnants were 4708 and 5262 rads (cGy), respectively, in CAPD patients
and from 17–659 rads [cGy; median, 70 rads (cGy)] in those with
normal renal function.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Factors determining estimated radiation doses to tissues such as red marrow and total body in our patients include 1) effective serum and total body half-times of radioiodine, 2) fractional radioiodine uptake by the thyroid remnant, 3) body size, and 4) administered dosage of Na131I (14, 17, 18, 21, 23, 25).
Urinary radioiodine and creatinine clearance rates were markedly diminished in our CAPD patients, as expected (11). Urinary radioiodine clearances were from 13–56% of crea-tinine clearances in our CAPD patients with creatinine clearances less than 5 mL/min compared with 50% to more than 100% in nondialyzed patients with creatinine clearances less than 10 mL/min (9, 10). Relatively lower urinary radioiodine clearances in our CAPD patients may relate to concurrent clearance by dialysis (9). In our patients with normal renal function, urinary radioiodine clearance averaged 25% of creatinine clearance, similar to the 22–38% previously reported (1, 4, 8, 9, 10).
Radioiodine clearance rates by CAPD were only 5 mL/min compare with 21 mL/min in ESRD patients during intermittent peritoneal dialysis therapy (2). Lower radioiodine clearance rates in our CAPD patients most likely relate to less frequent dialysate exchanges (3–5/day), compared to about 30 exchanges over 36 h/week with intermittent peritoneal dialysis (2). Higher concentration gradients for radioiodine and creatinine from blood to dialysate would occur with frequent exchanges, albeit for only 21% of each week (2). Prolonged dialysate dwell times in our CAPD patients would allow equilibration of radioiodine and creatinine across peritoneal membranes, resulting in lower concentration gradients and net clearance rates of radioiodine and creatinine. As CAPD therapy is continuous, dialysate radioiodine clearance averaged 51 L/week in our CAPD patients compared to about 44 L/week with intermittent peritoneal dialysis (2).
The net effect of impaired radioiodine clearance rates by residual renal function plus peritoneal dialysis in our CAPD patients was to prolong effective serum and total body half-times 5-fold compared with those in patients with normal renal function. Serum effective half-times in our CAPD patients (30–57 h) were similar to an ESRD patient receiving hemodialysis 48 h after radioiodine for thyroid cancer (47 h) (5), but shorter than in one reported CAPD patient with thyroid cancer (66 h) (27). Shorter effective serum radioiodine half-times in our CAPD patients may relate to higher daily excretion rates of radioiodine in dialysate (20–33% of the administered dose) and, in some, by urine (0–11%), than in the CAPD patient reported (7% by dialysis and 2% by urine) (27). In contrast, our patients with normal renal function had serum effective half-times ranging from 7–14 h, similar to reported values of 11–14 h (25).
Low thyroid uptakes in our thyroidectomized thyroid cancer patients may relate to the extent of surgical thyroidectomy, radiation thyroiditis, stable iodine uptake, and/or prior Na131I dosages for scanning or therapy. Remnant radioiodine uptake decreases gradually during 10–15 days after a therapeutic dosage of Na131I (18). Thus, radiation thyroiditis is unlikely. Serum stable iodine levels are increased in 93% of CAPD patients (12) and may account for low uptakes in our two thyroidectomized CAPD patients (3.5% and 2.9%, respectively) and in a reported thyroidectomized CAPD patient (2.5%) (27). In our CAPD patients with intact thyroid glands, oral stable iodine probably contributed to reduced uptakes of less than 3% (16).
In our thyroid cancer patients with normal renal function, a 5-mCi (185-MBq) scanning dosage of Na131I or previous Na131I ablative therapy probably reduced thyroid remnant uptakes. Posttherapy Na131I uptakes were reduced by up to 75% in as many as 67% of patients if thyroid remnants received 3500 rads (cGy) during a scanning dosage (28) and to 4–42% of pretreatment values (average, 15%) after a 5-mCi (185-MBq) scanning dosage (29). Thyroid remnant uptakes were 7% (23) to 18% (24) in reported thyroid cancer patients after Na131I scanning dosages of 1–2 mCi (37–74 MBq) (28). Thus, Na131I scanning doses should probably not exceed 2 mCi (74 MBq).
In our ESRD patients receiving CAPD therapy, radiation doses per mCi (per 37 MBq) of Na131I were 4.3-fold higher to red marrow and total body than in those with normal renal function, but similar to those in a patient receiving hemodialysis 48 h after Na131I administration (3). Consequently, when Na131I dosages were reduced to 18–20% of dosages in patients with normal renal function, total radiation doses to red marrow and total body in our CAPD patients were similar to those in patients with normal renal function (3).
Red marrow doses were lower in our thyroid cancer patients with normal renal function [0.12–0.19 rads/mCi (0.032–0.051 mGy/MBq)] than previously reported [0.24–0.65 rads/mCi (0.065–0.176 mGy/MBq)] (14), as were total body doses [ours, 0.12–0.18 rads/mCi (0.032–0.049 mGy/MBq); reported, 0.20–1.04 rads/mCi (0.054–0.281 mGy/MBq)] (18). Thyroidal radioiodine uptakes of less than 1% in our patients compared to 7–18% in reported thyroid cancer patients (23, 24) may account for these differences. In the study by Singh et al. (18), radiation doses to total body were 2-fold higher in patients with the highest absorbed thyroid doses per rad (cGy) than in those with the lowest absorbed thyroid doses per rad (cGy), supporting this possibility.
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Acknowledgments |
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Footnotes |
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Received December 2, 1999.
Revised April 11, 2000.
Revised June 6, 2000.
Accepted June 14, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, thyroid cancer patients; 
, patients with intact thyroid
glands who received stable iodine) and in thyroid cancer patients with
normal renal function (NL; 
; 1 rad/mCi = 1 cGy/37 MBq).