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99mTc-mercaptoacetyl Triglycine Renography to Monitor Renal Transplant Function Among Kidneys from Donors After Cardiac Death
99m
Tc-mercaptoacetyl Triglycine Renography to Monitor Renal Transplant Function Among Kidneys from Donors After Cardiac Death T. Majima, R. Hattori, Y. Funahashi, T. Komatsu, M. Kato, S. Yamada, O. Kamihira, and M. Goto ABSTRACT Purpose. Delayed graft function usually occurs after kidney transplantation from donors after cardiac death, It is important to monitor graft function during the anuric period, but there have been few useful tools. Consequently, we evaluated the availability of 99m-Tc mercaptoacetyltriglycine (MAG3) renography. Methods. Thirty-two patients underwent renal transplantation from donors after cardiac death between June 2, 2005, and April 14, 2011. One patient was excluded due to an acute rejection episode which developed during the dialysis period. The first 99mTc-MAG3 renogram was performed as early as possible after the operation and repeated until the patient was weaned from dialysis. The corrected tubular extraction rate (cTER; mL/min/ 1.73 m2) was calculated; it represents the MAG3 clearance corrected by body surface area. Results. cTER was low immediately after transplantation, but increased gradually until the patient was weaned from dialysis. A significant correlation was observed between early cTER and the period of dialysis-dependence (r ⫽ ⫺0.677, P ⬍ .001) as well as the short-term best corrected creatinine clearance (r ⫽ 0.526, P ⫽ .002). Conclusion. We observed that graft function can be monitored by routinely performing 99m Tc-MAG3 renography after transplantation of kidneys from donors after cardiac death. ENAL transplantation from donors after cardiac death has been a focus of investigation because there is a lack of donors. In these cases, 80% to 94.9% of recipients develop delayed graft function (DGF) generally requiring dialysis for approximately 2 weeks. Additionally, some authors have reported that primary nonfunction occurred in 8.7% to 16% of cases.1–3 Acute rejection (AR) episodes or surgical complications often occur coincidentally during the anuric period with critical impact on graft function. Thus, it is important to monitor the progress of kidney recovery. Other investigators have reported the usefulness of ultrasound and scintigram to evaluate graft function recovery. However, there are still few useful tools today. In the present study, we used 99mTc-mercaptoacetyl triglycine (MAG3) renography to quantitatively monitor graft function from donors after cardiac death during the anuric period.
R
MATERIALS AND METHODS Between June 2, 2005 and April 14, 2011 we performed 32 consecutive renal transplantations from donors after cardiac death, among which 31 recipients were entered into this study because the excluded subject developed an AR episode during the dialysis© 2012 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 49 –53 (2012)
dependent period. All grafts were obtained using in situ cooling after donor cardiac arrest, In beginning at an average of 8 minutes after arrest, with a total average ischemic time of 775 minutes. The 29 patients (93.5%) who developed DGF required dialysis for an average of 8 days (range, 1 to 28 days). All grafts functioned eventually (Table 1). 99m
Tc-MAG3 Renogram
In each case the first 99mTc-MAG3 renogram was performed within 4 days after the operation and repeated weekly thereafter until the recipient had been weaned from dialysis. The Renal Uptake New Quantitative (RUNQ) method was used to quantify graft function. Patients were injected with approximately 200 megabecquerels of From the Department of Urology (T.M., R.H., Y.F., M.G.), Nagoya University Hospital; the Department of Urology (T.K., M.K.), Chukyo Hospital; the Department of Urology (S.Y.), Okazaki Shimin Hospital; and the Department of Urology (O.K.), Komaki Shimin Hospital. Supported the Tokai Urological Clinical Trial Group. Address reprint requests to Tsuyoshi Majima, MD, Department of Urology, Nagoya University Hospital, 65, Tsurumaicho, Showa-Ku, Nagoya city, Aichi prefecture, Japan 466-0065. E-mail: [email protected] 0041-1345/–see front matter doi:10.1016/j.transproceed.2011.11.028 49
50
MAJIMA, HATTORI, FUNAHASHI ET AL Table 1. Patient Background
Donor Age (y) Cause of donor’s death
Recipient age (y) Ratio of male to female Dialysis-dependent period (d) Warm ischemic time (min) Total ischemic time (min)
Mean 48 (14 to 72) Subarachnoid hemorrhage 13 Suicide by hanging 5 Cerebral hemorrhage 10 Cerebral infarction 3 Mean 47 (range, 6 to 72) 21:10 Mean 7 (range, 1 to 16) Mean 8 (range, 0 to 57) Mean 775 (range, 91 to 1835)
99m
Tc-MAG3. Each dose was accurately measured by counting the radioactivity in the syringe before and after the injection. Immediately after administration and for 30 minutes thereafter, anterior images were obtained using a Hitachi/Philips SKY Light gamma camera (Japan) with a low-energy general purpose collimator. The regions of interest were drawn on the graft images with graft depth corrected by computed tomographic scan images. 99mTc-MAG3 renal uptake for 1 to 2 minutes after injection was calculated using a camera-based technique. 99mTc-MAG3 clearance corrected by body surface area, known as corrected tubular extraction rate (cTER), was obtained using the following regression equation: cTER (mL/min/1.73 m2) ⫽ 9.825X ⫹ 11.258, wherein X is the 99m Tc-MAG3 renal uptake rate for 1 to 2 minutes after injection.
Doppler Echogram Doppler echograms were performed on all patients as early as possible within 2 days after the operation and repeated regularly thereafter until weaning. The pulsatility index (PI) and the resistive index (RI) were calculated using the following formulae:
RESULTS Transition of cTER, PI, and RI
Changes in cTER based on the day of weaning showed an upward tendency during the dialysis-dependent period. The cTER on the day of weaning was significantly higher than those at 5 and 10 days before (P ⫽ .039 and P ⫽ .015, respectively). The cTER 10 days after had increased even more than that on the day of weaning, but the difference was insignificant (P ⫽ .08; Fig 1). Analyzing changes of PI and RI in the same way showed no definite trend during the dialysis-dependent period (data not shown). Early cTER, PI, and RI, and the Dialysis-dependent Period
We excluded the two patients who did not need dialysis after surgery. We correlated the relation between early cTER and the dialysis-dependent period (r ⫽ ⫺0.677, P ⬍ .001). The following regression formula was obtained: y ⫽ ⫺0.19X ⫹ 18.87 (R2 ⫽ 0.34; P ⬍ .001; Fig 2). No significant correlation was observed between early PI and RI and the dialysis-dependent period. Early cTER and Best cCCr
We estimated the relationship between early cTER and short-term best cCCr, which was defined as the cCCr at 2 months after the operation. Graft function in all cases was stable during this period. cCCr was calculated using the formula: cCCr ⫽ UCr*UV/PCr/1440*1.73/BSA where PCr is plasma creatinine concentration (mg/dL); UCr urinary cre-
PI ⫽ (peak systolic velocity – end diastolic velocity)/mean velocity RI ⫽ (peak systolic velocity – end diastolic velocity)/peak systolic velocity We analyzed the following: (1) the transition of cTER, PI, and RI data immediately after operation to weaning (2) the relationship between these data obtained early and the dialysis- dependent period, and (3) the relationship between the data and best corrected creatinine clearance (cCCr). All the procedures were performed in accordance with the Helsinki Declaration of 1975 and approved by our Institutional Review Board.
Case Record We analyzed the transition of the cTER in the one patient who was excluded due to an AR episode to evaluate the usefulness of 99m Tc-MAG3 renography for this diagnosis (Fig 4).
Statistical Analysis The Mann-Whitney U test was used to compare cTER differences over time. The correlation between early cTER and the dialysisdependent period was analyzed using Kendall rank correlation coefficient. Regression analysis was performed when there was a significant correlation. Correlations between early cTER and best cCCr were also analyzed using the Kendall rank correlation coefficient with comparison to PI and RI. P values less than .05 were considered statistically significant. All statistical analyses were performed using SPSS software.
Fig 1. The change in the cTER based on the day of weaning showed an upward tendency during the dialysis dependent period.
99m
Tc-MERCAPTOACETYL TRIGLYCINE RENOGRAPHY
Fig 2. While performing correlation analysis to model the relation between early cTER and the dialysis-dependent period, a significant correlation was found (R ⫽ ⫺0.677, P ⬍ .001). The following regression formula was obtained: y ⫽ ⫺0.19 ⫻ ⫹ 18.87, R2 ⫽ 0.34, P ⬍ .001.
atinine concentration (mg/dL); UV: urine volume (mL/d) and BSA: body surface area (m2) between early cTER and short-term best cCCr. A significant correlation was observed (r ⫽ 0.526, P ⫽ .002), obeying the regression formula: y ⫽ 0.40x ⫹ 24.02 (R2 ⫽ 0.33, P ⫽ .003; Fig 3). Early PI and RI, and Best cCCr
Estimating the relationship between early PI and RI and short-term best cCCr showed no significant correlation.
51
episodes or surgical complications often occur coincidentally during the anuric period, it is important to monitor the recovery of graft function. To date, ultrasound and scintigram have been used to evaluate the graft function in this setting. Trillaud et al performed a Doppler echogram at an average of 6 days after transplantation to calculate RI. There was no significant difference between RI values in cases of acute tubular necrosis (ATN) and normal recovery.4 Additionally, Chiang et al performed echograms at 1 week after deceased donor transplantation in 64 cases, all of which showed normal PI and RI values, although 37.5% developed primary dysfunction (Cr ⬎ 2 mg/dL).5 We observed no significant relationship between early PI and RI and the period of dialysis-dependences or short-term graft function. Although PI and RI have been used in clinical practice because of their simplicity and minimal invasiveness, they are not useful to evaluate graft function during the anuric period or to predict grafts prognosis. Heaf et al performed 99mTc-MAG3 renograms 1 day after transplantation from deceased donors categorizing renogram grades (RGs) based on the result and curves. They reported that cases with high RG were likely to display DGF,6 suggesting that renograms can estimate graft function during the dialysis-dependent period. However, because they used a morphologic method, a renogram curve, it was not quantitative. Tarek et al performed 99m Tc-MAG3 renograms 48 hours after transplantation to measure tubular function slope (TFS), in the curves during the tubular extraction phase. They reported significantly low TFS among the DGF group7 although this study was useful in that they used a quantitative index, they did not analyze the change in graft function during the anuric or the
Case Record
One patient was excluded from the study because of an AR episode. Figure 4 shows the evolution of her cTER. She should have been free from dialysis at the postoperative day (POD) 9, using the regression formula, in Fig 1 because the early cTER was 50.6 mL/min/1.73 m2. However, she was dialysis-dependent for 3 weeks. Steroid pulse therapy was administered at POD 20 because an AR was diagnosed by graft biopsy. She withdrew from dialysis on POD 28. The cTER showed a plateau because of the AR episode, but improved immediately after the pulse therapy (Fig 4). DISCUSSION
Despite an increase in kidney donors, there still are not sufficient organs. The current situation requires more donations after cardiac death. In Japan, where donation after brain death has not been accepted in the public’s mind, there has been more donation after cardiac death. Some reports have shown that 80% to 94.9% of kidney transplantations from donors after cardiac death develop DGF, with primary nonfunction in 5.4% to 16% cases. Because AR
Fig 3. While performing correlation analysis to model the relation between early cTER and best cCCr, a significant correlation was found (r ⫽ 0.526, P ⫽ .002). The following regression formula was obtained: y ⫽ 0.40x ⫹ 24.02 (R2 ⫽ 0.33, P ⫽ .003).
52
Fig 4. She should have been free from dialysis at postoperative day (POD) 8, using the regression formula from Fig 1. However, she was dialysis-dependent for 3 weeks because of AR. Steroid pulse therapy was provided from POD 20 and she withdrew from dialysis on POD 28. The cTER showed a plateau because of AR, but improved immediately after the pulse therapy.
relation between TFS and the dialysis-dependent period. The renogram seems to be useful, but few articles have accurately estimated graft function during this initial period. Because 99mTc-MAG3 can be injected in large volumes due to its unlikeliness to irradiate the entire human body, it provides an excellent image.8 –10 Today, it is used in various areas including transplantation. Additionally, MAG3 is mainly extracted by urinary tubules. We have undertaken this study taking note of the high reproducibility of the renogram and these properties of 99mTc-MAG3. Bubeck et al invented a quantitative method to evaluate 99mTc-MAG3 results: cTER is calculated with only one blood sample. By correcting plasma nuclide concentration using body surface area, they more accurately estimated renal function, even in infants using the same regression equation.11 Kubo et al analyzed the relationship between cTER calculated by the Bubeck method and renal uptake rate obtaining a regression formula independent of body weight and age.12 We have used this RUNQ method that enables calculation of cTER without blood sampling. In this study, we first evaluated the transition of cTER by regularly performing renograms begining shortly after the operation until weaning. We observed that cTER increased with time in the absence of a clinical event such as an AR episode. Elevation of cTER (ie, MAG3 clearance) signifies recovery of tubular function, or recovery from ATN, because MAG3 is mainly extracted from tubules. Secondly, it was possible to predict the day of weaning by calculating the early cTER. Because DGF usually develops in renal transplantations from donors after cardiac death, it has been difficult to predict when the onset and evolution of graft function occurs. In addition, some authors have reported the usefulness of renograms to estimate graft prognosis. Henk et al per-
MAJIMA, HATTORI, FUNAHASHI ET AL
formed MAG3 renograms within 48 hours after transplantation to calculate the 99mTc-MAG3 uptake in the first 10 minutes (MUC10). There were significant differences in MUC10 between cases displaying graft function at 5 years and those with no function.13 Russell et al performed 99m Tc-MAG3 renograms at 4 days after the operation to calculate effective renal plasma flow, the time from tracer administration to maximum background-corrected counting rate (peak time), and the ratio of uptake rate at 20 minutes to that at 3 minutes (R20:3). These values were suggested to predict graft function at 1 year.14 Our study also presents a significant relationship between early cTER and short-term graft function. As previously mentioned, early cTER reflects tubular function immediately after transplantation, namely the degree of tubular damage. Therefore, a poor result means that the function of the graft with more severe ATN will worsen afterwards, which is similar to the results of other published reports.15,16 Finally, our study indicated that 99mTc-MAG3 renography was a helpful adjunct for the diagnosis of other clinical events when reviewing the course of a patient who had an AR episode. Because we observed the usual cTER transition to predict the day of weaning based on early cTER, we are able to suspect that intervention of an event among cases that do not follow the trend. Consequently, we might be able to perform a timely graft biopsy. Previously it has been difficult to monitor graft function accurately during this period because of various concomitant clinical conditions, but 99mTc-MAG3 renography may be useful. In conclusion, 99mTc-MAG3 renography is a beneficial modality for monitoring the function of renal transplantations from donors after cardiac death, during the anuric period, predicting the day of weaning and the grafts prognosis, as well as awareness of potential adverse events. REFERENCES 1. Alonso A, Fernandez-Rivera C, Villaverde P, et al: Renal transplantation from non-heart beating donors: a single-center 10-year experience. Transplant Proc 37:3658, 2005 2. Gol MA, Buckley PE, Shenton BK, et al: Long-term renal function in kidneys from non-heart beating donors: a single-center experience. Transplantation 74:664, 2002 3. Gerstenkorn C: Non-heart beating donors: renewed source of organs for renal transplantation during the twenty-first century. World J Surg 27:489, 2003 4. Trillaud H, Merville P, Linh PTL: Color Doppler sonography in early renal transplantation follow-up: resistive index measurements versus power Doppler sonography. Am Roentgen Ray Soc 171:1611, 1998 5. Chiang Y-J, Chu S-H, Chuang C-K, et al: Resistive index cannot predict transplant kidney function. Transplant Proc 35:94, 2003 6. Heaf JG, Iversen J: Uses and limitations of renal scintigraphy in renal transplantation monitoring. Eur J Nuclear Med 27:871, 2000 7. EI-Maghraby TAF, Boom H, Camps JAJ, et al: Delayed graft function is characterized by reduced functional mass measured by 99m technetium-mercaptoacetyl- triglycine renography. Transplantation 74:203, 2002
99m
Tc-MERCAPTOACETYL TRIGLYCINE RENOGRAPHY
8. DuCret RP, Boudreau RJ, Gonzalez R, et al: Clinical efficacy of 99mtechnetium- mercaptoacetyltriglycine kit formulation in routine renal scintigraphy. J Urol 142:19, 1989 9. Russell CD, Thorstad BL, Yester MV, et al: Quantitation of renal function with 99mMAG3. J Nuclear Med 29:1931, 1988 10. Dubovsky EV, Russell CD, Yester MV, et al: Will 99mTcMAG3 replace 131I-OIH and 99mTc-DTPA in the follow-up of renal transplants? Contrib Nephrol 79:118, 1990 11. Bubeck B, Piepenburg R, Grethe U, et al: A new principle to normalize plasma concentrations allowing single-sample clearance determinations in both children and adults. Eur J Nuclear Med 19:511, 1992 12. Kubo A, Hashimoto J, Nakamura K, et al: Can 99mTcmercaptoacetyltriglycine (99mTc-MAG3) evaluate the renal func-
53 tion without blood sampling?: consensus report from multicenter study. Kaku Igaku 34:1101, 1997 13. Henk S, de Klerk JMH, Mertens JR, et al: Quantitative baseline renography 48 hours after renal transplantation predicts long-term graft survival. Eur J Nuclear Med 28:1677, 2001 14. Russell CD, Yang H, Gaston RS, et al: Prediction of renal transplant survival from early postoperative radioisotope studies. J Nuclear Med 41:1332, 2000 15. Shoskes DA, Cecka JM: Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 66:1697, 1998 16. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997
Tc-mercaptoacetyl Triglycine Renography to Monitor Renal Transplant Function Among Kidneys from Donors After Cardiac Death T. Majima, R. Hattori, Y. Funahashi, T. Komatsu, M. Kato, S. Yamada, O. Kamihira, and M. Goto ABSTRACT Purpose. Delayed graft function usually occurs after kidney transplantation from donors after cardiac death, It is important to monitor graft function during the anuric period, but there have been few useful tools. Consequently, we evaluated the availability of 99m-Tc mercaptoacetyltriglycine (MAG3) renography. Methods. Thirty-two patients underwent renal transplantation from donors after cardiac death between June 2, 2005, and April 14, 2011. One patient was excluded due to an acute rejection episode which developed during the dialysis period. The first 99mTc-MAG3 renogram was performed as early as possible after the operation and repeated until the patient was weaned from dialysis. The corrected tubular extraction rate (cTER; mL/min/ 1.73 m2) was calculated; it represents the MAG3 clearance corrected by body surface area. Results. cTER was low immediately after transplantation, but increased gradually until the patient was weaned from dialysis. A significant correlation was observed between early cTER and the period of dialysis-dependence (r ⫽ ⫺0.677, P ⬍ .001) as well as the short-term best corrected creatinine clearance (r ⫽ 0.526, P ⫽ .002). Conclusion. We observed that graft function can be monitored by routinely performing 99m Tc-MAG3 renography after transplantation of kidneys from donors after cardiac death. ENAL transplantation from donors after cardiac death has been a focus of investigation because there is a lack of donors. In these cases, 80% to 94.9% of recipients develop delayed graft function (DGF) generally requiring dialysis for approximately 2 weeks. Additionally, some authors have reported that primary nonfunction occurred in 8.7% to 16% of cases.1–3 Acute rejection (AR) episodes or surgical complications often occur coincidentally during the anuric period with critical impact on graft function. Thus, it is important to monitor the progress of kidney recovery. Other investigators have reported the usefulness of ultrasound and scintigram to evaluate graft function recovery. However, there are still few useful tools today. In the present study, we used 99mTc-mercaptoacetyl triglycine (MAG3) renography to quantitatively monitor graft function from donors after cardiac death during the anuric period.
R
MATERIALS AND METHODS Between June 2, 2005 and April 14, 2011 we performed 32 consecutive renal transplantations from donors after cardiac death, among which 31 recipients were entered into this study because the excluded subject developed an AR episode during the dialysis© 2012 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 49 –53 (2012)
dependent period. All grafts were obtained using in situ cooling after donor cardiac arrest, In beginning at an average of 8 minutes after arrest, with a total average ischemic time of 775 minutes. The 29 patients (93.5%) who developed DGF required dialysis for an average of 8 days (range, 1 to 28 days). All grafts functioned eventually (Table 1). 99m
Tc-MAG3 Renogram
In each case the first 99mTc-MAG3 renogram was performed within 4 days after the operation and repeated weekly thereafter until the recipient had been weaned from dialysis. The Renal Uptake New Quantitative (RUNQ) method was used to quantify graft function. Patients were injected with approximately 200 megabecquerels of From the Department of Urology (T.M., R.H., Y.F., M.G.), Nagoya University Hospital; the Department of Urology (T.K., M.K.), Chukyo Hospital; the Department of Urology (S.Y.), Okazaki Shimin Hospital; and the Department of Urology (O.K.), Komaki Shimin Hospital. Supported the Tokai Urological Clinical Trial Group. Address reprint requests to Tsuyoshi Majima, MD, Department of Urology, Nagoya University Hospital, 65, Tsurumaicho, Showa-Ku, Nagoya city, Aichi prefecture, Japan 466-0065. E-mail: [email protected] 0041-1345/–see front matter doi:10.1016/j.transproceed.2011.11.028 49
50
MAJIMA, HATTORI, FUNAHASHI ET AL Table 1. Patient Background
Donor Age (y) Cause of donor’s death
Recipient age (y) Ratio of male to female Dialysis-dependent period (d) Warm ischemic time (min) Total ischemic time (min)
Mean 48 (14 to 72) Subarachnoid hemorrhage 13 Suicide by hanging 5 Cerebral hemorrhage 10 Cerebral infarction 3 Mean 47 (range, 6 to 72) 21:10 Mean 7 (range, 1 to 16) Mean 8 (range, 0 to 57) Mean 775 (range, 91 to 1835)
99m
Tc-MAG3. Each dose was accurately measured by counting the radioactivity in the syringe before and after the injection. Immediately after administration and for 30 minutes thereafter, anterior images were obtained using a Hitachi/Philips SKY Light gamma camera (Japan) with a low-energy general purpose collimator. The regions of interest were drawn on the graft images with graft depth corrected by computed tomographic scan images. 99mTc-MAG3 renal uptake for 1 to 2 minutes after injection was calculated using a camera-based technique. 99mTc-MAG3 clearance corrected by body surface area, known as corrected tubular extraction rate (cTER), was obtained using the following regression equation: cTER (mL/min/1.73 m2) ⫽ 9.825X ⫹ 11.258, wherein X is the 99m Tc-MAG3 renal uptake rate for 1 to 2 minutes after injection.
Doppler Echogram Doppler echograms were performed on all patients as early as possible within 2 days after the operation and repeated regularly thereafter until weaning. The pulsatility index (PI) and the resistive index (RI) were calculated using the following formulae:
RESULTS Transition of cTER, PI, and RI
Changes in cTER based on the day of weaning showed an upward tendency during the dialysis-dependent period. The cTER on the day of weaning was significantly higher than those at 5 and 10 days before (P ⫽ .039 and P ⫽ .015, respectively). The cTER 10 days after had increased even more than that on the day of weaning, but the difference was insignificant (P ⫽ .08; Fig 1). Analyzing changes of PI and RI in the same way showed no definite trend during the dialysis-dependent period (data not shown). Early cTER, PI, and RI, and the Dialysis-dependent Period
We excluded the two patients who did not need dialysis after surgery. We correlated the relation between early cTER and the dialysis-dependent period (r ⫽ ⫺0.677, P ⬍ .001). The following regression formula was obtained: y ⫽ ⫺0.19X ⫹ 18.87 (R2 ⫽ 0.34; P ⬍ .001; Fig 2). No significant correlation was observed between early PI and RI and the dialysis-dependent period. Early cTER and Best cCCr
We estimated the relationship between early cTER and short-term best cCCr, which was defined as the cCCr at 2 months after the operation. Graft function in all cases was stable during this period. cCCr was calculated using the formula: cCCr ⫽ UCr*UV/PCr/1440*1.73/BSA where PCr is plasma creatinine concentration (mg/dL); UCr urinary cre-
PI ⫽ (peak systolic velocity – end diastolic velocity)/mean velocity RI ⫽ (peak systolic velocity – end diastolic velocity)/peak systolic velocity We analyzed the following: (1) the transition of cTER, PI, and RI data immediately after operation to weaning (2) the relationship between these data obtained early and the dialysis- dependent period, and (3) the relationship between the data and best corrected creatinine clearance (cCCr). All the procedures were performed in accordance with the Helsinki Declaration of 1975 and approved by our Institutional Review Board.
Case Record We analyzed the transition of the cTER in the one patient who was excluded due to an AR episode to evaluate the usefulness of 99m Tc-MAG3 renography for this diagnosis (Fig 4).
Statistical Analysis The Mann-Whitney U test was used to compare cTER differences over time. The correlation between early cTER and the dialysisdependent period was analyzed using Kendall rank correlation coefficient. Regression analysis was performed when there was a significant correlation. Correlations between early cTER and best cCCr were also analyzed using the Kendall rank correlation coefficient with comparison to PI and RI. P values less than .05 were considered statistically significant. All statistical analyses were performed using SPSS software.
Fig 1. The change in the cTER based on the day of weaning showed an upward tendency during the dialysis dependent period.
99m
Tc-MERCAPTOACETYL TRIGLYCINE RENOGRAPHY
Fig 2. While performing correlation analysis to model the relation between early cTER and the dialysis-dependent period, a significant correlation was found (R ⫽ ⫺0.677, P ⬍ .001). The following regression formula was obtained: y ⫽ ⫺0.19 ⫻ ⫹ 18.87, R2 ⫽ 0.34, P ⬍ .001.
atinine concentration (mg/dL); UV: urine volume (mL/d) and BSA: body surface area (m2) between early cTER and short-term best cCCr. A significant correlation was observed (r ⫽ 0.526, P ⫽ .002), obeying the regression formula: y ⫽ 0.40x ⫹ 24.02 (R2 ⫽ 0.33, P ⫽ .003; Fig 3). Early PI and RI, and Best cCCr
Estimating the relationship between early PI and RI and short-term best cCCr showed no significant correlation.
51
episodes or surgical complications often occur coincidentally during the anuric period, it is important to monitor the recovery of graft function. To date, ultrasound and scintigram have been used to evaluate the graft function in this setting. Trillaud et al performed a Doppler echogram at an average of 6 days after transplantation to calculate RI. There was no significant difference between RI values in cases of acute tubular necrosis (ATN) and normal recovery.4 Additionally, Chiang et al performed echograms at 1 week after deceased donor transplantation in 64 cases, all of which showed normal PI and RI values, although 37.5% developed primary dysfunction (Cr ⬎ 2 mg/dL).5 We observed no significant relationship between early PI and RI and the period of dialysis-dependences or short-term graft function. Although PI and RI have been used in clinical practice because of their simplicity and minimal invasiveness, they are not useful to evaluate graft function during the anuric period or to predict grafts prognosis. Heaf et al performed 99mTc-MAG3 renograms 1 day after transplantation from deceased donors categorizing renogram grades (RGs) based on the result and curves. They reported that cases with high RG were likely to display DGF,6 suggesting that renograms can estimate graft function during the dialysis-dependent period. However, because they used a morphologic method, a renogram curve, it was not quantitative. Tarek et al performed 99m Tc-MAG3 renograms 48 hours after transplantation to measure tubular function slope (TFS), in the curves during the tubular extraction phase. They reported significantly low TFS among the DGF group7 although this study was useful in that they used a quantitative index, they did not analyze the change in graft function during the anuric or the
Case Record
One patient was excluded from the study because of an AR episode. Figure 4 shows the evolution of her cTER. She should have been free from dialysis at the postoperative day (POD) 9, using the regression formula, in Fig 1 because the early cTER was 50.6 mL/min/1.73 m2. However, she was dialysis-dependent for 3 weeks. Steroid pulse therapy was administered at POD 20 because an AR was diagnosed by graft biopsy. She withdrew from dialysis on POD 28. The cTER showed a plateau because of the AR episode, but improved immediately after the pulse therapy (Fig 4). DISCUSSION
Despite an increase in kidney donors, there still are not sufficient organs. The current situation requires more donations after cardiac death. In Japan, where donation after brain death has not been accepted in the public’s mind, there has been more donation after cardiac death. Some reports have shown that 80% to 94.9% of kidney transplantations from donors after cardiac death develop DGF, with primary nonfunction in 5.4% to 16% cases. Because AR
Fig 3. While performing correlation analysis to model the relation between early cTER and best cCCr, a significant correlation was found (r ⫽ 0.526, P ⫽ .002). The following regression formula was obtained: y ⫽ 0.40x ⫹ 24.02 (R2 ⫽ 0.33, P ⫽ .003).
52
Fig 4. She should have been free from dialysis at postoperative day (POD) 8, using the regression formula from Fig 1. However, she was dialysis-dependent for 3 weeks because of AR. Steroid pulse therapy was provided from POD 20 and she withdrew from dialysis on POD 28. The cTER showed a plateau because of AR, but improved immediately after the pulse therapy.
relation between TFS and the dialysis-dependent period. The renogram seems to be useful, but few articles have accurately estimated graft function during this initial period. Because 99mTc-MAG3 can be injected in large volumes due to its unlikeliness to irradiate the entire human body, it provides an excellent image.8 –10 Today, it is used in various areas including transplantation. Additionally, MAG3 is mainly extracted by urinary tubules. We have undertaken this study taking note of the high reproducibility of the renogram and these properties of 99mTc-MAG3. Bubeck et al invented a quantitative method to evaluate 99mTc-MAG3 results: cTER is calculated with only one blood sample. By correcting plasma nuclide concentration using body surface area, they more accurately estimated renal function, even in infants using the same regression equation.11 Kubo et al analyzed the relationship between cTER calculated by the Bubeck method and renal uptake rate obtaining a regression formula independent of body weight and age.12 We have used this RUNQ method that enables calculation of cTER without blood sampling. In this study, we first evaluated the transition of cTER by regularly performing renograms begining shortly after the operation until weaning. We observed that cTER increased with time in the absence of a clinical event such as an AR episode. Elevation of cTER (ie, MAG3 clearance) signifies recovery of tubular function, or recovery from ATN, because MAG3 is mainly extracted from tubules. Secondly, it was possible to predict the day of weaning by calculating the early cTER. Because DGF usually develops in renal transplantations from donors after cardiac death, it has been difficult to predict when the onset and evolution of graft function occurs. In addition, some authors have reported the usefulness of renograms to estimate graft prognosis. Henk et al per-
MAJIMA, HATTORI, FUNAHASHI ET AL
formed MAG3 renograms within 48 hours after transplantation to calculate the 99mTc-MAG3 uptake in the first 10 minutes (MUC10). There were significant differences in MUC10 between cases displaying graft function at 5 years and those with no function.13 Russell et al performed 99m Tc-MAG3 renograms at 4 days after the operation to calculate effective renal plasma flow, the time from tracer administration to maximum background-corrected counting rate (peak time), and the ratio of uptake rate at 20 minutes to that at 3 minutes (R20:3). These values were suggested to predict graft function at 1 year.14 Our study also presents a significant relationship between early cTER and short-term graft function. As previously mentioned, early cTER reflects tubular function immediately after transplantation, namely the degree of tubular damage. Therefore, a poor result means that the function of the graft with more severe ATN will worsen afterwards, which is similar to the results of other published reports.15,16 Finally, our study indicated that 99mTc-MAG3 renography was a helpful adjunct for the diagnosis of other clinical events when reviewing the course of a patient who had an AR episode. Because we observed the usual cTER transition to predict the day of weaning based on early cTER, we are able to suspect that intervention of an event among cases that do not follow the trend. Consequently, we might be able to perform a timely graft biopsy. Previously it has been difficult to monitor graft function accurately during this period because of various concomitant clinical conditions, but 99mTc-MAG3 renography may be useful. In conclusion, 99mTc-MAG3 renography is a beneficial modality for monitoring the function of renal transplantations from donors after cardiac death, during the anuric period, predicting the day of weaning and the grafts prognosis, as well as awareness of potential adverse events. REFERENCES 1. Alonso A, Fernandez-Rivera C, Villaverde P, et al: Renal transplantation from non-heart beating donors: a single-center 10-year experience. Transplant Proc 37:3658, 2005 2. Gol MA, Buckley PE, Shenton BK, et al: Long-term renal function in kidneys from non-heart beating donors: a single-center experience. Transplantation 74:664, 2002 3. Gerstenkorn C: Non-heart beating donors: renewed source of organs for renal transplantation during the twenty-first century. World J Surg 27:489, 2003 4. Trillaud H, Merville P, Linh PTL: Color Doppler sonography in early renal transplantation follow-up: resistive index measurements versus power Doppler sonography. Am Roentgen Ray Soc 171:1611, 1998 5. Chiang Y-J, Chu S-H, Chuang C-K, et al: Resistive index cannot predict transplant kidney function. Transplant Proc 35:94, 2003 6. Heaf JG, Iversen J: Uses and limitations of renal scintigraphy in renal transplantation monitoring. Eur J Nuclear Med 27:871, 2000 7. EI-Maghraby TAF, Boom H, Camps JAJ, et al: Delayed graft function is characterized by reduced functional mass measured by 99m technetium-mercaptoacetyl- triglycine renography. Transplantation 74:203, 2002
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8. DuCret RP, Boudreau RJ, Gonzalez R, et al: Clinical efficacy of 99mtechnetium- mercaptoacetyltriglycine kit formulation in routine renal scintigraphy. J Urol 142:19, 1989 9. Russell CD, Thorstad BL, Yester MV, et al: Quantitation of renal function with 99mMAG3. J Nuclear Med 29:1931, 1988 10. Dubovsky EV, Russell CD, Yester MV, et al: Will 99mTcMAG3 replace 131I-OIH and 99mTc-DTPA in the follow-up of renal transplants? Contrib Nephrol 79:118, 1990 11. Bubeck B, Piepenburg R, Grethe U, et al: A new principle to normalize plasma concentrations allowing single-sample clearance determinations in both children and adults. Eur J Nuclear Med 19:511, 1992 12. Kubo A, Hashimoto J, Nakamura K, et al: Can 99mTcmercaptoacetyltriglycine (99mTc-MAG3) evaluate the renal func-
53 tion without blood sampling?: consensus report from multicenter study. Kaku Igaku 34:1101, 1997 13. Henk S, de Klerk JMH, Mertens JR, et al: Quantitative baseline renography 48 hours after renal transplantation predicts long-term graft survival. Eur J Nuclear Med 28:1677, 2001 14. Russell CD, Yang H, Gaston RS, et al: Prediction of renal transplant survival from early postoperative radioisotope studies. J Nuclear Med 41:1332, 2000 15. Shoskes DA, Cecka JM: Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation 66:1697, 1998 16. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997