|Year : 2014 | Volume
| Issue : 4 | Page : 733-740
|Power doppler sonography in early renal transplantation: Does it differentiate acute graft rejection from acute tubular necrosis?
Haytham M Shebel1, Ahmed Akl2, Ahmed Dawood1, Tarek A El-Diasty1, Ahmed A Shokeir3, Mohamed A Ghoneim3
1 Department of Radiology, Urology and Nephrology Center, Mansoura, Egypt
2 Department of Nephrology, Urology and Nephrology Center, Mansoura, Egypt
3 Department of Urology, Urology and Nephrology Center, Mansoura, Egypt
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|Date of Web Publication||24-Jun-2014|
| Abstract|| |
To evaluate the role of power Doppler in the identification and differentiation between acute renal transplant rejection and acute tubular necrosis (ATN), we studied 67 live donor renal transplant recipients. All patients were examined by spectral and power Doppler sono-graphy. Assessment of cortical perfusion (CP) by power Doppler was subjective, using our grading score system: P0 (normal CP); homogenous cortical blush extending to the capsule, P1 (reduced CP); cortical vascular cut-off at interlobular level, P2 (markedly reduced CP); scattered cortical color flow at the interlobar level. Renal biopsies were performed during acute graft dysfunction. Pathological diagnoses were based on Banff classification 1997. The Mann- Whitney test was used to test the difference between CP grades with respect to serum creatinine (SCr), and resistive index (RI). For 38 episodes of acute graft rejection grade I, power Doppler showed that CP was P1 and RI ranging from 0.78 to 0.89. For 21 episodes of acute graft rejection grade II, power Doppler showed that CP was P1, with RI ranging from 0.88 to >1. Only one case of grade III rejection had a CP of P2. Twelve biopsies of ATN had CP of P0 and RI ranging from 0.80 to 0.89 There was a statistically significant correlation between CP grading and SCr (P <0.01) as well as between CP grading and RI (P <0.05). CP grading had a higher sensitivity in the detection of early acute rejection compared with RI and cross-sectional area measurements. We conclude that power Doppler is a non-invasive sensitive technique that may help in the detection and differentiation between acute renal transplant rejection and ATN, particularly in the early post-transplantation period.
|How to cite this article:|
Shebel HM, Akl A, Dawood A, El-Diasty TA, Shokeir AA, Ghoneim MA. Power doppler sonography in early renal transplantation: Does it differentiate acute graft rejection from acute tubular necrosis?. Saudi J Kidney Dis Transpl 2014;25:733-40
|How to cite this URL:|
Shebel HM, Akl A, Dawood A, El-Diasty TA, Shokeir AA, Ghoneim MA. Power doppler sonography in early renal transplantation: Does it differentiate acute graft rejection from acute tubular necrosis?. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Dec 3];25:733-40. Available from: https://www.sjkdt.org/text.asp?2014/25/4/733/134948
| Introduction|| |
Renal transplantation is the best modality of treatment for patients with end-stage renal disease, as it usually permits a long-term quality of life superior to that achievable by dialysis.  Kidney grafts are retrieved from living or from deceased donors. Acute graft rejection and acute tubular necrosis (ATN) that may result from kidney exposure to prolonged periods of warm ischemia constitute two important causes for early acute graft dysfunction.  The differentiation among causes of transplant graft dysfunction can be made most often by percutaneous biopsy with the hazards of inva-siveness. 
Neither standard Color nor spectral Doppler sonographies are able to diagnose or differentiate between acute graft rejection and ATN.  Power Doppler, which often detects blood flow better than standard color Doppler, has been shown to depict blood flow in normal kidneys and kidney transplants extremely well. 
The aim of this prospective study is to evaluate the role of power Doppler sonography in the diagnosis of acute graft rejection and its capability to differentiate between acute graft rejection and ATN, where the line of management is completely different.
| Patients and Methods|| |
Sixty-seven live donor renal transplant recipients (54 males, 13 females) were included in the study from (March 2004 to February 2005). The mean age of the patients was 30 years (range, 16-50 years). Transplanted kidneys were examined daily from the first day after operation until discharge from the hospital, where the hospital stay ranged from 14- 20 days. Clinical parameters and serum crea-tinine (SCr) were monitored daily.
All patients were examined by gray scale, spectral and power Doppler sonography during the same sonographic examination. The machine used was Acuson-sequoia 512 (Acuson, Mountain View, CA, USA) with a 5 MHZ multi-frequency curved linear array transducer. All examinations were performed by the same examiner. The examination started with gray scale evaluation to exclude obstruction and peri-renal fluid collections. Resistive index (RI) was calculated by averaging at least three measurements at the interlobar levels. The mean RI of each kidney was calculated and then categorized according to its power Doppler pattern.
Power Doppler examination was optimized for each patient to obtain the maximum amount of vascularity in the cortex during Day 1 and Day 2 post-operatively as a basic study for further comparison using the same equipment, while the pulse repetition frequency ranged from 13-17 Hz and an energy setting of 25 dB with gain optimized according to Rubin et al  to detect low-volume and low-velocity flow states, where it was enforced until there was just no background noise visible. The same standard settings formats were used for each patient in each follow-up study. Optimization of power Doppler gain for each case was performed through selection of an area of 2-3 cm of graft parenchyma, region of interest (ROI) and compared with a control area of 1- 2 cm selected outside the graft capsule.
Assessment of cortical perfusion (CP) by power Doppler was subjective, using our per-fusion grading score system, where normal CP (P0) defined homogenous cortical blush extending to the graft capsule, reduced CP (P1) represented cortical vascular cut-off at the inter-lobular level leaving a sub-capsular cortical zone of no color flow signals and markedly reduced CP (P2) showed scattered cortical color flow signals at the interlobar arteries producing patchy cortical perfusion.
Seventy-six fine-needle core biopsies were performed through an automatic biopsy gun under ultrasound guidance and indicated for the evaluation of acute graft dysfunctions. All biopsies were reviewed by an experienced and independent renal pathologist. Pathological diagnoses were based on Banff Schema 1997  by which acute rejection was classified into three grades (G): Mild (GI) with significant interstitial infiltration and moderate tubulitis, but no vasculitis; moderate (G II) with significant interstitial infiltration, severe tubulitis and mild to moderate vasculitis; severe (G III) with severe intimal arteritis, interstitial hemorrhage and focal infractions. Borderline changes were used only in case of mild tublitis and mild to moderate interstitial infiltration.
| Statistical Analysis|| |
The provisional sonographic diagnosis and CP grades were compared with the final histo-pathological diagnosis and/or the response to therapy. The mean SCr and RI of each CP grade were calculated. The Mann-Whitney test was used to calculate the difference between CP grades with respect to SCr and RI. Receiver-operator characteristic curve analysis was used to measure the sensitivity and specificity of the CP grades, RI and cross-sectional area for the detection of early acute graft rejection. All analyses were carried out using the Statistical Package for Social Sciences (SPSS) for windows, release 16 (SPSS Inc. Chicago, IL, USA).
| Results|| |
All cases had normal clinical parameters and laboratory investigations including SCr within the first four days post-transplantation except one patient who developed acute graft dysfunction on the 2 nd day after the operation. Twenty-three (34%) patients had acute graft dysfunction within the first 14 days in the form of increased SCr and oliguria, while 30 (44%) patients developed acute graft dysfunction after 14 days. Demographic data are described in [Table 1] and [Table 2].
|Table 2: Forty-four episodes of acute graft dysfunction were evaluated. The results and number of cases were summarized.|
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All normally functioning renal transplants at the early post-operative period revealed homo-genously power Doppler signals throughout the entire cortex giving the cortical blush with reduced blush in the medullary portions P0 CP that extended to the graft capsules. The mean RI was 0.65 ± 0.2 (range, 0.59-0.72) [Figure 1].
|Figure 1: Power Doppler picture of normally functioning renal transplant at the early post-operative period revealed a homogenously obtained power Doppler signal throughout the entire cortex giving cortical blush with reduced blush in the medullary portions P0 CP extending to the graft capsule. The mean RI was 0.65 ± 0.2 (normal range, 0.59–0.72).|
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Five (7%) recipients had smooth post-operative course without any episodes of acute graft dysfunction within the period of this study. Nine (13%) recipients who had episodes of acute graft dysfunction other than acute rejection or ATN as (acute cyclosporine nephrotoxicity, obstructive uropathy and acute pyelonephritis) were excluded from the study. The other 53 cases had 76 episodes of graft dysfunction. The final histopathological diagnosis of these cases was either acute tubular necrosis or acute rejection.
[Figure 2] shows the different histopathological grades of acute rejection and the number of documented graft biopsies. [Figure 3] shows Doppler evaluation during four of these episodes, which revealed P0 cortical perfusion and RI <0.73; histopathological borderline changes were described. Sonographic evaluation during 38 (50%) episodes of acute graft dysfunction demonstrated mild reduction of cortical perfusion P1 with RI (range, 0.78- 0.89). The final pathologic diagnosis was mild acute rejection (GI) [Figure 3]A. In 21 (27%) episodes of acute graft dysfunction, the final pathologic diagnosis was moderate acute rejection (GII), with RI (range, 0.88-1.00) and P1 cortical perfusion [Figure 3]B. Only one (1%) case, which had pathologically proven severe acute graft rejection (GIII), showed reversed diastolic flow and P2 cortical per-fusion [Figure 3]C. Doppler findings of 12 recipients who had pathologically proven ATN revealed elevated RI (range, 0.80-0.89) and cortical perfusion P0 [Figure 3]D; they were treated conservatively.
|Figure 2: Different histopathological grades of acute rejection and number of documented graft biopsies.|
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|Figure 3: Power Doppler evaluation of four cases of different acute graft dysfunction. (A) Borderline histopathological changes with power Doppler revealed P0 cortical perfusion and RI <0.73(GI). (B) Acute graft dysfunction due to moderate acute rejection (GII) with RI (range, 0.88 to >1) and P1 cortical perfusion. (C) Pathologically proven severe acute graft rejection (GIII) showed reversed diastolic flow and P2 cortical perfusion. (D) Doppler findings of pathologically proven ATN revealed elevated RI (range, 0.80–0.89) and the cortical perfusion is P0.|
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The recovery period ranged from 15-35 days, during which daily Doppler scanning was performed to measure RI and grades of cortical perfusion. We found that cortical perfu-sion grades changed from P0 to PI in eight cases 5-7 days after the initial diagnosis of ATN, while the grade remained unchanged for the other four cases, which had shorter recovery time. Cortical perfusion grades versus histopathology classification are demonstrated in [Table 3].
|Table 3: Spectral and power Doppler findings in cases of borderline rejection.|
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Acute rejection ranging from grades I to III was associated with cortical hypoperfusion in 60 of 64 (93%) episodes, while the episodes of borderline changes (n = 4) were not associated with changes in the CP grades. The presence of ATN (n = 12) was associated with no change in the cortical perfusion in the first 5-7 days; thereafter, cortical hypoperfusion was demonstrated in eight (66%) cases. There was a statistically significant correlation between the cortical perfusion grades and each of SCr values (P <0.01) and RI values (P <0.05). [Table 4] shows that the measurement of cortical perfusion was more accurate (87.8%) with high sensitivity (82%) and specificity (100%) than the resistive index and cyclos-porine A titer (CSA).
[Table 5] shows the comparisons of the CP grades, RI and CSA. The CP grads revealed the highest total accuracy in measurement compared to the other methods.
| Discussion|| |
Many attempts have been made to evaluate renal transplants with color and spectral Dop-pler sonography. , Based on resistive index measurements, color Doppler sonography had a limited value in the differentiation among the various etiologies of renal transplant dys-function.  In renal allograft, power Doppler detects cortical perfusion, which depends on the integrity of small vessels that are usually early affected in renal transplant dysfunctions, especially with acute rejection and ATN and CSA nephrotoxicity.  Both acute rejection and ATN affect the microcirculation either through direct injury to the vessel wall or indirectly through compression of the capillary lumen by interstitial edema.  In our study, we investigated the capability of the power Doppler in the detection of the slow flow in these areas of small vessels either due to direct affection as in acute rejection or indirect affection as in ATN.
In our study, we observed 64 episodes of acute rejection and 12 episodes of ATN. The mean RI values were above normal in both conditions, either in acute rejection or ATN, with no cut-off value between the two entities. An increase in RI occurs in various other conditions such as renal vein thrombosis, graft infections, compressive peri-renal fluid collection and obstructive uropathy. ,,, Both retrospective and prospective studies had shown that normally functioning transplants and those with graft dysfunction could not be differentiated by measuring the RI.  Furthermore, some cases of acute transplant rejection had a non-elevated RI. , However, the pattern of resistive index changes can be meaningful as reported by Konety and Jordon, 2000,  who documented that the resistive index tends to increase in both acute rejection and ATN, but it decreases after a period of time in ATN, while it persists or progresses into higher degrees in rejection.
Generally, color Doppler is capable of displaying three parameters of the signals including flow direction and frequency and their changes overtime. Power Doppler displays the missing color parameter, the intensity or power of the signal.  In our study, the reduction of cortical perfusion was a constant feature of the different grades of acute rejection. Despite that all our donors are living related, ATN developed in 12 cases because of the application of a new technique of laparoscopic nephrectomy in four cases and multiple renal arteries in the other eight cases; therefore, these cases were subjected to prolonged warm ischemia time. The change in our Doppler scoring system from P0 of eight cases in the first 5-7 days to P1 after this period is presumably due to marked edema and prolonged compression upon the small vessels of the cortex distal to arcuate arteries, which finally manifested by cortical hypoperfusion (P1) resembling those cases of GI and GII acute rejection. These ATN cases, which developed hypoperfusion, had prolonged recovery time than the other cases, which exhibited a constant Doppler pattern P0 from the start of the graft dysfunction.
Power Doppler examination in our study revealed a nearly constant Doppler sign in cases of acute rejection (93%), which is cortical hypoperfusion during the acute insult of the graft dysfunction, while this sign was absent in cases of ATN, especially in the first 5-7 days. These results are in controversy with some authors as Trillaud et al,  who reported that power Doppler grades and RI failed to distinguish between tubulopathy and rejection. Also, Hilborn et al  suggested that the power Doppler appearance does not correlate with pathology grading of rejection, as in their results both GI and GII vascular rejection had no focal abnormalities. Furthermore, our results supported the suggestion that power Doppler could be helpful in the differentiation between ATN with swelling of the graft with decreased but preserved perfusion on one hand and acute transplant rejection with reduced perfusion on the other hand.  These findings agree with many scintigraphic studies that reported preservation of cortical perfusion in ATN.  Sidu et al  found that the significance of power Doppler in diagnosing acute renal transplant rejection was its specificity that reached to 100% with positive predictive value of 100% and negative predictive value of 33%.
The correlation between our power Doppler scoring system with SCr and RI proved to be statistically significant in cases of acute rejection, which is in agreement with Gaschen et al,  who reported that the correlation between power Doppler appearance of inter-lobular vasculature with RI and Scr and crea-tinine clearance proved to be statistically significant. However, Trillaud et al  found no significant correlation between power Dop-pler grades, SCr and creatinine clearance at the immediate post-operative period, but there was a statistically significant correlation between creatinine clearance and power Doppler grades 12 months post-transplantation. The controversy between our results and those of other authors may be attributed to the large scale and the continuous close follow-up studies of our kidney transplant recipients as well as the sensitivity of the US equipment in detecting blood flow and the pathological classification used for correlating the Doppler results.
In conclusion, power Doppler sonography is a sensitive and specific technique in the detection and differentiation of early acute renal transplant rejection and ATN, particularly in the early post-transplantation period.
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Department of Nephrology, Urology and Nephrology Center, Mansoura
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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