- Email: [email protected]
Noninvasive acute rejection diagnosis in kidney transplantion
Noninvasive Acute Rejection Diagnosis in Kidney Transplantion O. Salgado
D
ESPITE IMPROVED immunosuppression, acute rejection (AR) has remained a serious complication affecting the survival of kidney transplants.1,2 In addition, AR is a major risk factor for chronic rejection, which is currently the major cause of late graft loss.3,4 Early diagnosis of AR is essential to limit the extent and severity of graft damage. The main goal of noninvasive diagnostic techniques is to provide early evidence of an ongoing AR and, as far as possible, to rule out other cause of graft dysfunction.
CLINICAL MANIFESTATIONS
Classical manifestations of AR are graft tenderness, fever, oliguria, proteinuria, lymphocyturia, deteriorating graft function.5 The use of newer and more potent immunosuppressive agents has profoundly modified the local and systemic manifestations of acute rejection, making its clinical course more insidious and thus rendering early diagnosis more difficult.4 For this reason, the absence of clinical symptoms does not exclude rejection.
IMMUNE MONITORING
For years investigators have attempted to identify markers of immune function in blood, urine, and the graft itself.6 More recently, Li et al7 reported that the measurement in urine of mRNA encoding two cytotoxic granule proteins, perforin and granzyme B, is a useful noninvasive test to predict acute renal graft rejection. In their study, Li et al7 did not observe any correlation between the severity of AR and the levels of perforin or granzyme B mRNA. In addition, the presence of vascular lesions could not be predicted by this technique.4 Further investigations appears to be necessary in the future to validate this method.
From the Center of Experimental Surgery, University of Zulia and Nephrology Department, University Hospital, Maracaibo, Venezuela. Address reprint requests to Octavio J. Salgado, MD, Apartado Postal 1430 Maracaibo 4001-A, Venezuela.
Fig 1. Basal B mode sonographies (A and C) of two different cadaveric renal grafts presenting with acute rejection posteriorly. The corresponding control sonographies (C and D) done during each rejection episode showed a thickening of the collecting system (C) in one of the cases and a diminution of renal sinus area (D) in the other as most prominent sonographic rejection signs. © 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03480-2
Transplantation Proceedings, 34, 2543–2544 (2002)
2543
2544
SALGADO
RENAL SONOGRAPHY
Color Doppler sonograpy (CDS) is the most useful noninvasive diagnostic methods for the differential diagnosis of AR. CDS may provide accurate real-time B mode kidney graft imaging with simultaneous display of intrarenal Doppler flow pattern and distribution. In addition, currently available CDS equipment is provided with software that permits direct calculation of impedance indexes from Doppler waveforms. Differential diagnosis of AR, which includes other common causes of graft dysfunction, such as urinary obstruction due intrinsic (ureteral stenosis) or extrinsic (lymphocele, hematoma) causes, can be readily assessed by B mode imaging.8 However, changes in graft appearance on B mode sonography (Fig 1), such as decreased renal sinus area, thickening of the collecting system, prominence of the pyramids, increased graft size, etc, initially thought to be predictive for AR, have proved later to be nonspecific.9 Similarly, the elevation of Doppler impedance indexes such as pulsatility (PI) or resistive (RI) index, contrary to the initial reports, have been shown to not be specific for AR but to occur most frequently in acute tubular necrosis.10 However, unexplained sharp elevations of impedance indexes occurring in the early posttrasplant period might suggest underlying vascular rejection11 (Fig 2). Three-dimensional ultrasound (3D-US) seems to be a more accurate method to assess graft volume changes and perirenal fluid collections. However, no studies have been conducted yet to evaluate its advantages over bidimensional ultrasound for the differential diagnosis of AR.
RENAL SCINTIGRAPHY AND OTHER RENAL IMAGING TECHNIQUES
Renal scintigraphy may show delayed or decreased Tc or In DPTA perfusion as well as delayed orthoiodohipppurate or Tc 99-m MAG 3 excretion in rejecting grafts. However, those findings are not specific for AR.12 Other noninvasive diagnostic imaging techniques, such as computed tomography and magnetic resonance (MR) imaging, usually do not provide additional information in case of AR than that obtained with conventional CDS.13 More recently, it has been reported that contrast-enhanced MR renograms using gadolinium DPTA would show distinct time-versus-signal intensity curves in AR.14 However, the data are still too limited.
CONCLUSION
Despite improving noninvasive diagnostic techniques for monitoring kidney grafts, the definite diagnosis of AR continues to be contingent on histologic findings. However, the correct use and interpretation of current noninvasive methods, in particular CDS, may be very helpful to establish definite indications for graft biopsy.
Fig 2. In the upper scan a normal intrarenal Doppler flow pattern with blunted peak systolic deflections and persistent antegrade flow during the diastole can be observed. Pulsatility index (PI) value is 0.88. In contrast, the lower scan shows sharp-pointed systolic deflections associated with retrograde diastolic flow and extremely elevated PI value (7.5) corresponding to a graft with severe vascular rejection.
REFERENCES 1. Knight RJ, Burrows L, Bodian C: Transplantation 72:69, 2001 2. Gjertson DW: Clin Transpl, 159, 2001 3. Moss A, Najarian JS, Sutherland DE, et al: Clin Transpl:159, 2000 4. Solilllou JP: NEJM 334:13, 2001 5. Kahan B, Ponticelli C: Principles and Practice of Renal Transplantation. London: Martin Dunitz Lmtd; 2000, p 846 6. Van Oers MHJ, Van der Hieden AAPAM, Aarden LA: Clin Exp Immunol 71:314, 1988 7. Li B, Hartono C, Ding R, et al: NEJM 334:947, 2001 8. Salgado O, Martin M, Urdaneta B, et al: Transplant Proc 31:2241, 1999 9. Hollenbeck M, Hilbert N, Meusel F, et al: Clin Invest 72:609, 1994 10. Salgado O, Garcı´a R, Rinco ´n O, et al: Transplant Proc 28:3339, 1996 11. Salgado O, Garcı´a R, Henrı´quez C, et al: J Ultrasound Med 16:699, 1997 12. Haef JG, Iversen J: Eur J Nucl Med 27:871, 2000 13. Liou JT, Lee JK, Heiken JP, et al: Radiology 179:61, 1991 14. Sharma RK, Gupta RK, Poptani H, et al: Transplantation 59:1405, 1995
D
ESPITE IMPROVED immunosuppression, acute rejection (AR) has remained a serious complication affecting the survival of kidney transplants.1,2 In addition, AR is a major risk factor for chronic rejection, which is currently the major cause of late graft loss.3,4 Early diagnosis of AR is essential to limit the extent and severity of graft damage. The main goal of noninvasive diagnostic techniques is to provide early evidence of an ongoing AR and, as far as possible, to rule out other cause of graft dysfunction.
CLINICAL MANIFESTATIONS
Classical manifestations of AR are graft tenderness, fever, oliguria, proteinuria, lymphocyturia, deteriorating graft function.5 The use of newer and more potent immunosuppressive agents has profoundly modified the local and systemic manifestations of acute rejection, making its clinical course more insidious and thus rendering early diagnosis more difficult.4 For this reason, the absence of clinical symptoms does not exclude rejection.
IMMUNE MONITORING
For years investigators have attempted to identify markers of immune function in blood, urine, and the graft itself.6 More recently, Li et al7 reported that the measurement in urine of mRNA encoding two cytotoxic granule proteins, perforin and granzyme B, is a useful noninvasive test to predict acute renal graft rejection. In their study, Li et al7 did not observe any correlation between the severity of AR and the levels of perforin or granzyme B mRNA. In addition, the presence of vascular lesions could not be predicted by this technique.4 Further investigations appears to be necessary in the future to validate this method.
From the Center of Experimental Surgery, University of Zulia and Nephrology Department, University Hospital, Maracaibo, Venezuela. Address reprint requests to Octavio J. Salgado, MD, Apartado Postal 1430 Maracaibo 4001-A, Venezuela.
Fig 1. Basal B mode sonographies (A and C) of two different cadaveric renal grafts presenting with acute rejection posteriorly. The corresponding control sonographies (C and D) done during each rejection episode showed a thickening of the collecting system (C) in one of the cases and a diminution of renal sinus area (D) in the other as most prominent sonographic rejection signs. © 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03480-2
Transplantation Proceedings, 34, 2543–2544 (2002)
2543
2544
SALGADO
RENAL SONOGRAPHY
Color Doppler sonograpy (CDS) is the most useful noninvasive diagnostic methods for the differential diagnosis of AR. CDS may provide accurate real-time B mode kidney graft imaging with simultaneous display of intrarenal Doppler flow pattern and distribution. In addition, currently available CDS equipment is provided with software that permits direct calculation of impedance indexes from Doppler waveforms. Differential diagnosis of AR, which includes other common causes of graft dysfunction, such as urinary obstruction due intrinsic (ureteral stenosis) or extrinsic (lymphocele, hematoma) causes, can be readily assessed by B mode imaging.8 However, changes in graft appearance on B mode sonography (Fig 1), such as decreased renal sinus area, thickening of the collecting system, prominence of the pyramids, increased graft size, etc, initially thought to be predictive for AR, have proved later to be nonspecific.9 Similarly, the elevation of Doppler impedance indexes such as pulsatility (PI) or resistive (RI) index, contrary to the initial reports, have been shown to not be specific for AR but to occur most frequently in acute tubular necrosis.10 However, unexplained sharp elevations of impedance indexes occurring in the early posttrasplant period might suggest underlying vascular rejection11 (Fig 2). Three-dimensional ultrasound (3D-US) seems to be a more accurate method to assess graft volume changes and perirenal fluid collections. However, no studies have been conducted yet to evaluate its advantages over bidimensional ultrasound for the differential diagnosis of AR.
RENAL SCINTIGRAPHY AND OTHER RENAL IMAGING TECHNIQUES
Renal scintigraphy may show delayed or decreased Tc or In DPTA perfusion as well as delayed orthoiodohipppurate or Tc 99-m MAG 3 excretion in rejecting grafts. However, those findings are not specific for AR.12 Other noninvasive diagnostic imaging techniques, such as computed tomography and magnetic resonance (MR) imaging, usually do not provide additional information in case of AR than that obtained with conventional CDS.13 More recently, it has been reported that contrast-enhanced MR renograms using gadolinium DPTA would show distinct time-versus-signal intensity curves in AR.14 However, the data are still too limited.
CONCLUSION
Despite improving noninvasive diagnostic techniques for monitoring kidney grafts, the definite diagnosis of AR continues to be contingent on histologic findings. However, the correct use and interpretation of current noninvasive methods, in particular CDS, may be very helpful to establish definite indications for graft biopsy.
Fig 2. In the upper scan a normal intrarenal Doppler flow pattern with blunted peak systolic deflections and persistent antegrade flow during the diastole can be observed. Pulsatility index (PI) value is 0.88. In contrast, the lower scan shows sharp-pointed systolic deflections associated with retrograde diastolic flow and extremely elevated PI value (7.5) corresponding to a graft with severe vascular rejection.
REFERENCES 1. Knight RJ, Burrows L, Bodian C: Transplantation 72:69, 2001 2. Gjertson DW: Clin Transpl, 159, 2001 3. Moss A, Najarian JS, Sutherland DE, et al: Clin Transpl:159, 2000 4. Solilllou JP: NEJM 334:13, 2001 5. Kahan B, Ponticelli C: Principles and Practice of Renal Transplantation. London: Martin Dunitz Lmtd; 2000, p 846 6. Van Oers MHJ, Van der Hieden AAPAM, Aarden LA: Clin Exp Immunol 71:314, 1988 7. Li B, Hartono C, Ding R, et al: NEJM 334:947, 2001 8. Salgado O, Martin M, Urdaneta B, et al: Transplant Proc 31:2241, 1999 9. Hollenbeck M, Hilbert N, Meusel F, et al: Clin Invest 72:609, 1994 10. Salgado O, Garcı´a R, Rinco ´n O, et al: Transplant Proc 28:3339, 1996 11. Salgado O, Garcı´a R, Henrı´quez C, et al: J Ultrasound Med 16:699, 1997 12. Haef JG, Iversen J: Eur J Nucl Med 27:871, 2000 13. Liou JT, Lee JK, Heiken JP, et al: Radiology 179:61, 1991 14. Sharma RK, Gupta RK, Poptani H, et al: Transplantation 59:1405, 1995