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Imaging of Renal Transplant: Utility and Spectrum of Diagnostic Findings
Imaging of Renal Transplant: Utility and Spectrum of Diagnostic Findings Khaled M. Elsayes, MD,a Christine O. Menias, MD,c Jonathon Willatt, MD,b Shadi Azar, MD,b Howard J. Harvin, MD,c and Joel F. Platt, MDb
Several noninvasive imaging techniques have been developed and improved over recent years that facilitate detection of both vascular and nonvascular postoperative complications as well as diagnosis of diseases related to the transplanted organ itself. In this article, we present a multi-modality review of the spectrum of pathology related to renal transplantation.
Introduction Kidney transplantation is the treatment of choice for end-stage renal disease.1 A successful kidney transplant improves quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis.2-4 Several noninvasive imaging techniques have been developed and improved over recent years that facilitate detection of both vascular and nonvascular postoperative complications as well as diagnosis of diseases related to the transplanted organ itself. Ultrasound with color Doppler imaging is usually the first-line imaging modality with morphologic visualization of the renal parenchyma and measuring the resistive indices (resistive indices (RI) ⫽ peak systole ⫺ end diastole/peak systole), followed by unenhanced/enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Nephrogenic systemic fibrosis is a newly described disorder occurring in persons with renal failure. Gadolinium-based con-
From the aDepartment of Radiology, MD Anderson Cancer Center, Houston, TX; bDepartment of Radiology, University of Michigan Health Center, Ann Arbor, MI; and cMallinckrodt Institute of Radiology, Washington University, St. Louis, MO. Reprint requests: Khaled M. Elsayes, MD, Assistant Professor, Department of Radiology, University of Michigan Health Center, Ann Arbor, MI 48109-0030. E-mail: [email protected]. Curr Probl Diagn Radiol 2011;40:127-139. © 2011 Published by Mosby, Inc. 0363-0188/$36.00 ⫹ 0 doi:10.1067/j.cpradiol.2010.06.001
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trast used in MRI has been suggested as a dosedependent cause. The risk associated with gadolinium may differ by contrast agent and dialysis modality. Use of gadolinium-based contrast agents should be avoided when possible in patients with renal failure. In this article, we present a multi-modality review of the spectrum of pathology related to renal transplantation. Renal allografts are placed in both intraperitoneal and extraperitoneal locations in the iliac fossa. The transplant vessels are anastomosed to the external or internal iliac vessels, and the donor ureter is anastomosed at the inside of the bladder wall of the recipient bladder following the creation of a submucosal vesical tunnel near the trigone. Early complications, occurring in the first few weeks following transplantation, are usually related to the surgical procedure. Late complications are usually due to immunosuppression or drug toxicity. Four portions of the transplant kidney should be examined radiologically: the renal parenchyma, the collecting system and ureter, the vasculature, and the extrarenal spaces.
Parenchymal Pathology Allograft Rejection Acute and chronic rejection are the most frequent causes of both early and late allograft failure. New immunosuppression regimens have reduced the incidence of acute rejection to 10%-15% compared with 60% reported rates in the 1980s.5 Despite the use of antirejection therapy, acute rejection decreases allograft survival by between 18% and 27% at 1 year and has a detrimental effect on long-term graft survival. Acute rejection should be suspected in any patient with rising creatinine. Associated symptoms and signs include decreased urine output and hypertension, al-
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FIG 1. A 61-year-old male with chronic rejection of renal transplant. Contrast-enhanced CT scan revealed evidence of cortical thinning (arrow).
though in most cases, patients are asymptomatic. The differential diagnosis for rejection includes acute tubular necrosis. This entity tends to occur during the first 2 weeks post transplantation and may resolve spontaneously. Chronic renal transplant rejection is a poorly understood entity defined as renal allograft dysfunction occurring at least 3 months post transplant in the absence of active acute rejection, drug toxicity, or other diseases. Diagnosis rests on slowly rising plasma creatinine concentration, increasing proteinuria, and worsening hypertension.6 Pathologic findings following biopsy include thickening of the glomerular capillary walls and patchy interstitial fibrosis.7 The ultrasound appearances of both acute and chronic rejection can include a reduction in corticomedullary differentiation, increased echogenicity, prominent medullary pyramids, graft enlargement, and urothelial thickening. Thinning of the cortex and mild collecting system dilatation occurs at the later stages of chronic rejection. However, these are nonspecific findings and accurate diagnosis depends on clinical factors and in some cases biopsy. Although nonspecific, elevated RI can occur in the presence of both acute and chronic rejection. An elevated RI above 0.8 in patients with acute rejection has been associated with poor longterm renal allograft function.8-10 The appearances at CT of acute and chronic rejection include cortical thinning (Fig 1), loss of cortico-
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FIG 2. A 49-year-old male with chronic rejection of renal transplant. Contrast-enhanced CT in the corticomedullary phase revealed loss of corticomedullary differentiation.
FIG 3. A 52-year-old female with chronic rejection of renal transplant. Contrast-enhanced CT revealed coarse calcifications.
medullary differentiation (Fig 2), decreased graft enhancement, delayed or absent contrast excretion, shrinkage in the later phases, and coarse calcifications11 (Fig 3). MRI demonstrates T1 shortening of the renal cortex, which contributes also to loss of corticomedullary differentiation on the contrast-enhanced fat-suppressed T1-weighted sequence.12 Recent research with blood-oxygen level-dependent MRI has
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FIG 4. A 57-year-old male with renal transplant, presenting with fever. Ultrasound revealed a hypoechoic complex area representing an abscess with surrounding hyperemia. Aspiration yielded Nocardia asteroides. (Color version of figure is available online.)
FIG 6. A 55-year-old male, presenting 3 years post transplant and 2 years following renal artery dissection secondary to angioplasty for renal artery stenosis. Color Doppler ultrasound (A) revealed absence of flow in the lower pole of allograft, representing a renal infarct (arrow). Contrast-enhanced CT (B) revealed nonenhancement of lower pole (arrow). (Color version of figure is available online.)
FIG 5. A 48-year-old female with renal transplant, presenting with fever. Contrast-enhanced CT revealed a wedge-shaped low-attenuation area, representing pyelonephritis.
shown some progress in differentiating acute rejection from acute tubular necrosis and a normal functioning kidney.13
Infection Infection is a common complication following the surgery and immunosuppression is also related to renal
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transplantation.14 Cytomegalovirus is the most common opportunistic pathogen.15 Presentation may be delayed owing to the immunosuppressed status. The appearance of pyelonephritis is nonspecific on ultrasound. A focal area of decreased echogenicity indicates more advanced disease. An abscess typically appears cystic and there may be increased color flow in the adjacent renal parenchyma (Fig 4). Gas bubbles within the abscess may produce echogenic lines and reverberation artifact. Fungus balls appear as echogenic, variably shadowing masses in the collecting system. Pyonephrosis causes low-level echoes within an often dilated collecting system.
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FIG 7. A 59-year-old male, presenting 1 year post transplant, with cervical lymphadenopathy. (A) Unenhanced CT shows a contour-deforming mass at the interpolar region of the left kidney (arrow). On T1-weighted image (B), the lesion exhibits low signal intensity (arrow) with a heterogeneous signal intensity on T2-weighted imaging (arrow in C), representing a pathologically proven PTLD.
Pyelonephritis when seen on CT appears as a hypodense wedge-shaped region, more apparent following intravenous contrast (Fig 5). An abscess will appear as a nonenhancing low-attenuation mass with attenuation values often higher than those of simple fluid. The presence of internal gas bubbles is often diagnostic.
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Infarction Infarction can occur because of vascular insults, which cause segmental or diffuse infarcts, or from torsion of the kidney on its pedicle,16 resulting in infarction of the whole kidney. Other causes of infarction include rejection, infection, and accidental or
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FIG 8. A 55-year-old female, 5 years post transplant. Ultrasound revealed extensive cortical calcification (arrows), representing cortical nephrocalcinosis.
iatrogenic trauma. Urinary output decreases and there may be pain related to an inflammatory response in the visceral peritoneum. The ultrasound appearance can mimic that of pyelonephritis, with an area of decreased echogenicity with focal areas of decreased color flow (Fig 6A). CT often shows focal areas of decreased attenuation after contrast (Fig 6B). Infarction of the whole kidney leads to global lack of enhancement and atrophy of the allograft in the longer term. MRI can be employed without using IV contrast, which may be an advantage in this clinical context. Low signal intensity is seen on both T1-weighted and T2-weighted sequences unless there is hemorrhage, in which case there will be high signal intensity on T1-weighted imaging.17,18 The magnetic resonance contrast-enhanced sequence, if used, shows focal areas of decreased perfusion.
Tumor Lymphoproliferative disorders are the most common malignancies complicating organ transplantation, accounting for 21% of all malignancies compared with 5% of malignancies in the general population.19 The pathogenesis of post transplant lymphoproliferative disease (PTLD) is related to B-cell proliferation induced by infection with Epstein–Barr virus in the setting of chronic immunosuppression.20 Because the development of PTLD is related to the degree of immunosuppression, prevention largely relies on limiting patient exposure to aggressive immunosuppressive regimens.21 PTLD occurs in approximately 1% of
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FIG 9. End-stage failed allografts. (A) Densely, calcified right iliac fossa allograft 19 years post transplant (arrow). Normally functioning left iliac fossa graft, 2 years post transplant. (B) Nonenhancing, atrophic infarcted allograft with prominent renal sinus fat.
patients, 30-50 times higher than in the general population.22 PTLD involving the kidney favors parenchymal tissue close to the renal hilum.23 On ultrasound, PTLD can be visualized as a nonspecific hypoechoic mass. Varying degrees of enhancement are seen on CT, whereas on MRI there is low signal intensity on T1- and variable signal intensity on T2-weighted imaging (Fig 7). The incidence of other cancers, including thyroid, renal, hepatic, skin, and gastric cancers, as well as of Kaposi sarcoma, is also increased in patients with renal transplants.24 This is related to the degree of immunosuppression. Primary renal cancers tend to affect the native kidneys more than the transplant kidney.
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FIG. 10. A 60-year-old male, 3 days post transplant. Doppler US arterial waveform shows reversed prolonged diastolic flow, representing renal vein thrombosis. (Color version of figure is available online.)
Cortical Nephrocalcinosis This is a rare entity that is most likely related to chronic rejection. An echogenic rim is seen on ultrasound, reflecting cortical calcium deposition. Flecks of often peripheral calcification may be seen on imaging (Fig 8).
End-Stage Failed Kidney In the aftermath of chronic renal failure, the transplant kidney undergoes atrophy and, eventually, punctate or diffuse calcification of the parenchyma (Fig 9A). The renal sinus fat becomes more prominent (Fig 9B). Calcification of the renal artery can also be seen. By this stage, the kidney is nonfunctioning and a further transplant may have to be performed.
FIG 11. A 65-year-old male, 6 days post transplant. Spectral Doppler (A) demonstrates no parenchymal flow. Power Doppler (B) reveals flow in the main artery to the level of the hilum, but no flow in the renal parenchyma. (Color version of figure is available online.)
Vascular Pathology Renal Artery and Vein Thrombosis Thrombosis can occur with or without rejection. Thrombosis may result from intimal dissection in the case of an artery or from kinking of both arteries and veins.25 Risk factors for arterial thrombosis include hypotension, and multiple renal arteries, as well as intimal dissection and kinking of the vessel. Risk factors for venous thrombosis include hypercoagulability, hematomas or lymphoceles causing compression, anastomotic stenosis, and extension of a deep venous thrombosis. The incidence ranges from 0.4% to 6%.26 Patients with lupus, antiphospholipid
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antibodies, or a history of thromboembolic disease may benefit from continued warfarin therapy.27 Thrombosis of the renal artery and vein is associated with a sudden decrease in urine output. Renal vein thrombosis, but not usually artery thrombosis, is associated with a tender, swollen allograft. Both entities can present with hematuria and graft dysfunction. Doppler interrogation demonstrates echogenic material in the vein and reversal of flow in the main renal artery in diastole in the case of renal vein thrombosis (Fig 10), and with reduced or absent flow to the kidney in the case of renal artery thrombosis (Fig 11).
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FIG 12. Magnetic resonance angiography shows a focal stenosis at the anastomosis of the donor artery to the common iliac artery (arrow).
Color Doppler ultrasound can be technically challenging, but a velocity of over 200 cm/s in the transplant renal artery is regarded as highly suggestive.29 Distal to the stenosis, aliasing and spectral broadening can be seen signifying turbulence created by the disordered flow proximal and distal to the rapidly flowing blood in the stenotic segment.30 Magnetic resonance angiography is an accurate modality in confirming the diagnosis and does not have risks associated with nephrotoxic contrast agents, ionizing radiation, or arterial catheterization31 (Fig 12). Stenoses proximal to the origin of the transplant renal artery, most often related to atherosclerotic disease, can produce a “pseudo-stenosis.” Graft dysfunction and hypertension are again the sequelae, but it is important to make the distinction so that appropriate management can be carried out (Fig 13). FIG 13. A 67-year-old female, 13 years post transplant. Magnetic resonance angiography shows an atherosclerotic plaque in external iliac artery (arrow) proximal to end-to-side anastomosis. This was successfully treated with angioplasty.
Renal Artery Stenosis The incidence of post renal transplant renal artery stenosis is around 1%.28 The stenosis can be related to atherosclerotic disease in the native artery, anastomotic stenosis related to the suture, or post anastomotic stenosis due to external compression, kinking, or rejection. Patients present with hypertension resistant to therapy and deterioration in renal function.
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Renal Artery Pseudoaneurysm Both arteriovenous fistula and pseudoaneurysm are seen in renal transplants following percutaneous biopsy. A pseudoaneurysm will appear as a cystic structure on gray-scale ultrasound, but will demonstrate intense vascular flow on color imaging. There may be bidirectional flow in the neck of the pseudoaneurysm (Fig 14). Occasionally, a pseudoaneurysm will form at the site of the anastomosis, secondary to incomplete closure32 (Fig 15). An arteriovenous fistula can be differentiated from a pseudoaneurysm by high-velocity flow extending
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FIG 14. A 64-year-old male, 5 years posttransplant. Gray-scale ultrasound (A), color Doppler ultrasound (B) revealed an intense flow in a cystic structure with a to-and-fro pattern, representing pseudoaneurysm. (Color version of figure is available online.)
FIG 15. A 55-year-old male, 7 years posttransplant. Contrast-enhanced CT revealed a pseudoaneurysm with thrombus near anastomosis (arrow).
FIG 17. A 46-year-old male presenting with swelling at graft site 2 weeks post transplant. Ultrasound revealed the presence of anechoic peri-transplant fluid collection, representing urinoma (arrow).
from a feeding artery. An arterial pattern of flow can be identified in a draining vein to confirm the diagnosis.
Fluid Collections FIG 16. A 53-year-old male presenting with pain at graft site 2 weeks post transplant. Ultrasound revealed allograft hydronephrosis due to compression of ureter by a lymphocele (not shown in the single limited image), 2 months post transplant.
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A variety of postoperative fluid collections can be seen. Peri-transplant abscesses are rare but potentially the most serious of postoperative fluid collections, and
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FIG 18. A 59-year-old female presenting with fever 2 years post transplant. Ultrasound (A) and CT (B) revealed the presence of peri-transplant fluid collection with low-level echoes on ultrasound, and rim enhancement on CT, representing a perinephric abscess (arrow). Culture of the aspirate revealed Pseudomonas aerginosa.
FIG 19. A 49-year-old male presenting with swelling at graft site 3 weeks post transplant. Ultrasound and CT revealed the presence of peri-transplant fluid collection, representing a lymphocele (arrow).
therefore, should always be excluded first.33 Urinary leaks are generally seen in the first 3 weeks after transplant, occurring because of damage to the collecting system or ureter during surgery, to inadequate anastomosis, or to distal ureteric necrosis. They are seen in up to 6% of transplants.34 Seromas and hematomas also develop in the immediate postoperative period and are generally self-limiting, although intervention is occasionally required.24 Hematomas can form in both subcapsular and extrarenal spaces.
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Lymphoceles are the most commonly seen fluid collections after renal transplantation. Although lymphoceles generally form in the postoperative period, they can also occur months and years later. These can cause ureteric obstruction (Fig 16), compression of the renal artery and vein resulting in stenosis and thrombosis, and compression of lymphatic draining the lower limb, resulting in unilateral edema.35 Ultrasound is commonly used for assessment of post transplant fluid collections. Diagnosis can often be made with a combination of imaging appearances and clinical factors. Abscess, lymphoceles, and urinomas (Fig 17) are visualized as anechoic simple cystic structures, although chronic abscesses can become more complex (Fig 18) and may exhibit increased flow in the walls, and lymphoceles can develop thin septations (Fig 19).17 Urinomas, hematomas, and lymphoceles can become infected. Gas bubbles in abscesses can be identified on ultrasound as echogenic structures with ring down artifacts in the nondependent parts and are easily identified at CT. Hematomas can also be very complex on ultrasound (Figs 20 and 21). The CT attenuation values for lymphoceles and urinomas tend to be lower than those of abscesses and hematomas. Hematomas can be heterogeneous on CT as blood products evolve over time. MRI will also reflect the heterogeneity of blood products and will show high T1-weighted components. Ultrasound-guided aspiration is frequently used to identify organisms. The complexity of different fluid collections often makes drainage difficult, and many
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FIG 20. A 47-year-old female presenting with pain at graft site 2 months post transplant, 1 day after biopsy. Ultrasound and CT revealed the presence of crescent-shaped fluid collection, representing subcapsular hematoma (arrow).
FIG 21. A 52-year-old male presenting with pain at graft site 2 weeks post transplant. Ultrasound and CT revealed the presence of peri-transplant fluid collection, representing hematoma (arrow).
of them resolve spontaneously or are self-limiting. Surgical intervention is rarely required.25
Collecting System Pathology Ureteral Strictures The incidence of ureteral strictures has been reduced to around 1% owing to improved surgical techniques.36,37 The cause is most commonly vascular insufficiency at the distal ureter (Fig 22). Calculi, kinking of the ureter due to adhesions, fibrosis, and extrinsic compression are less common. Urinary obstruction often presents later than with the normal kidney because the kidney is denervated and pain is felt at a later stage when the capsule is distended. Mild collecting system dilatation is not uncommon in the
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renal transplant and is not related to obstruction. The resistive index parameters used for the native kidney are unproven in the transplant kidney.10 Scintigraphy is occasionally required to evaluate for obstruction as opposed to “benign” dilatation of the collecting system.
Calculi The incidence of renal and ureteric calculi is low in the transplant kidney despite hypercalcemia related to the underlying renal impairment.38,39 This can be seen as a late complication. Ureteral stricture, chronic infection, and renal tubular acidosis are also implicated. Stones can also be carried over from the donor kidney.40
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FIG 22. A 48-year-old male with renal transplant. Ultrasound shows a dilated renal collecting system and ureter (A), with thickening of the distal ureter (arrow in B). Antegrade pyelography following the insertion of a nephrostomy confirms a distal stricture (arrow in C). (Color version of figure is available online.)
FIG 23. (A, B) A 57-year-old female, presenting with hematuria 8 years post transplant. CT revealed thick urothelial calcification (arrow), representing alkaline-encrusted pyelitis. Urinalysis revealed alkaline urine, and multiple urine cultures with gram-positive rods.
Alkaline-Encrusted Pyelitis Alkaline encrusted pyelitis is a rare infectious disease characterized by encrustations in the wall of the upper urinary tract, surrounded by severe inflammation. Destruction of kidney grafts can occur, resulting in end-stage renal failure. Corynebacterium is almost exclusively associated with this disease. The most important predisposing
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factors are previous urological procedures and an immunosuppressed state.41 Urothelial calcification and perinephric stranding can be seen on unenhanced CT (Fig 23).
Transitional Cell Carcinoma The incidence of transitional cell carcinoma is increased in the renal transplant population.42,43 This
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FIG 24. A 63-year-old male, presenting with hematuria 10 years post transplant. Ultrasound of allograft shows solid lesion in renal pelvis (arrow), representing a pathologically proven TCC. (Color version of figure is available online.)
may be attributed to the use of cyclophosphamide44 and to analgesic nephropathy.42 The pattern of growth is widely disseminated in this population. Diagnosis is likely to be delayed because of the wide differential diagnosis of hematuria and urinary obstruction, but suspicion should be raised in the event of identification of urothelial thickening and masses (Fig 24). Urine cytology will be useful in this scenario.
Conclusions Complications of renal allograft transplantation occur in both the short and the long term. Imaging plays a major role alongside clinical evaluation in the diagnosis of these complications. A systematic approach to image review and a thorough understanding of the clinical background are essential for diagnosing these complications.
REFERENCES 1. Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med 1994;331:365-76. 2. Ojo AO, Port FK, Wolfe RA, et al. Comparative mortality risks of chronic dialysis and cadaveric transplantation in black end-stage renal disease patients. Am J Kidney Dis 1994;24: 59-64. 3. Port FK, Wolfe RA, Mauger EA, et al. Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA 1993;270:1339-43. 4. Schnuelle P, Lorenz D, Trede M, et al. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998;9:2135-41.
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5. Cohen DJ, St Martin L, Christensen LL, et al. Kidney and pancreas transplantation in the United States, 1995-2004. Am J Transplant 2006;6(Pt 2):1153-69. 6. Monaco AP, Burke JF Jr, Ferguson RM, et al. Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion. Am J Kidney Dis 1999;33:150-60. 7. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713-23. 8. Radermacher J, Mengel M, Ellis S, et al. The renal arterial resistance index and renal allograft survival. N Engl J Med 2003;349:115-24. 9. Tublin ME, Bude RO, Platt JF. The resistive index in renal Doppler sonography: where do we stand? [Review]. AJR 2003;180:885-92. 10. Wollenberg K, Waibel B, Pisarski P, et al. Careful clinical monitoring in comparison to sequential Doppler sonography for the detection of acute rejection in the early phase after renal transplantation. Transpl Int 2000;13(suppl 1):S45-51. 11. Gayer G, Apter S, Katz R, et al. Findings in ten patients with failed renal allografts: comparison with findings in functional grafts. Eur J Radiol 2000;36:133-8. 12. Neimatallah MA, Dong Q, Schoenberg SO, et al. Magnetic resonance imaging in renal transplantation. J Magn Reson Imaging 1999;10:357-68. 13. Sadowski EA, Fain SB, Alford SK, et al. Assessment of acute renal transplant rejection with blood oxygen level-dependent MR imaging: initial experience. Radiology 2005;236:911-9. 14. Rubin RH. Infectious disease complications of renal transplantation. Kidney Int 1993;44:221-36. 15. Carstens J, Andersen HK, Spencer E, et al. Cytomegalovirus infection in renal transplant recipients. Transpl Infect Dis 2006;8:203-12. 16. Wong-You-Cheong JJ, Grumbach K, Krebs TL, et al. Torsion of intraperitoneal renal transplants: imaging appearances. AJR 1998;171:1355-9. 17. Akbar SA, Jafri SZ, Amendola MA, et al. Complications of renal transplantation. RadioGraphics 2005;25:1335-56. 18. Kim SH, Park JH, Han JK, et al. Infarction of the kidney: Role of contrast enhanced MRI. J Comput Assist Tomogr 1992;16: 924-8. 19. Penn I. Cancers complicating organ transplantation. N Engl J Med 1990;323:1767-9. 20. Kotton CN, Fishman JA. Viral infection in the renal transplant recipient. J Am Soc Nephrol 2005;16:1758-74. 21. Shapiro R, Scantlebury VP, Jordan ML, et al. FK506 in pediatric kidney transplantation—Primary and rescue experience. Pediatr Nephrol 1995;9(suppl):S43-8. 22. Caillard S, Lelong C, Pessione F, et al. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: Report of 230 cases from the French Registry. Am J Transplant 2006;6:2735-42. 23. Vrachliotis TG, Vaswani KK, Davies EA, et al. Findings in posttransplantation lymphoproliferative disorder of renal transplants. AJR 2000;175:183-8. 24. Vegso G, Toth M, Hidvegi M, et al. Malignancies after renal transplantation during 33 years at a single center. Pathol Oncol Res 2007;13:63-9.
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25. Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial 2005;18:505-10. 26. Osman Y, Shokeir A, Ali-el-Dein B, et al. Vascular complications after live donor renal transplantation: study of risk factors and effects on graft and patient survival. J Urol 2003;169:859-62. 27. Kujovich JL. Thrombophilia and thrombotic problems in renal transplant patients. Transplantation 2004;77:959-64. 28. Polak WG, Jezior D, Garcarek J, et al. Incidence and outcome of transplant renal artery stenosis: single center experience. Transplant Proc 2006;38:131-2. 29. de Morais RH, Muglia VF, Mamere AE, et al. Duplex Doppler sonography of transplant renal artery stenosis. J Clin Ultrasound 2003;31:135-41. 30. Baxter GM. Imaging in renal transplantation. Ultrasound Q 2003;19:123-38. 31. Zhang H, Prince MR, Renal MR. Angiography. Magn Reson Imaging Clin N Am 2004;12:487-503, vi. 32. Koo CK, Rodger S, Baxter GM. Extra-renal pseudoaneurysm: An uncommon complication following renal transplantation. Clin Radiol 1999;54:755-8. 33. Edelstein HE, McCabe RE, Lieberman E. Perinephric abscess in renal transplant recipients: report of seven cases and review. Rev Infect Dis 1989;11:569-77. 34. Nargund V, Cranston D. Urological complications after renal transplantation. Transplant Rev 1996;10:24-33.
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35. Samhan M, Al-Mousawi M. Lymphocele following renal transplantation. Saudi J Kidney Disord Transpl 2006;17:34-7. 36. Breda A, Bui MH, Liao JC, et al. Incidence of ureteral strictures after laparoscopic donor nephrectomy. J Urol 2006; 176:1065-8. 37. Dalgic A, Boyvat F, Karakayali H, et al. Urologic complications in 1523 renal transplantations: The Baskent University experience. Transplant Proc 2006;38:543-7. 38. Challacombe B, Dasgupta P, Tiptaft R, et al. Multimodal management of urolithiasis in renal transplantation. BJU Int 2005;96:385-9. 39. Streeter EH, Little DM, Cranston DW, et al. The urological complications of renal transplantation: a series of 1535 patients. BJU Int 2002;90:627-34. 40. Devasia A, Chacko N, Gnanaraj L, et al. Stone-bearing live-donor kidneys for transplantation. BJU Int 2005;95: 394-7. 41. Van Hooland S, Vandooren AK, Lerut E, et al. Alkaline encrusted pyelitis. Acta Clin Belg 2005;60:369-72. 42. Swindle P, Falk M, Rigby R, et al. Transitional cell carcinoma in renal transplant recipients: the influence of compound analgesics. Br J Urol 1998;81:229-33. 43. Wu MJ, Lian JD, Yang CR, et al. High cumulative incidence of urinary tract transitional cell carcinoma after kidney transplantation in Taiwan. Am J Kidney Dis 2004;43:1091-7. 44. Levine LA, Richie JP. Urological complications of cyclophosphamide. J Urol 1989;141:1063-9.
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Several noninvasive imaging techniques have been developed and improved over recent years that facilitate detection of both vascular and nonvascular postoperative complications as well as diagnosis of diseases related to the transplanted organ itself. In this article, we present a multi-modality review of the spectrum of pathology related to renal transplantation.
Introduction Kidney transplantation is the treatment of choice for end-stage renal disease.1 A successful kidney transplant improves quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis.2-4 Several noninvasive imaging techniques have been developed and improved over recent years that facilitate detection of both vascular and nonvascular postoperative complications as well as diagnosis of diseases related to the transplanted organ itself. Ultrasound with color Doppler imaging is usually the first-line imaging modality with morphologic visualization of the renal parenchyma and measuring the resistive indices (resistive indices (RI) ⫽ peak systole ⫺ end diastole/peak systole), followed by unenhanced/enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Nephrogenic systemic fibrosis is a newly described disorder occurring in persons with renal failure. Gadolinium-based con-
From the aDepartment of Radiology, MD Anderson Cancer Center, Houston, TX; bDepartment of Radiology, University of Michigan Health Center, Ann Arbor, MI; and cMallinckrodt Institute of Radiology, Washington University, St. Louis, MO. Reprint requests: Khaled M. Elsayes, MD, Assistant Professor, Department of Radiology, University of Michigan Health Center, Ann Arbor, MI 48109-0030. E-mail: [email protected]. Curr Probl Diagn Radiol 2011;40:127-139. © 2011 Published by Mosby, Inc. 0363-0188/$36.00 ⫹ 0 doi:10.1067/j.cpradiol.2010.06.001
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trast used in MRI has been suggested as a dosedependent cause. The risk associated with gadolinium may differ by contrast agent and dialysis modality. Use of gadolinium-based contrast agents should be avoided when possible in patients with renal failure. In this article, we present a multi-modality review of the spectrum of pathology related to renal transplantation. Renal allografts are placed in both intraperitoneal and extraperitoneal locations in the iliac fossa. The transplant vessels are anastomosed to the external or internal iliac vessels, and the donor ureter is anastomosed at the inside of the bladder wall of the recipient bladder following the creation of a submucosal vesical tunnel near the trigone. Early complications, occurring in the first few weeks following transplantation, are usually related to the surgical procedure. Late complications are usually due to immunosuppression or drug toxicity. Four portions of the transplant kidney should be examined radiologically: the renal parenchyma, the collecting system and ureter, the vasculature, and the extrarenal spaces.
Parenchymal Pathology Allograft Rejection Acute and chronic rejection are the most frequent causes of both early and late allograft failure. New immunosuppression regimens have reduced the incidence of acute rejection to 10%-15% compared with 60% reported rates in the 1980s.5 Despite the use of antirejection therapy, acute rejection decreases allograft survival by between 18% and 27% at 1 year and has a detrimental effect on long-term graft survival. Acute rejection should be suspected in any patient with rising creatinine. Associated symptoms and signs include decreased urine output and hypertension, al-
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FIG 1. A 61-year-old male with chronic rejection of renal transplant. Contrast-enhanced CT scan revealed evidence of cortical thinning (arrow).
though in most cases, patients are asymptomatic. The differential diagnosis for rejection includes acute tubular necrosis. This entity tends to occur during the first 2 weeks post transplantation and may resolve spontaneously. Chronic renal transplant rejection is a poorly understood entity defined as renal allograft dysfunction occurring at least 3 months post transplant in the absence of active acute rejection, drug toxicity, or other diseases. Diagnosis rests on slowly rising plasma creatinine concentration, increasing proteinuria, and worsening hypertension.6 Pathologic findings following biopsy include thickening of the glomerular capillary walls and patchy interstitial fibrosis.7 The ultrasound appearances of both acute and chronic rejection can include a reduction in corticomedullary differentiation, increased echogenicity, prominent medullary pyramids, graft enlargement, and urothelial thickening. Thinning of the cortex and mild collecting system dilatation occurs at the later stages of chronic rejection. However, these are nonspecific findings and accurate diagnosis depends on clinical factors and in some cases biopsy. Although nonspecific, elevated RI can occur in the presence of both acute and chronic rejection. An elevated RI above 0.8 in patients with acute rejection has been associated with poor longterm renal allograft function.8-10 The appearances at CT of acute and chronic rejection include cortical thinning (Fig 1), loss of cortico-
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FIG 2. A 49-year-old male with chronic rejection of renal transplant. Contrast-enhanced CT in the corticomedullary phase revealed loss of corticomedullary differentiation.
FIG 3. A 52-year-old female with chronic rejection of renal transplant. Contrast-enhanced CT revealed coarse calcifications.
medullary differentiation (Fig 2), decreased graft enhancement, delayed or absent contrast excretion, shrinkage in the later phases, and coarse calcifications11 (Fig 3). MRI demonstrates T1 shortening of the renal cortex, which contributes also to loss of corticomedullary differentiation on the contrast-enhanced fat-suppressed T1-weighted sequence.12 Recent research with blood-oxygen level-dependent MRI has
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FIG 4. A 57-year-old male with renal transplant, presenting with fever. Ultrasound revealed a hypoechoic complex area representing an abscess with surrounding hyperemia. Aspiration yielded Nocardia asteroides. (Color version of figure is available online.)
FIG 6. A 55-year-old male, presenting 3 years post transplant and 2 years following renal artery dissection secondary to angioplasty for renal artery stenosis. Color Doppler ultrasound (A) revealed absence of flow in the lower pole of allograft, representing a renal infarct (arrow). Contrast-enhanced CT (B) revealed nonenhancement of lower pole (arrow). (Color version of figure is available online.)
FIG 5. A 48-year-old female with renal transplant, presenting with fever. Contrast-enhanced CT revealed a wedge-shaped low-attenuation area, representing pyelonephritis.
shown some progress in differentiating acute rejection from acute tubular necrosis and a normal functioning kidney.13
Infection Infection is a common complication following the surgery and immunosuppression is also related to renal
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transplantation.14 Cytomegalovirus is the most common opportunistic pathogen.15 Presentation may be delayed owing to the immunosuppressed status. The appearance of pyelonephritis is nonspecific on ultrasound. A focal area of decreased echogenicity indicates more advanced disease. An abscess typically appears cystic and there may be increased color flow in the adjacent renal parenchyma (Fig 4). Gas bubbles within the abscess may produce echogenic lines and reverberation artifact. Fungus balls appear as echogenic, variably shadowing masses in the collecting system. Pyonephrosis causes low-level echoes within an often dilated collecting system.
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FIG 7. A 59-year-old male, presenting 1 year post transplant, with cervical lymphadenopathy. (A) Unenhanced CT shows a contour-deforming mass at the interpolar region of the left kidney (arrow). On T1-weighted image (B), the lesion exhibits low signal intensity (arrow) with a heterogeneous signal intensity on T2-weighted imaging (arrow in C), representing a pathologically proven PTLD.
Pyelonephritis when seen on CT appears as a hypodense wedge-shaped region, more apparent following intravenous contrast (Fig 5). An abscess will appear as a nonenhancing low-attenuation mass with attenuation values often higher than those of simple fluid. The presence of internal gas bubbles is often diagnostic.
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Infarction Infarction can occur because of vascular insults, which cause segmental or diffuse infarcts, or from torsion of the kidney on its pedicle,16 resulting in infarction of the whole kidney. Other causes of infarction include rejection, infection, and accidental or
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FIG 8. A 55-year-old female, 5 years post transplant. Ultrasound revealed extensive cortical calcification (arrows), representing cortical nephrocalcinosis.
iatrogenic trauma. Urinary output decreases and there may be pain related to an inflammatory response in the visceral peritoneum. The ultrasound appearance can mimic that of pyelonephritis, with an area of decreased echogenicity with focal areas of decreased color flow (Fig 6A). CT often shows focal areas of decreased attenuation after contrast (Fig 6B). Infarction of the whole kidney leads to global lack of enhancement and atrophy of the allograft in the longer term. MRI can be employed without using IV contrast, which may be an advantage in this clinical context. Low signal intensity is seen on both T1-weighted and T2-weighted sequences unless there is hemorrhage, in which case there will be high signal intensity on T1-weighted imaging.17,18 The magnetic resonance contrast-enhanced sequence, if used, shows focal areas of decreased perfusion.
Tumor Lymphoproliferative disorders are the most common malignancies complicating organ transplantation, accounting for 21% of all malignancies compared with 5% of malignancies in the general population.19 The pathogenesis of post transplant lymphoproliferative disease (PTLD) is related to B-cell proliferation induced by infection with Epstein–Barr virus in the setting of chronic immunosuppression.20 Because the development of PTLD is related to the degree of immunosuppression, prevention largely relies on limiting patient exposure to aggressive immunosuppressive regimens.21 PTLD occurs in approximately 1% of
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FIG 9. End-stage failed allografts. (A) Densely, calcified right iliac fossa allograft 19 years post transplant (arrow). Normally functioning left iliac fossa graft, 2 years post transplant. (B) Nonenhancing, atrophic infarcted allograft with prominent renal sinus fat.
patients, 30-50 times higher than in the general population.22 PTLD involving the kidney favors parenchymal tissue close to the renal hilum.23 On ultrasound, PTLD can be visualized as a nonspecific hypoechoic mass. Varying degrees of enhancement are seen on CT, whereas on MRI there is low signal intensity on T1- and variable signal intensity on T2-weighted imaging (Fig 7). The incidence of other cancers, including thyroid, renal, hepatic, skin, and gastric cancers, as well as of Kaposi sarcoma, is also increased in patients with renal transplants.24 This is related to the degree of immunosuppression. Primary renal cancers tend to affect the native kidneys more than the transplant kidney.
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FIG. 10. A 60-year-old male, 3 days post transplant. Doppler US arterial waveform shows reversed prolonged diastolic flow, representing renal vein thrombosis. (Color version of figure is available online.)
Cortical Nephrocalcinosis This is a rare entity that is most likely related to chronic rejection. An echogenic rim is seen on ultrasound, reflecting cortical calcium deposition. Flecks of often peripheral calcification may be seen on imaging (Fig 8).
End-Stage Failed Kidney In the aftermath of chronic renal failure, the transplant kidney undergoes atrophy and, eventually, punctate or diffuse calcification of the parenchyma (Fig 9A). The renal sinus fat becomes more prominent (Fig 9B). Calcification of the renal artery can also be seen. By this stage, the kidney is nonfunctioning and a further transplant may have to be performed.
FIG 11. A 65-year-old male, 6 days post transplant. Spectral Doppler (A) demonstrates no parenchymal flow. Power Doppler (B) reveals flow in the main artery to the level of the hilum, but no flow in the renal parenchyma. (Color version of figure is available online.)
Vascular Pathology Renal Artery and Vein Thrombosis Thrombosis can occur with or without rejection. Thrombosis may result from intimal dissection in the case of an artery or from kinking of both arteries and veins.25 Risk factors for arterial thrombosis include hypotension, and multiple renal arteries, as well as intimal dissection and kinking of the vessel. Risk factors for venous thrombosis include hypercoagulability, hematomas or lymphoceles causing compression, anastomotic stenosis, and extension of a deep venous thrombosis. The incidence ranges from 0.4% to 6%.26 Patients with lupus, antiphospholipid
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antibodies, or a history of thromboembolic disease may benefit from continued warfarin therapy.27 Thrombosis of the renal artery and vein is associated with a sudden decrease in urine output. Renal vein thrombosis, but not usually artery thrombosis, is associated with a tender, swollen allograft. Both entities can present with hematuria and graft dysfunction. Doppler interrogation demonstrates echogenic material in the vein and reversal of flow in the main renal artery in diastole in the case of renal vein thrombosis (Fig 10), and with reduced or absent flow to the kidney in the case of renal artery thrombosis (Fig 11).
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FIG 12. Magnetic resonance angiography shows a focal stenosis at the anastomosis of the donor artery to the common iliac artery (arrow).
Color Doppler ultrasound can be technically challenging, but a velocity of over 200 cm/s in the transplant renal artery is regarded as highly suggestive.29 Distal to the stenosis, aliasing and spectral broadening can be seen signifying turbulence created by the disordered flow proximal and distal to the rapidly flowing blood in the stenotic segment.30 Magnetic resonance angiography is an accurate modality in confirming the diagnosis and does not have risks associated with nephrotoxic contrast agents, ionizing radiation, or arterial catheterization31 (Fig 12). Stenoses proximal to the origin of the transplant renal artery, most often related to atherosclerotic disease, can produce a “pseudo-stenosis.” Graft dysfunction and hypertension are again the sequelae, but it is important to make the distinction so that appropriate management can be carried out (Fig 13). FIG 13. A 67-year-old female, 13 years post transplant. Magnetic resonance angiography shows an atherosclerotic plaque in external iliac artery (arrow) proximal to end-to-side anastomosis. This was successfully treated with angioplasty.
Renal Artery Stenosis The incidence of post renal transplant renal artery stenosis is around 1%.28 The stenosis can be related to atherosclerotic disease in the native artery, anastomotic stenosis related to the suture, or post anastomotic stenosis due to external compression, kinking, or rejection. Patients present with hypertension resistant to therapy and deterioration in renal function.
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Renal Artery Pseudoaneurysm Both arteriovenous fistula and pseudoaneurysm are seen in renal transplants following percutaneous biopsy. A pseudoaneurysm will appear as a cystic structure on gray-scale ultrasound, but will demonstrate intense vascular flow on color imaging. There may be bidirectional flow in the neck of the pseudoaneurysm (Fig 14). Occasionally, a pseudoaneurysm will form at the site of the anastomosis, secondary to incomplete closure32 (Fig 15). An arteriovenous fistula can be differentiated from a pseudoaneurysm by high-velocity flow extending
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FIG 14. A 64-year-old male, 5 years posttransplant. Gray-scale ultrasound (A), color Doppler ultrasound (B) revealed an intense flow in a cystic structure with a to-and-fro pattern, representing pseudoaneurysm. (Color version of figure is available online.)
FIG 15. A 55-year-old male, 7 years posttransplant. Contrast-enhanced CT revealed a pseudoaneurysm with thrombus near anastomosis (arrow).
FIG 17. A 46-year-old male presenting with swelling at graft site 2 weeks post transplant. Ultrasound revealed the presence of anechoic peri-transplant fluid collection, representing urinoma (arrow).
from a feeding artery. An arterial pattern of flow can be identified in a draining vein to confirm the diagnosis.
Fluid Collections FIG 16. A 53-year-old male presenting with pain at graft site 2 weeks post transplant. Ultrasound revealed allograft hydronephrosis due to compression of ureter by a lymphocele (not shown in the single limited image), 2 months post transplant.
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A variety of postoperative fluid collections can be seen. Peri-transplant abscesses are rare but potentially the most serious of postoperative fluid collections, and
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FIG 18. A 59-year-old female presenting with fever 2 years post transplant. Ultrasound (A) and CT (B) revealed the presence of peri-transplant fluid collection with low-level echoes on ultrasound, and rim enhancement on CT, representing a perinephric abscess (arrow). Culture of the aspirate revealed Pseudomonas aerginosa.
FIG 19. A 49-year-old male presenting with swelling at graft site 3 weeks post transplant. Ultrasound and CT revealed the presence of peri-transplant fluid collection, representing a lymphocele (arrow).
therefore, should always be excluded first.33 Urinary leaks are generally seen in the first 3 weeks after transplant, occurring because of damage to the collecting system or ureter during surgery, to inadequate anastomosis, or to distal ureteric necrosis. They are seen in up to 6% of transplants.34 Seromas and hematomas also develop in the immediate postoperative period and are generally self-limiting, although intervention is occasionally required.24 Hematomas can form in both subcapsular and extrarenal spaces.
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Lymphoceles are the most commonly seen fluid collections after renal transplantation. Although lymphoceles generally form in the postoperative period, they can also occur months and years later. These can cause ureteric obstruction (Fig 16), compression of the renal artery and vein resulting in stenosis and thrombosis, and compression of lymphatic draining the lower limb, resulting in unilateral edema.35 Ultrasound is commonly used for assessment of post transplant fluid collections. Diagnosis can often be made with a combination of imaging appearances and clinical factors. Abscess, lymphoceles, and urinomas (Fig 17) are visualized as anechoic simple cystic structures, although chronic abscesses can become more complex (Fig 18) and may exhibit increased flow in the walls, and lymphoceles can develop thin septations (Fig 19).17 Urinomas, hematomas, and lymphoceles can become infected. Gas bubbles in abscesses can be identified on ultrasound as echogenic structures with ring down artifacts in the nondependent parts and are easily identified at CT. Hematomas can also be very complex on ultrasound (Figs 20 and 21). The CT attenuation values for lymphoceles and urinomas tend to be lower than those of abscesses and hematomas. Hematomas can be heterogeneous on CT as blood products evolve over time. MRI will also reflect the heterogeneity of blood products and will show high T1-weighted components. Ultrasound-guided aspiration is frequently used to identify organisms. The complexity of different fluid collections often makes drainage difficult, and many
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FIG 20. A 47-year-old female presenting with pain at graft site 2 months post transplant, 1 day after biopsy. Ultrasound and CT revealed the presence of crescent-shaped fluid collection, representing subcapsular hematoma (arrow).
FIG 21. A 52-year-old male presenting with pain at graft site 2 weeks post transplant. Ultrasound and CT revealed the presence of peri-transplant fluid collection, representing hematoma (arrow).
of them resolve spontaneously or are self-limiting. Surgical intervention is rarely required.25
Collecting System Pathology Ureteral Strictures The incidence of ureteral strictures has been reduced to around 1% owing to improved surgical techniques.36,37 The cause is most commonly vascular insufficiency at the distal ureter (Fig 22). Calculi, kinking of the ureter due to adhesions, fibrosis, and extrinsic compression are less common. Urinary obstruction often presents later than with the normal kidney because the kidney is denervated and pain is felt at a later stage when the capsule is distended. Mild collecting system dilatation is not uncommon in the
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renal transplant and is not related to obstruction. The resistive index parameters used for the native kidney are unproven in the transplant kidney.10 Scintigraphy is occasionally required to evaluate for obstruction as opposed to “benign” dilatation of the collecting system.
Calculi The incidence of renal and ureteric calculi is low in the transplant kidney despite hypercalcemia related to the underlying renal impairment.38,39 This can be seen as a late complication. Ureteral stricture, chronic infection, and renal tubular acidosis are also implicated. Stones can also be carried over from the donor kidney.40
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FIG 22. A 48-year-old male with renal transplant. Ultrasound shows a dilated renal collecting system and ureter (A), with thickening of the distal ureter (arrow in B). Antegrade pyelography following the insertion of a nephrostomy confirms a distal stricture (arrow in C). (Color version of figure is available online.)
FIG 23. (A, B) A 57-year-old female, presenting with hematuria 8 years post transplant. CT revealed thick urothelial calcification (arrow), representing alkaline-encrusted pyelitis. Urinalysis revealed alkaline urine, and multiple urine cultures with gram-positive rods.
Alkaline-Encrusted Pyelitis Alkaline encrusted pyelitis is a rare infectious disease characterized by encrustations in the wall of the upper urinary tract, surrounded by severe inflammation. Destruction of kidney grafts can occur, resulting in end-stage renal failure. Corynebacterium is almost exclusively associated with this disease. The most important predisposing
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factors are previous urological procedures and an immunosuppressed state.41 Urothelial calcification and perinephric stranding can be seen on unenhanced CT (Fig 23).
Transitional Cell Carcinoma The incidence of transitional cell carcinoma is increased in the renal transplant population.42,43 This
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FIG 24. A 63-year-old male, presenting with hematuria 10 years post transplant. Ultrasound of allograft shows solid lesion in renal pelvis (arrow), representing a pathologically proven TCC. (Color version of figure is available online.)
may be attributed to the use of cyclophosphamide44 and to analgesic nephropathy.42 The pattern of growth is widely disseminated in this population. Diagnosis is likely to be delayed because of the wide differential diagnosis of hematuria and urinary obstruction, but suspicion should be raised in the event of identification of urothelial thickening and masses (Fig 24). Urine cytology will be useful in this scenario.
Conclusions Complications of renal allograft transplantation occur in both the short and the long term. Imaging plays a major role alongside clinical evaluation in the diagnosis of these complications. A systematic approach to image review and a thorough understanding of the clinical background are essential for diagnosing these complications.
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35. Samhan M, Al-Mousawi M. Lymphocele following renal transplantation. Saudi J Kidney Disord Transpl 2006;17:34-7. 36. Breda A, Bui MH, Liao JC, et al. Incidence of ureteral strictures after laparoscopic donor nephrectomy. J Urol 2006; 176:1065-8. 37. Dalgic A, Boyvat F, Karakayali H, et al. Urologic complications in 1523 renal transplantations: The Baskent University experience. Transplant Proc 2006;38:543-7. 38. Challacombe B, Dasgupta P, Tiptaft R, et al. Multimodal management of urolithiasis in renal transplantation. BJU Int 2005;96:385-9. 39. Streeter EH, Little DM, Cranston DW, et al. The urological complications of renal transplantation: a series of 1535 patients. BJU Int 2002;90:627-34. 40. Devasia A, Chacko N, Gnanaraj L, et al. Stone-bearing live-donor kidneys for transplantation. BJU Int 2005;95: 394-7. 41. Van Hooland S, Vandooren AK, Lerut E, et al. Alkaline encrusted pyelitis. Acta Clin Belg 2005;60:369-72. 42. Swindle P, Falk M, Rigby R, et al. Transitional cell carcinoma in renal transplant recipients: the influence of compound analgesics. Br J Urol 1998;81:229-33. 43. Wu MJ, Lian JD, Yang CR, et al. High cumulative incidence of urinary tract transitional cell carcinoma after kidney transplantation in Taiwan. Am J Kidney Dis 2004;43:1091-7. 44. Levine LA, Richie JP. Urological complications of cyclophosphamide. J Urol 1989;141:1063-9.
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