Microsoft word - tradravelli3.ruolo nel tx . doc.doc
US sonography in renal transplant: what role?
Our experience in recent years, together with the literature of the same period, allows us to
state that, from the early seventies (1), when our radiology colleagues were the first to undertake the US study of renal transplant, to these days, the technology has undergone fascinating developments and US has, at the same time, experienced a sort of “clinical-sonographic evolution”, entering into the differential diagnosis of not only surgical complications, both urological and vascular (2-4, 11, 17, 20, 23), but medical complications as well (5-9, 12, 15, 17-19, 21, 22, 24, 26-28, 49-51). Ultrasonography has endowed transplant nephrology with unhoped-for potentialities, which have proven in time to be vital and to offer almost immediate solutions to clinical problems of great relevance for allograft follow-up. The interplay between transplant nephrology and ultrasonology has yielded striking results, which have narrowed the role of histological diagnosis, with enormous repercussions in terms of human costs and of health expenditure as well. For these reasons I think the role of allograft ultrasonography in nephrology is specific and cannot be replaced by competences that aren’t closely related to clinical practice. This contribution, though not expecting to be conclusive, aims to take stock of the role US has played (and, thanks to its acknowledged role, is still playing) in transplant diagnostics. It will subsequently consider how such role has evolved and end offering some cues for a reflection on the future of transplant ultrasonology, now more urgently than ever requested to cope with unavoidable ethical issues.
At its dawn US dealt with the differential diagnosis of surgical and medical complications,
acute rejection being among the latter. Its contribution then extended to biopsy control, post-biopsy monitoring, pre-explantation evaluation, as well as interventional management and/or US support in vascular and urological complications (10-12, 21, 24, 83-87). With the introduction of new therapeutic protocols, from the nineties on, a clinical problem arose: that of “chronic allograft nephropathy” (CAN) or “chronic allograft dysfunction” (CAD) (65, 67, 74, 75, 90), with the consequent irreversible decline in renal function, which is well-known to be linked to immunologic and non-immunologic factors, among which the toxicity of calcineurin inhibitors (CNI) is not secondary. Our studies began in December 1987 and have continued in subsequent years. To date we have about 9,300 “clinical” ultrasonographies on allograft in total, where by “clinical” we mean supported by cytohistologic, laboratory and therapeutic evidence. Already in the early nineties (29), such studies enabled us, after dealing with acute rejection diagnosis, to address the problem of calcineurin-inhibitors-induced nephrotoxicity, characterized by a specific US pattern. Hricack generically described such pattern, at the beginning of the eighties, as “nephrotoxicity” in the native kidney (34) and we confirmed it, by means of cyto-histological evidence, in the transplanted kidney. Thus, ultrasound depicted nephrotoxicity in renal transplant 12 years before the first scientific works appeared (58). On the basis of histological correlation (mainly for acute rejection) and cytological correlation (mainly for nephrotoxicity), it has since demonstrated high rates of diagnostic sensitivity and specificity (in our case series ,100% and 98% ,respectively, in acute rejection and 88% and 100%, respectively, in nephrotoxicity).
A potential corollary to this eminently clinic role of US is the study of toxicity mechanisms
of drugs even in the native kidney. Some data (30-32, 65) regarding the clinical presentation of “chronic allograft nephropathy” (“chronic allograft dysfunction”) of partially non-immunologic nephrotoxic origin (75) lead to the hypothesis of potentially ubiquitous mechanisms involving subcellular structures (57): such mechanisms, which are consistent with the US picture, offer exciting prospects for potential use of the new technologies. A second corollary concerns health expenditure. As early as 2001-2002, we calculated how much could be saved yearly reducing the dosage of immunosuppressant. The calculation was based on the costs of drugs reported by the hospital-based pharmacy of Azienda Ospedaliera di Brescia in February 2002. Merely reducing
tacrolimus by 1 mg (current mean dosage is 7-8 mg per day , about 50% of the dosage in 1996) the yearly saving amounts to about €650 for each patient.
Current dosages of cyclosporine (presenting an intraindividual variability in blood level
judged unacceptable by experts) have been reduced, too, by 10-30% after the introduction of blood level evaluation at baseline and 2 hours after administration. A reduction by 25mg per day saves €216 yearly for each patient. Because of many variables, some of which are imponderable, haematic levels assessment is imprecise, both for cyclosporin and for other immunosuppressants, which makes the method not very reliable as a tool for therapy monitoring.
Another, collateral but not secondary, problem is that hospital-based pharmacies have
extremely expensive stocks, which are not usually bought back by pharmaceutical companies and accumulate as a consequence of continual changes in therapeutic protocols.
On the other hand, the kind of approach to therapy monitoring “alternative” to US suggested
by Rush in the early nineties, namely sequential protocol biopsy (protocol biopsy) (59), elicited, and still elicits, some perplexities. Notwithstanding recent publications (89-94), it is still controversial, and rightly so. On this subject we wish to mention that our 13-year retrospective case analysis on post-biopsy complications in tx (39) made clear that, although thin needles (18g) were used, the incidence of major complications (FAV) is 4 times higher in allograft (0.8%) than in the native kidney: 3 cases resulted in emergency explantation owing to the rupture of the pseudoaneurysm that had formed on the renal artery; 3 cases (0,4%) lead to embolization. Moreover our data seem to suggest that embolization inevitably leads to dialysis, owing to possible and, indeed, likely alterations in intrarenal circulation with consequent overwork for residual nephrons. Earlier US monitoring (starting 24-48 hours after transplant, but, if necessary, even possible while the patient is still in the operating room) would instead allow an accurate and careful transplant management and also a reduction in health care expenditure. More on this later.
In the field of differential diagnosis of medical complications, US also enabled us to
describe two kinds of rejection (predominantly “vascular” and/or predominantly “interstitial”) (37) and also, as early as the year 2000, the pattern of subclinical rejection (38), defined on the basis of alterations in Doppler and Colour Doppler parameters occurring in temporal sequence. We managed to identify subclinical rejection comparing the succession of such alterations with the outcome of the considered patients’ clinical course in histologically proven rejection, since a comparison with the histological picture of subclinical rejection, which can still only be defined on the basis of protocol biopsies (88-95), is not possible.
Let’s turn to the future. The abovementioned results have been achieved resorting to minimal (and easily available)
technology, yet combined with a precise and rigorous method, so as to avoid the sort of operator-dependence that has always been a burden to US diagnostics and will certainly be minimized by contrast agents (UCA). However the problem of training a good sonographer remains and the experts claim this accounts for the most considerable item of expenditure in ultrasonology.
What stated above shows that, while new extremely potent drugs are shifting the focus from
acute rejection to irreversible CAN-related loss of the renal function, with cyclosporine-induced damage, already at year 10, making such drug unacceptable for long-term immunosuppression (68, 69, 72, 76), the current, and in some respects potential, role of ultrasound is mainly clinical, or as was authoritatively stated back in 2002, “sophisticated”. In this context the challenges ultrasonology intends to face nowadays are method standardization on one hand and, definitely, therapy optimization/personalisation on the other. However, it is now already clearly evident that no other diagnostic method can guide clinical practice with the same reliability, non-invasiveness, repeatability , combined with an obvious cost containment.
Over the years clinical practice has provided ultrasonology with research grounds, which
were unexpected in its beginning and ultrasonology has learnt from clinical practice to focus on more and more precise goals, using sophisticated and always evolving technologies: 3D
ultrasonography (40), harmonic imaging and other imaging sequences, matrix probes, B-flow, elastosonography, contrast agents (UCA) (35-38). Especially second generation non-toxic UCA used with low mechanical index and in association with particular imaging sequences (pulse inversion, harmonic imaging, stimulated acoustic emission), have the advantage over other innovations to allow a numerical definition of some parameters, thus reducing operator-dependence, which has always hindered the standardization of US examinations. Renal perfusion can thus be adequately assessed, even in the peripheral parenchyma, on the arcuate arteries, and defined through numeric parameters, thus obtaining functional evaluation (52, 53, 79-81). The role has changed from strictly morphologic to morphologic-functional but even the more and more realistic possibility of a therapeutic role is approaching, through the use of contrast agents as “vehicles” for active pharmaceutical ingredients (48-50, 54, 55). It goes without saying that the first application of such agents, having vascular distribution, is the treatment of vascular complications and a more precise definition of any mass (41, 45). The opportunity of defining numeric indices will however allow methodologic standardization, even in the field of the differential diagnosis of medical complications, with enormous repercussions on clinical practice (as well as on training, as sonographers will have to be trained to perform correct contrastographic examinations, combined with new imaging sequences). All these potentialities, however, need to be weighed up, now already, against the cost-benefit ratio, so as to avoid an indiscriminate use, which may have a negative spillover effect on health care expenditures. Indications should instead be specified.
As for their potential therapeutic use (48-50, 55), even in renal transplant, I think an exciting
future is in store for us. Yet, at the same time, the new technologies urgently require Guidelines to be established, a grid and diagnostic paths to be defined, the cost-benefit ratio to be determined, dedicated operators for transplant Centres to be trained and, lastly, centres of excellence to be identified. All this has two aims: on one hand, to restrain pharmaceutical expenditure and, on the other, to limit the risks for the patient and for the allograft: this is the last facet I would like to deal with.
In recent years the focus in nephrology has undoubtedly shifted from acute rejection to slow
and irreversible decline in renal function, defined “chronic transplant nephropathy” or “chronic allograft dysfunction”; back in 2002 the two major experts, P.Halloran and B.Kahan, were wondering what the best immunosuppressive option might be.
The most authoritative transplant surgeons claim that histology doesn’t always succeed in
glomerulonephritis and transplant glomerulopathy; moreover it only detects damage when it is already at an advanced and irreparable stage; lastly, in our experience, it fails to distinguish the relative importance of the two components when acute and chronic lesions occur together. In our case series, sonography has shown better correlation with clinical diagnosis (92%) than histological investigation has (88%). This achievement on the part of ultrasound confirms its unchallenged role, not to be replaced, at this moment, by any other imaging technique, and certainly not by (cyto)-histologic investigation.
With regard to the literature, we reported, on the basis of ultrasound, calcineurin-inhibitors-
induced nephrotoxicity as early as 1991, whereas the first work on the subject and on the negative effects of excessive immunodepression (with an increase, particularly, of lymphoproliferative disorders) was published in 2001 (58). Subsequently other works (59-60) pointed out an improved renal function in patients who, because of a histological diagnose for CAN, or for other reasons, had reduced or discontinued CNI, introducing, or continuing, the assumption of mycophenolate, either with or without steroid at low dosage.
More recently other works (64, 68, 69, 71) have pointed out that pathologies, of probable
iatrogenic origin, have cleared up by reducing immunosuppressive therapy, without any decline in renal function.
Such observations have inspired research to seek for non-nephrotoxic drugs, some of which,
though, are burdened with other side effects, probably not entirely known yet (introduction of new
protocols dates back ten years). The authors conclude that the only acceptable therapeutic option is, at the moment, the reduction of immunosuppressive therapy (68, 69, 72, 76), with a view both to preserve renal function and to improve patient survival. However, the following questions still remain to be answered: “ To what extent?”, “How?”, “On the basis of which parameters?”.
A vital future role for ultrasound will definitely be to shed light on possible toxicity
mechanisms underlying the US picture, which will also have a potential and important impact on the problem of nephrotoxicity in the native kidney, and, maybe, to cope with the problem of irreversible functional loss (where’s the point of no return?) throwing light, in a non-invasive way, on the damage as it arises. Only thus can the proposal of protocol biopsies be handled (56, 88-95), with an honestly critical attitude. Such diagnostic technique should of course be preliminary to the search for therapeutic options which, as shown, could issue from ultrasonology itself, through the use of microbubbles contrast agents as vectors for targeted localized release, with adequate rupture frequencies of active pharmaceutical ingredients (48-50)
Considering these clinical demands the renewed role for ultrasound is going to be,
preliminarily, a better definition (and therefore standardization) of the pattern of kidney in functional balance (that, besides, we have already described) through a focused and standardized use of technologic innovations, followed by the definition of numeric indices. Whichever the kind of therapeutic protocol in use (be it nephrotoxic or non nephrotoxic) the abovementioned tasks are preliminary to the achievement of the therapy optimization and personalization already asked of US in cardiology and oncology.
Furthermore, there is the organizational and managerial problem of identifying centres of
excellence, already provided for at ministerial level, among those already being referred to as teaching hospitals and supposed to provide training in new US technologies.
In conclusion, I believe that, considering the results achieved so far, US monitoring, when in
the hands of clinicians or of skilled physicians is, already now, proving to be able to help contain health care expenditure, thanks to: 1) reduced hospitalizations due to surgical complications, acute rejection and/or iatrogenic pathologies (hospitalizations in the first 24 months after transplantation, including the first 6, are now mostly linked to infectious complications deriving from excessive immunodepression) (76); 2) decrease in problems related to post-biopsy FAV ( the occurrence of major complications is 4 times higher in allograft than in the native kidney, their outcome being either explantation or irreversible loss of renal function) (39).
In the future US could lead to further savings, reducing dosages and/or stocks in hospital
pharmacies, as a consequence of establishing the appropriate therapeutic protocol for each patient.
I think what stated above shows that the role of ultrasound in transplant management also
has an intrinsically bioethical value, as it is a non-invasive method with high humanizing diagnostic-(therapeutic) potential.
Enabling the allograft to live longer entails reducing the number of patients that might
potentially resume dialysis and register again on the waiting list, thus contributing to reducing organ demand, always far exceeding supply. The data from the Istituo Superiore di Sanità give an idea of such discrepancy: of the 7,451 patients on the renal transplant waiting list in 2001, only 18.6% received an organ in the following year. In January 2004 more than 40,000 people were listed in Europe for renal transplant. In this context any effort to improve transplant management, in the direction of prolonging the life of the allograft (and of the patient, in the first place) is bound to contribute positively to reducing such disproportion and, indirectly, also to facing an issue Prof. Girolamo Sirchia mentioned at the conference “Medicine and Human Dignity”, held in Bari in November 2004. Prof. Sirchia, at the time Health Minister, called it “ the most urgent bioethical issue today’s medicine has to face besides stem cells: the organ trade”.
Back in 2003 the anthropologists at Berkeley University reported organ trade (79). It seemed
to be a problem with no relevance to the Italian context, but in June 2005 headlines in national newspapers made one suspect its existence also in Italy. The same topic appeared also in the electronic issue of the journal Kidney International in February 2006, together with the proposal
from overseas to legalize the trade; moreover, the topic came to the fore again on the cover of the March issue of the same journal; the media have recently talked about it; the problem can’t be eluded any longer, yet it requires mindful and honest critical analysis of all its facets and of possible clinical, anthropological, psychological and social implications.
Considering what has been stated above, I believe that, because of the direct or indirect role
of US in transplantation problems, the definition “clinical-sonographic evolution”, which may have seemed a challenge at first, is actually a fact, though certainly still evolving. I also think that, owing to some of its potential uses, US “are showing the way to outlining more extensive studies in the future”, an expression I allow myself to borrow from an esteemed colleague, much more illustrious than I am.
I think US diagnostics well represents what, from a bioethical perspective, has been
described as the aim of a science serving mankind: “to suggest some instruments to find again the ways of human and spiritual wisdom and inspire research to engage in the pursuit of new processes of real humanization” (78).
Considering the reasons stated above and acting in the primary interest of transplanted
patients, who can’t any longer be denied an US examination , competently performed by, possibly, dedicated physicians, I believe any difficulty , unrelated to the search for a better quality of life for each patient, must be overcome. REFERENCES
1. Leopold G. Renal transplant size measured by reflected ultrasound. Radiology 1970; 95:
2. Silver TM, et al. Peritransplants fluid collections. Radiology 1981; 138: 145-51. 3. Hricack H. Evaluation of acute post transplant renal failure by US. Radiology 1979; 133:
4. Hricack H, et al. Acute post-transplantation renal failure, differential diagnosis by
5. Hricack H, et al. The renal sinus during allograft rejection. Sonographic and histopathologic
6. Birnholz JC, et al. Submucosal edema of the collecting system: a new ultrasonic sign of
severe acute renal allograft rejection. Radiology 1985; 154: 190.
7. Ravelli M. Monitoraggio ecografico del rigetto acuto nel trapianto renale. Studio di 61
episodi e confronto con la scintigrafia con radio colloide (US monitoring of acute rejection in renal transplant. A study of 61 episodes and comparison with radiocolloid scintigraphy). Nefrologia, Dialisi, Trapianto 1990: 265-71. (Italian)
8. Saarinen O. Duplex US and acute allograft rejection. Transpl Proc 1990; 22 (1): 167-8. 9. Buckley AR. The distinction between acute transplant rejection and cyclosporine
nephrotoxicity: value of Duplex sonography. AJR 1987; 149: 521-5.
10. Hubsch PJS, et al. Evaluation of arteriovenous fistulas and pseudoaneurysms in renal
allograft following percutaneous needle biopsy. J US Med 1990; 9:95-100.
11. Renowden SA, et al. Duplex and colour flow sonography in the diagnosis of post-biopsy
arteriovenous fistulae in the transplant kidney. Clinical Radiol 1992; 45: 233-7.
12. Plainfossé MC, et al. Vascular complications in the adult kidney transplant recipient. J Clin
13. Montemezzi S, et al. Eco e colordoppler intrarenale: patologia di interesse nefrologico
(Intrarenal Echo and Color Doppler: a pathology of nephrologic interest). Arch It Urol 1992; 44 (Suppl 2): S131-8. (Italian)
14. Hollenbeck M. New diagnostic techniques in clinical nephrology. Colour code duplex
sonography for evaluation of renal transplants – tool or toy for the nephrologists? NDT 1994; 9: 1822-8.
15. Rana DS, et al. Color doppler studies of the transplant renal artery in patients with allograft
rejection – correlation with graft biopsy. Transplant Proc 1992; 24 (5): 1886.
16. Delaney V, et al. Comparison of fine needle aspiration biopsy, Doppler US and radionuclide
scintigraphy in the diagnosis of acute allograft dysfunction in renal transplant recipients: sensitivity, specificity and cost analysis. Nephron 1993; 63: 263-72.
17. Rollino C, et al. Colour coded Doppler sonography in monitoring native kidney biopsies.
18. Rivolta R, et al. Semeiotica colordoppler nel rene trapiantato (Colordoppler semeiotics in the transplanted kidney). Radiol Med 1993; 85 (Suppl 1): S68-74. (Italian)
19. Cunningham JJ, et al. Sonographic “white line sign” for detection of minimal mucosal
thickening in renal transplant. Urology 1990; 35 (4): 367-70.
20. Ravelli M, et al. Monitoraggio ecografico del trapianto renale. Conferma del quadro di
nefrotossicità da ciclosporina in 96 episodi reversibili. (US monitoring of renal transplant. Confirmation of the picture of cyclosporine-induced nephrotoxicity in 96 reversible episodes). Abs 35° Congresso Naz. SIN, Bari 1994. (Italian)
21. Felten H, et al. Renovascular hypertension after renal transplantation – don’t look only after
22. Salgado O, et al. Renal duplex ultrasonography in the diagnosis and follow-up of a case of
accelerated transplant rejection treated with OKT3. J US Med 1997; 16: 699-702.
23. Saarinen O. Diagnostic value of resistive index of renal transplants in the early postoperative
period. Acta Radiologica 1991; 32 (2): !66-9.
24. Chirrosel P. Echodoppler des artéres rénales. Imagerie artérielle non invasive. Modalités
techniques et analyse critique. Masson 1996: 106-17.
25. Ravelli M. Monitoraggio ecografico del trapianto renale. Caratterizzazione dei quadri di
rigetto acuto tardivo (42 episodi) (US monitoring of renal transplant. Characterisation of pictures of late acute rejection (42 episodes). G Ital Nefrol 1996; 13 (Suppl 7): S104. (Italian)
26. Campani R, et al. Mezzi di contrasto per ecografia: esperienza attuale (US contrast agents: the current experience). Radiol Med 1994; 87 (Suppl 1): S55. (Italian)
27. Ravelli M. et al. Monitoraggio ecografico del trapianto renale: ecografia ed ecocolordoppler
sono metodiche alternative o complementari nella diagnostica del rigetto acuto? Risultati di 12 mesi di osservazione (US monitoring of renal transplant: are sonography and echo-color Doppler alternative or complementary methods in the diagnosis of acute rejection? The results of a 12-month observation). G Ital Nefrol 1996; 13 (Suppl 7): S104. (Italian)
28. Argalia G. et al. L’ecodoppler nel rigetto cronico del rene trapiantato (Echo-Doppler in chronic rejection of the transplanted kidney). Radiol Med 1995; 90: 272-7. (Italian)
29. Ravelli M. Monitoraggio ecografico del trapianto renale. E’ possibile una diagnosi
differenziale tra rigetto acuto e nefrotossicità da ciclosporina?
30. Puschett JB. The spectrum of cyclosporine nephrotoxicity. Am J Nephrol 1990; 10: 296-
31. Hay R. Alterations in molecular structure of renal mitochondria associated with
cyclosporine A treatment. Clin Nephrol 1986; 25 ( Suppl 1): S23-6.
32. Bennet WM. Comparison of cyclosporine nephrotoxicity with amynoglycoside
nephrotoxicity. Clin Nephrol 1986; 25 ( Suppl 1): S 126-9.
33. Bach JF. Factors predicitive of cyclosporine induced nephrotoxicity. The role of
cyclosporine blood levels. Transpl Proc 1990; 22 (3): 1296-8.
34. Hricack H. Renal parenchymal disease: sonographic-histologic correlations. Radiology
35. Zompatori M, et al. Diagnostica per immagini del rene trapiantato (Diagnostic imaging of the transplanted kidney). Gaggi ed. 1986.(Italian)
36. Ravelli M, Palano MG, Maiorca R. Monitoraggio ecografico del trapianto renale. Esiste un
ruolo diagnostico specifico per il color doppler? Risultati preliminari a 18 mesi di osservazione (US monitoring of the renal transplant. Is there a specific diagnostic role for color Doppler? Preliminary results over an 18-month observation period). G Ital Nefrol 1995; 12 (Suppl 5): S92. (Italian)
37. Ravelli M, Zani R, Maiorca R. Caratterizzazione color doppler del rigetto acuto nel trapianto
renale: conferma dell’esistenza di 2 distinti patterns e loro rilevanza clinica (Color Doppler characterisation of acute rejection in renal transplant: confirmation of the existence of two distinguished patterns and their clinical relevance). G Ital Nefrol 1998; 15 (Suppl 10): S82. (Italian)
38. Ravelli M,Maiorca R. Monitoraggio ecodoppler del trapianto renale: importanza dello studio
degli indici di flusso nella identificazione del quadro di pre-rigetto. Risultati a 5 anni di osservazione (Echo Doppler monitoring of renal transplant : importance of the study of flow indices in identifying the picture of pre-rejection. Results over a 5- year observation period). G Ital Nefrol 2000; 17: 105. (Italian)
39. Ravelli M. Monitoraggio ecografico del trapianto renale. Revisione delle complicanze
postbioptiche a 13 anni di osservazione. (US monitoring of renal transplant. A review of post-biopsy complications over a 13-year observation period) Giornale Italiano di Ultrasonologia 2001; 4: 248-9. (Italian)
40. Balen FG, et al. Review ultrasound contrast agents. Clinical Radiology 1994; 49: 77-82.41. Forsberg F, et al. Parenchymal enhancement and tumor visualization using a new
sonographic contrast agent. J US Med 1995; 14: 949-57.
42. Goldberg BB, et al. Ultrasound contrast agents: a review. Ultrasound Med Biol 1994; 20 (4):
43. Filippone A, et al. Utilità di un nuovo mezzo di contrasto ecografico. SH U 508 A
(Levovist) nello studio con ecocolordoppler della patologia renale (Usefulness of a new US contrast agent. SH U 508 A ( Levovist) in echo-color Doppler of renal pathologies) . Radiol Med 1994; 87 (Suppl 1): S50-8. (Italian)
44. Cosgrove D. Tumor vascularity. Angiology 1996; 7 ( Suppl 2): S55-61. 45. Goldberg BB, et al. Echo-enhancing agents in tumors, advances in echo imaging using
contrast enhancement. Kluwer Acad Publishers 2nd ed 1997, 585-614.
46. Rankin RN, et al. Three dimensional sonographic reconstruction. Techniques and diagnostic
47. Dixon KA, et al. Evidence-based diagnostic radiology. Lancet 1997, 350: 509-12. 48. Shortencarier MJ, et al. A method for radiation-force localized drug delivery using gas-filled
lipospheres. Trans Ultrason Ferroelectr Feq Control 2004; 51(7): 822-31.
49. Bekeredjan R, et al. Use of ultrasound contrast agents for gene or drug delivery in
cardiovascular medicine. J Am Coll Cardiol 2005; 45(3): 329-35.
50. Dijkmans PA, et al. Microbubbles and ultrasound: from diagnosis to therapy. Eur J
51. Fisher T, et al. Early post operative ultrasound of kidney transplants: evaluation of contrast
medium dynamics using time-intensity curves. Rofo 2004; 176 (4): 472-7.
52. Drelich-Zbroja A, et al. Renal artery stenosis: value of contrast-enhanced ultrasonography.
53. Krix M, et al. A multivessel model describing replenishment kinetics of ultrasound contrast
agent for quantification of tissue perfusion. Ultrasound Med Biol 2003; 29 (10): 1421-30.
54. Weller GE, et al. Ultrasound imaging of acute cardiac transplant rejection with
microbubbles targeted to intracellular adhesion molecule-1. Circulation 2003; 15 (2): 218-24.
55. Hauff P, et al. Molecular targeting of limphnodes with L-selecting ligand-specific US
contrast agent: a feasibility study in mice and dogs. Radiology 2004; 231(3): 611-2.
56. Rush DN, et al. Sequential protocol biopsies in renal transplant patients. Clinicopathological
correlations using Banff schema. Transplantation 1995, 59(4): 511-4.
57. Hameed R, et al. Mitochondrial cytopathy presenting with focal segmental
glomerulosclerosis, hypoparathyroidism, sensorial deafness and progressive neurological disease. Postgrad Med J 2001; 77: 523-6.
58. Weir MR, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in
patients with chronic allograft nephropathy. Kidney Int 2001; 59(4): 1567-73.
59. Engelen W, et al. Four cases of red blood cell aplasia in association with the use of
mycophenolate mofetil in renal transplant patients. Clin Nephrology 2003; 60: 119-24.
60. Shmitz M, et al. Infection with polyomavirus type BK after transplantation. Clin Nephrol
61. De Ortuzar MG. Ethics and quality of life of kidney transplant patient. Transplant Proc
62. Meola M, et al. Free-hand ultrasound-guided renal biopsy: report of 650 consecutive cases.
63. Guba M, et al. Pro- and anti- cancer effects of immunosuppressive agents used in organ
transplantation. Transplantation 2004; 77: 1777-82.
64. Euvrard S, et al. Immunosuppressants and skin cancer in transplant patients: focus on
rapamycin. Dermatol Surg 2004; 30: 628-33.
65. Nankivell BJ, et al. The natural history of chronic allograft nephropaty. N Eng J Med 2003;
66. Finstere J, et al. Sirolimus miopathy. Transplantation 2003; 76: 1773-4. 67. Baltzan MA, et al. Prevention of CAN graft loss in the medium term without HLA disparity
reduction. Transplant Proc 2003; 335: 2400-02.
68. Harada H, et al. A case of plasmacytic Hyperplasia arising in a kidney allograft salvaged
with immunosuppression reduction alone. Clin Transplant 2004; 18 ( Suppl 11): S50-53.
69. Han Jak Ryu, et al. Complete resolution of posttransplant lymphoproliferative disorder
(diffuse large B-cell Lymphoma) with reduction of immunosuppressive therapy. Yonsei Med J 2004; 45: 527-32.
70. Fishereder M, et al. New immunosuppressive strategies in renal transplant recipients. J
71. Karakus S., et al. Acute myeloid leukaemia 4 years after Kaposi’s sarcoma in a renal
transplant recipient. Onkologie 2004; 27: 163-5.
72. Shapiro R. Low toxicity immunosuppressive protocols in renal transplantation. Keio J Med
73. First MR, et al. New drugs to improve transplant outcomes. Transplantation 2004; 77
74. Cattaneo D, et al. Functional loss of the transplanted kidney: Immunological and non
immunological actors. G Ital Nefrol 2004; 21 ( Suppl 26): S28-33.
75. Vincenti F. A decade of progress in kidney transplantation. Transplantation 2004; 77
76. Sgreccia E. Manuale di Bioetica (Bioethics handbook): Ed. Vita e Pensiero 2000; 1: 42-7;
105-06, 125-7, 193-8, 206, 220-3, 687. (Italian)
77. Piana G. Bioetica – alla ricerca di nuovi modelli.(Bioethics: in search of new models)
78. Hughes NS, et al. Keeping an eye on human traffic of organs. Lancet 2003; 361: 1645-8. 79. Wiesman M, et al. Perfusione renale studiata con software phase-inversion e mezzo di
contrasto ecografico (Renal perfusion studied with phase-inversion software and US contrast agent). Clin Nephrol 2004; 62: 423-31. (Italian)
80. Corréas JM. Contrast-enhanced ultrasonography of native and transplanted kidney diseases.
Eur Radiol 1999; 9 ( Suppl 3 ): S394-400.
81. Lefevre F, et al. Contrast-enhanced sonography of the renal transplant using triggered pulse-
inversion imaging: preliminary results. Ultrasound Med Biol 2002; 28: 303-14.
82. White M, et al. Percutaneous drainage of postoperative abdominal and pelvic lymphoceles.
83. Platt JF, et al. Duplex Doppler US of the kidney: differentiation of obstructive from non
obstructive dilatation. Radiology 1989; 171: 515-17.
84. Shaw JFL, et al. Ultrasound assessment of the problem kidney transplant: a surgical
85. Taylor K, et al. Vascular complication in renal allograft: detection with duplex Doppler US.
86. Dodd GD, et al. Imaging of vascular complication associated with renal transplants. AJR
87. Nankivell BJ, et al. Natural history, risk factors, and impact of subclinical rejection in
kidney transplantation. Transplantation 2004; 78(2): 242-9.
88. Veronese FV, et al. Prevalence and immunohistochemical findings of subclinical kidney
allograft rejection and its association with graft outcome. Clin Transplant 2004; 18: 357-64.
89. Laftavi MR, et al. Randomized prospective trial of early steroid withdrawal compared with
low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety. Surgery 2005; 137: 364-71.
90. Miyagi M, et al. Significance of subclinical rejection in early renal allograft biopsies for
chronic allograft dysfunction. Clin Transplant 2005; 19: 456-65.
91. Masin-Spasovska J, et al. Protocol biopsies in kidney transplant recipients: histologic
findings as prognostic markers for graft function and outcome. Transplant Proc 2005; 37: 705-08.
92. Seikku I, et al. Better renal function with enhanced immunosuppression and protocol
biopsies after kidney transplantation in children. Pediatr Transplant 2005; 9: 754-62.
93. Rowshani AT, et al. Hyperexpression of the granzyme B inhibitor PI-9 in human renal
allografts; a potential mechanism for stable renal function in patients with subclinical rejection. Kidney Int 2004; 66: 1417-22.
94. Roberts ISD, et al. Subclinical rejection and borderline changes in early protocol biopsy
specimen after renal transplantation. Transplantation 2004; 77(8): 1194-8.
95. Friedman EA, et al. Payment for donor kidneys. Pros and cons. Kidney Int 2006; 69(6): 960-
Cost-effective single-chip solution for stereo_äìÉqìåÉë=olj=píÉêÉç=eÉ~ÇëÉí=pçäìíáçåheadset and wireless speaker applicationsA2DP1.2 and AVRCP1.0 profiles enabled withSBC encoder for streaming audio over BluetoothMP3 decoder for improved audio quality andHigh-quality audio 95dB SNR on DAC playbackFastStream, CSR’s low-latency codec for videoHFP 1.5 (includes 3-way