Archived Editor's Picks
Created:   6/21/2011
Contains:  252 items

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Posttransplant sCD30 as a Predictor of Kidney Graft Outcome

Süsal, Caner; Döhler, Bernd; Sadeghi, Mahmoud; More

Transplantation . 91(12):1364-1369, June 27, 2011.

Editors Pick - June 27, 2011 The availability of a reliable biomarker that allows identification of those patients most at risk of graft rejection following renal transplantation would aid post-transplant management considerably. A potential candidate molecule is sCD30 - the soluble form of the transmembrane glycoprotein CD30. CD30 is a member of the tumour necrosis factor receptor superfamily and is expressed by activated T and B cells. In normal health only very low levels of sCD30 are present in the serum but in a variety of inflammatory conditions sCD30 is released from activated CD30 expressing lymphocytes and high levels can be detected in the serum. Süsal et al have evaluated whether the level of sCD30 in the serum after renal transplantation predicts subsequent graft loss. In a prospective multicentre study sCD30 levels were found to be high (>40 U/ml) in 113 (9%) of 1,262 patients evaluated at day 30 following transplantation, and a high sCD30 level was associated with reduced graft survival at three years (78% versus 90%). The authors conclude that post-transplant sCD30 levels independently predict subsequent graft survival. There is a need now to determine whether adjusting the level of immunosuppression in those recipients with a high sCD30 level at day 30 will prevent subsequent graft damage and improve transplant survival.

Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation

Stifft, Frank; Stolk, Leo M.L.; Undre, Nasrullah; More

Transplantation . 97(7):775-780, April 15, 2014.

Editor Comment

The calcineurin inhibitor tacrolimus was, for many years, available only as an immediate release formulation requiring twice-daily administration. More recently a prolonged release formulation of tacrolimus, requiring only once-daily administration, became available and has been shown to have a safety and efficacy profile comparable to that of the immediate release formulation. Tacrolimus has a narrow therapeutic window and therapeutic monitoring of blood levels is neccessary to ensure efficacy of treatment and avoid toxicity. Moreover, it has been suggested that high within-patient variability in tacrolimus levels is a risk factor for inferior long-term transplant outcome following kidney transplantation. Any difference in the relative intra-patient variability for the two formulations of tacrolimus is therefore of particular interest. In this issue Stifft et al report a carefully performed pharmacokinetic study undertaken in stable renal transplant patients before and after conversion from the immediate to the prolonged release tacrolimus formulation. Intra-patient variability of tacrolimus was determined from multiple measurements of area under the curve 24-hour blood concentration-time before and after conversion. Switching to prolonged release tacrolimus resulted in a significant improvement of the intra-patient coefficient of variation of the blood concentration-time curve from 14% to 11%. Recipients with the Cyp3A5*1/*3 Cytochrome P450 genotype had a numerically larger improvement in the coefficient of variation than those with the P450 3A5*3/*3 genotype although, as the authors acknowledge, only a small number of patients studied carried the latter allele. The authors ascribe the improvement in coefficient of variation to the intrinsic pharmacokinetic properties of the slow release tacrolimus formulation, rather than improved adherence of patients to therapy. The findings are very interesting but it is important to appreciate that the long-term clinical significance of reduced intra-patient variability in tacrolimus exposure is not known and requires further study.

Impact of Donor-Transmitted Atherosclerosis on Early Cardiac Allograft Vasculopathy: New Findings by Three-Dimensional Intravascular Ultrasound Analysis

Yamasaki, Masao; Sakurai, Ryota; Hirohata, Atsushi; More

Transplantation . 91(12):1406-1411, June 27, 2011.

Editors Pick - June 27, 2011 Cardiac allograft vasculopathy is a major cause of mortality after heart transplantation. Because of the shortage of donor hearts for transplantation, more hearts with pre-existing coronary artery atherosclerosis are being used for transplantation. An important question, therefore, is whether or not the presence of pre-existing donor coronary artery disease leads to plaque progression and accelerates the development of cardiac allograft vasculopathy. Advances in cardiac imaging now allow this question to be addressed with more precision than was previously possible and Yamasaki et al have used serial 3-dimensional intravascular ultrasound (IVU) analysis to investigate the impact of donor atherosclerosis on plaque progression early after heart transplantation. From their analysis of 49 patients who had IVU at both baseline and one year, they report that 61% of donor hearts had atherosclerotic lesions at transplantation and that this was a major risk factor for the development of rapid plaque progression elsewhere in the coronary arteries. While the mechanism whereby donor atherosclerosis accelerates plaque progression is unclear the findings from this preliminary study have considerable clinical implications and there is now a need for them to be validated in a larger recipient cohort with longer follow up.

Consideration of Donor Age and Human Leukocyte Antigen Matching in the Setting of Multiple Potential Living Kidney Donors

Rizzari, Michael D.; Suszynski, Thomas M.; Gillingham, Kristen J.; More

Transplantation . 92(1):70-75, July 15, 2011.

Editors Pick - July 15, 2011 Issue For those patients with end-stage renal disease who are fortunate to have a choice of potential living donors, an important consideration in selecting the most appropriate donor is knowledge of the donor factors that influence subsequent recipient and graft survival. Rizzari and colleagues add to the increasing body of knowledge in this area by reporting the results of a large single centre study designed to determine the impact of donor and recipient risk factors on patient and graft survival. They report that advanced donor age (> 65 years old) and a poorly HLA matched graft (5 or 6 HLA mismatches) are independent predictors of patient and graft survival and that where there is a choice of multiple willing living donors, these factors should inform the decision making process. Their findings are also relevant to paired kidney exchange schemes and they suggest that donor age and HLA mismatch should be taken into account when planning paired exchange with a view to maximising transplant benefit.

Densitometric Threshold and Vertebral Fractures in Heart Transplant Patients

Dalle Carbonare, Luca; Zanatta, Mirko; Braga, Vania; More

Transplantation . 92(1):106-111, July 15, 2011.

Editors Pick - July 15, 2011 Issue As the results of transplantation have improved in terms of patient and graft survival, attention is focussing increasingly on managing the associated major comorbid conditions. Of these bone disease is an important and often neglected area. It's causes are multifactorial but immunosuppressive agents play an important role. Following transplantation significant bone loss is common and results in fragility fractures, particularly of the spine and hip. Dalle Carbonare et al report the results of a retrospective cross-sectional analysis in a relatively large series of heart transplant recipients. Their comprehensive evaluation included assessment of biochemistry, physical activity and dietary intake, as well as bone densitometry and spinal X ray. They confirmed the high prevalence of vertebral fractures previously noted in such patients (40% of patients in their series) but noted that standard densitometric criteria for osteoporosis did not reliably predict bone fragility. The authors suggest that the threshold for abnormal bone density should be increased in this patient population. In addition, because they observed widespread Vitamin D deficiency they emphasised the importance of ensuring adequate vitamin D supplementation after transplantation.

Type I Interferon Pathway Mediates Renal Ischemia/Reperfusion Injury

Freitas, Maria Cecilia S.; Uchida, Yoichiro; Lassman, Charles; More

Transplantation . 92(2):131-138, July 27, 2011.

Editors Comment:

Ischemia reperfusion (I/R) injury during organ transplantation may cause graft dysfunction and amplify allograft rejection. The molecular mechanisms involved are complex but include activation of innate immunity via Toll like-receptors (TLR). Freitas et al have shown previously that the type-1 interferon (IFN) pathway plays an important role in TLR-triggered inflammation and I/R injury of the liver. Type 1 interferons (including interferon-α and interferon-β) are pleiotropic cytokines produced by a wide variety of cell types (including lymphocytes, macrophages and dendritic cells) that bind to the IFN-α Receptor, causing macrophage and NK cell activation and recruitment, and a proinflammatory cytokine response. Freitas et al have now gone on to examine the role of type-1 IFN signalling in a mouse model of renal I/R injury (45 minute occlusion of the renal pedicle). They show that disruption of type-1 IFN signalling (genetic IFN-α Receptor deficiency) confers protection against the inflammation and renal injury normally caused by I/R in this model. In contrast to wild type mice, those that were deficient for the IFNR-α Receptor retained good renal function. Compared to their wild-type counterparts, their kidneys showed reduced tissue injury, less leukocyte infiltration and an attenuated proinflammatory cytokine response. The authors conclude that targeting the type-1 IFN pathway is a novel and potentially effective strategy for reducing the impact of I/R on the kidney.

Prophylactic Peritoneal Fenestration to Prevent Morbidity After Kidney Transplantation: A Randomized Study

Syversveen, Trygve; Midtvedt, Karsten; Brabrand, Knut; More

Transplantation . 92(2):196-202, July 27, 2011.

Editors Comment:

Lymphocele formation is a relatively common complication after kidney transplantation. Most lymphoceles are asymptomatic but if large they may cause pressure on adjacent structures and require radiological or surgical intervention. The cause of lymphoceles is incompletely understood but risk factors include the use of mTOR inhibitors and high dose steroids. Syverseveen et from the Oslo University Hospital hypothesised that prophylactic fenestration of the peritoneum adjacent to the kidney at the time of implantation would reduce the incidence of lymphocele formation and have examined this in a single centre randomised controlled trial. The primary end-point was incidence of symptomatic lymphoceles (requiring radiological or surgical intervention) within one year. On an intention to treat basis, 10 of 61 recipients (16.4%) recipients developed symptomatic lymphoceles in the standard surgery group compared to only 3 out of 69 (4.3%) in the fenestration group (p=0.02). Peritoneal fenestration also reduced the incidence of asymptomatic perinephric collections detected by ultrasound examination from 66% to 37% (p=0.005). The incidence of lymphoceles in the control group was higher than might be expected from the literature and the relatively high dose of steroids given may have contributed to this. In addition wound drains were not used routinely during implantation. Before prophylactic fenestration can be recommended for routine use further clinical evaluation is required.

Hepatic Steatosis and Normothermic Perfusion—Preliminary Experiments in a Porcine Model

Jamieson, Russell W.; Zilvetti, Miguel; Roy, Debabrata; More

Transplantation . 92(3):289-295, August 15, 2011.

Editors Comment

The presence of moderate to severe steatosis in donor livers is associated with an increased risk of primary non-function and often leads to organs that might otherwise have been suitable for transplantation being discarded. Because many such organs display adequate function before organ retrieval it is thought that steatotic livers are particularly intolerant to the cold ischaemic injury inflicted during hypothermic storage. One way to potentially ameliorate this problem could be to use normothermic instead of cold preservation. Jamieson et al have examined the feasibility of this in a pig model in which hepatic steatosis was induced by a combination of a high fat diet and streptozotocin. They demonstrate in preliminary experiments that steatotic livers can be subjected to extended warm preservation on an ex vivo perfusion circuit in which the liver is perfused with oxygenated blood warmed to 39 degree centigrade. Steatotic livers showed evidence of satisfactory function ex vivo and there was a suggestion that the level of steatosis was reduced by around 50% at 48 hours. Clearly these findings need to be confirmed and extended to include transplantation of the warm-perfused livers but the findings are promising.

Lower Malignancy Rates in Renal Allograft Recipients Converted to Sirolimus-Based, Calcineurin Inhibitor-Free Immunotherapy: 24-Month Results From the CONVERT Trial

Alberú, Josefina; Pascoe, Michael D.; Campistol, Josep M.; More

Transplantation . 92(3):303-310, August 15, 2011.

Editors Comment

Nearly all types of malignancy are more common after transplantation than in the general population, particularly non-melanotic skin cancers. This is an unfortunate consequence of the immunosuppressive drugs required to prevent rejection but it may be possible to offset this risk at least in part. The mTOR inhibitors are known to have anti-tumour activity and increasing evidence suggests their use instead of calcineurin inhibitors (CNI) may help reduce the risk of malignancy. Adding to this evidence, Alberú et al report that renal transplant recipients randomised to conversion from CNI-based to sirolimus-based immunosuppression have significantly lower rates of non-melanoma skin cancer than their counterparts who continued on CNI maintenance therapy. A numerical reduction in other types of malignancy at two years following conversion was also observed but was not statistically significant. All patients received an anti-proliferative agent and steroids and the authors were not able to exclude the possibility that the overall level of immunosuppression was greater in those continuing on CNI-based therapy. Nevertheless, this study adds to the growing body of evidence suggesting that mTOR-based immunosuppression may have the advantage of reducing the long-term risk of malignant disease in transplant recipients.

Conversion of Long-Term Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus: A Randomized, Multicenter, 24-Month Study

Holdaas, Hallvard; Rostaing, Lionel; Serón, Daniel; More

Transplantation . 92(4):410-418, August 27, 2011.

Editor Comment

Conversion of renal transplant recipients from CNI-based to mTOR inhibitor-based immunosuppression within the first 6 months after transplantation may help to preserve renal function but is a similar benefit seen with later conversion? This question was addressed in the multicentre randomised controlled reported by Holdaas et al in recipients who were >6 months (a mean of >five years) after transplantation and had renal impairment (defined as a GFR of 30-70 ml/min/1.73m2). A three arm comparison of CNI elimination, CNI minimisation (both with initiation of the mTOR inhibitor everolimus) and CNI continuation showed no difference between the groups in the primary end-point (measured GFR 24 months after conversion). Moreover, drug related adverse events were more common in the groups receiving everolimus. The principal conclusion from this study therefore is that there is no overall benefit in terms of renal function in introducing everolimus and minimising or eliminating CNI therapy in the patient group studied.

Deleterious Impact of Mismatching for Human Leukocyte Antigen-C in Presensitized Recipients of Kidney Transplants

Tran, Thuong Hien; Döhler, Bernd; Heinold, Andreas; More

Transplantation . 92(4):419-425, August 27, 2011.

Editor Comment

The HLA-C locus is not usually considered important in terms of HLA matching for kidney transplantation but is this view correct? Historical studies suggesting that HLA-C matching does not influence transplant outcome may not be reliable for two reasons. First they use serological techniques to type HLA-C and these are much less reliable than currently available molecular typing techniques. Second, the strong linkage disequilibrium between HLA-C and HLA-B may have confounded the results from previous analyses. The report by Tran et al investigating the role of HLA-C matching in a large multicentre cohort of kidney transplant recipients suggests a need to revise our view about HLA-C. While in non-sensitised recipients, HLA-C mismatch did not influence graft survival, in sensitised recipients it had a strong adverse influence on graft survival, comparable in magnitude to that for HLA-DR. These findings highlight the need to define the presence of donor specific HLA-C antibodies in potential recipients but this is still technically challenging and until the technical problems with defining HLA-C antibodies reliably can be overcome an alternative approach would be to match for HLA-C as well as HLA-A, B and DR in recipients with preformed HLA antibodies.

HLA Antibody Specification Using Single-Antigen Beads—A Technical Solution for the Prozone Effect

Schnaidt, Martina; Weinstock, Christof; Jurisic, Marija; More

Transplantation . 92(5):510-515, September 15, 2011.

Editor Comment

Single antigen beads combined with Luminex technology have revolutionised the detection of HLA antibodies in the sera of patients listed for transplantation. However, caution is required when performing such assays because if appropriate steps are not taken antibody levels may be underestimated due to a prozone effect. The cause of the prozone effect in this type of assay is unclear and while assaying serial dilutions of sera would optimise interpretation of the results the cost of the additional single antigen beads required makes this very expensive option. The findings of Schnaidt et al are therefore of particular interest and point to the complement component C1 as the cause for the prozone effect in the single antigen bead detection assay. EDTA effectively destroys C1 and based on their findings the authors recommend addition of EDTA to the serum of highly sensitised patients to avoid a prozone effect.

Impact of Adjuvant Immunotherapy Using Liver Allograft-Derived Lymphocytes on Bacteremia in Living-Donor Liver Transplantation

Tashiro, Hirotaka; Ishiyama, Kohei; Ohira, Masahiro; More

Transplantation . 92(5):575-580, September 15, 2011.

Editor Comment

In an effort to reduce recurrence of hepatocellular carcinoma or hepatitis C following live donor liver transplantation, clinicians from the Hiroshima University Hospital in Japan have been giving adjuvant immunotherapy in the form of liver allograft derived lymphocytes. These are flushed via the portal vein from the donor liver lobe ex vivo, activated with IL-2, and then administered to the recipient on day three. Hypothesising that such therapy may also reduce the incidence of bacteremia after transplantation, Tashiro et al undertook a retrospective case matched study and found that bacteremia was significantly lower in the 21 patients who received immunotherapy than their 21 controls (5% versus 29%). Caution is required in drawing too strong a conclusion, given the retrospective nature of the study and the scope for selection bias. However, the findings are intriguing and because bacteremia is often associated with inferior outcome after liver transplantation, warrant further study.

Zinc Transporter 8 Autoantibodies Increase the Predictive Value of Islet Autoantibodies for Function Loss of Technically Successful Solitary Pancreas Transplant

Occhipinti, Margherita; Lampasona, Vito; Vistoli, Fabio; More

Transplantation . 92(6):674-677, September 27, 2011.

Editor Comment

Monitoring outcomes of pancreatic transplants is at best difficult. There are many causes for failure of a pancreatic graft, which may be technical, immunological or other. Undiagnosed and under-treated rejection may be one reason why outcomes of solitary pancreas transplants are inferior to those of combined kidney-pancreas transplants. One of the factors leading to pancreas graft failure is recurrence or de novo appearance of autoimmunity. Islet cell autoantibodies are a well recognised marker of autoimmunity in type 1 diabetes(T1DM) although they do not appear to play a role in the destruction of the islet cells.

There have been several studies looking at the relevance of auto-antibodies in rejection and the titre of autoantiobodies against glutamic acid decarboxylase and insulinoma-associated protein2 correlate well with graft failure. The recent recognition of antibodies against the zinc transporter-8 as another marker of T1DM have prompted this study evaluating their rle in patients with T1DM who have received a solitary pancreas graft and, in a small nmber of patients, they found that measurement of all three autoantibodies increased the sensitivity of predicting graft loss.

The study raises clinical interest: this may help in the monitoring of patients although it remains to be shown that early changes in treatment, triggered by changes in auto-antibody titres, will improve outcomes but also raises again the value of monitoring auto-antibodies in evaluating graft function. This applies not just to pancreas but to other solid organs.

Increased Risk of Severe Recurrence of Hepatitis C Virus in Liver Transplant Recipients of Donation After Cardiac Death Allografts

Hernandez-Alejandro, Roberto; Croome, Kris P.; Quan, Douglas; More

Transplantation . 92(6):686-689, September 27, 2011.

Editor Comment

Recurrence of Hepatitis C is the allograft of increasing importance as the number of patients with HCV infection needing a transplant increases. Current anti-viral therapy has only a limited impact on the recurrence, primarily because of toxicity of the treatment and the relative ineffectiveness. A number of factors have been associated with recurrence, of which perhaps the most important are donor age and the amount and type of immunosuppression. With the increased use of organs from donors after circulatory death, it is clearly sensible to examine the impact of DCD donors on recurrence.

Clinicians from London, Ontario, have done a comparison of outcomes of recipients with HCV who received DCD and DBD livers and show that the outcomes are worse in the recipients of DCD livers. There are of course limitations to the study: numbers are relatively small, the retrospective nature of the analysis and the many factors that might impact on the severity of recurrence and on graft survival. Nonetheless, these conclusions are of importance. While confirmation of conclusions in another cohort is always important, these findings should impact on how organs from deceased donors are allocated. To balance equity, justice, utility and benefit is always a challenge but these conclusions suggest that consideration should be given to giving those with HCV infection priority for organs donated by younger donors after brain death. Modelling and wider debate is required to evaluate the impact of such an approach.

Ganciclovir Transiently Attenuates Murine Cytomegalovirus-Associated Renal Allograft Inflammation

Shimamura, Masako; Saunders, Ute; Rha, Brian; More

Transplantation . 92(7):759-766, October 15, 2011.

Editor Comment

The role of CMV in inducing graft and systemic disease is well accepted. For patients at high risk of developing disease, such as those CMV-negative recipients with a positive donor, prophylaxis with ganciclovir or valganciclovir will, if not prevent disease in all, at least delay disease. Clinical studies of ganciclovir prophylaxis have drawn inconsistent conclusions on outcome. The association between CMV and chronic graft disease and chronic rejection is becoming more evident and it is clear that CMV infection has a wider impact on immune function. In this study, the authors have used a murine model of kidney transplantation to test their hypothesis that ganciclovir prophylaxis might reduce intra-graft inflammation and found that while ganciclovir was give, intra-graft inflammation was less. There are of course limitations with extrapolating data form animal to human models but this must be balanced against the fact that the impact of other factors can be excluded. Ganciclovir is usually well tolerated but does have side-effects: the conclusions from this study are challenging but they do not, in my view, justify the routine use of ganciclovir beyond its current indications but do provide further insights into the complex interaction between graft and CMV.

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal

Heilman, Raymond L.; Younan, Kerrie; Wadei, Hani M.; More

Transplantation . 92(7):767-773, October 15, 2011.

Editor Comment

As transplantation has become a routine procedure, attention of clinicians has increasingly focussed on long-term outcomes and the impact of immunosuppressive agents is becoming increasingly under scrutiny. Until tolerance can be achieved, immunosuppression is needed and the impact of side-effects, both general such as infection and malignancy and drug-specific, such as nephrotoxicity, are a price to pay. However, careful choice of agent can minimise the impact of adverse side-effects. In this study, Heilman and colleagues from the Mayo Clinic report the outcomes of a prospective study of 122 kidney transplant recipients receiving rapid withdrawal of corticosteroids with tacrolimus and sirolimus, randomised to either tacrolimus and mycophenolate or sirolimus and mycophenolate, They found that switching from a tacrolimus based regimen to sirolimus-based regimen was poorly tolerated and was not associated with a better outcome. The place of sirolimus is yet to be fully established: certainly in those with malignancy, there is a clear potential benefit and for those with CNI-associated nephro- or other toxicity, it is a useful option. The spectrum of toxicity of sirolimus differs from other drug so, in my view, sirolimus provides a valuable option in selected patients but may not prove to be a panacea to mitigate the toxicity of other agents.

Hypothermic Machine Perfusion Ameliorates Ischemia-Reperfusion Injury in Rat Lungs From Non-Heart-Beating Donors

Nakajima, Daisuke; Chen, Fengshi; Yamada, Tetsu; More

Transplantation . 92(8):858-863, October 27, 2011.

Editor Comment

As the need for organs continues to outstrip supply, surgeons have looked for novel sources of organ donors. The use of organs from donors after circulatory death (DCD) is increasing and, as experience continues to grow, it is becoming clear that organs from DCD donors are becoming an increasing source of life-saving organs. Outcomes for kidneys may be similar to those from donors after brain death whereas livers may fare worse, primarily because of ischemic cholangiopathy. Lungs from DCD donors function reasonably but surgeons and others are looking at ways of improving outcomes and allowing more organs to become transplantable. Use of ex vivo lung perfusion does appear to offer advances not only in improving function of retrieved lungs but may allow otherwise un-useable lungs to be transplanted effectively. Here the teams from Kyoto report outcomes of two approaches to improve viability in animal models. In the first paper, they showed that short-term hypoperfusion improved lung tissue energy levels and ameliorated ischemic reperfusion injury in mice; in the second, unrelated paper, they suggested that, in their dog model, mechanical ventilation pre-procurement improves graft function, at least in the short term, by reducing reperfusion injury. Of course there are concerns; numbers studied are small, the mice experiments did not involve transplantation and for the canine studies, follow-up was short. The studies took place in a controlled and planned way unlike many DCD donations. Extrapolation of findings from mice and dogs to man must be done with caution. There are ongoing ethical issues about what is acceptable to do in deceased donors. Nonetheless, these studies do indicate that pre-implantation interventions can improve graft function and potentially increase both the quality and number of grafts and will reinforce studies to improve donor management and treatment of the graft.

Relative Survival of Transplant Patients: Quantifying Surplus Mortality Among Renal Transplant Recipients Compared With the General Population

Gondos, Adam; Brenner, Hermann

Transplantation . 92(8):913-917, October 27, 2011.

Editor Comment

The aim of transplantation is to increase the quality and quantity of life for the recipients. With the increasing success of solid organ transplantation, outcome measures have moved from simply looking at one year survival to 5, 10 and 20 year survival. Indeed, for a child, survival could be considered in terms of 30 or even 50 years. In allograft recipients, survival is limited by many factors, including the legacy of extra-organ disease associated with end-organ failure (such as cardiovascular disease in those with renal failure), the impact of disease recurrence and the consequences of treatment which may be general, such as an increased risk of some cancers and infections, and drug specific disease such as renal failure or diabetes. Allograft recipients are, of course, also at risk of all the other conditions that may affect non-transplanted people. Survival after transplantation is usually very good but not normal, either in quality or quantity, In addition to looking at survival probability, others are looking at life years gained because of the transplant (that is compared with not having a transplant) and comparison with a normal matched population. Those liver recipients, who have survived one year post transplant, will lose, on average, 7 to 8 years compared with a normal age and sex matched control (this loss of life years is probably an underestimate since the most of transplanted population have been selected as being without other diseases). The loss of life years is greatest in the younger and is affected by indication and gender. Here, the Heidelberg group have looked at relative survival gradients in kidney recipients and show that, for a 5 year absolute survival, survival rates are reduced compared with a matched normal population. Information provided will be not only of interest to the transplant community but also the recipients and their families. Thus, while huge advances have been made in improving the lives of countless allograft recipients, there is still much to be done. Provision of such data not only draws attention to this gap but highlights the need to continue to focus on the general health of the recipient as well as the welfare of the graft.

Estimating Glomerular Filtration Rate in Kidney Transplant Recipients: Performance Over Time of Four Creatinine-Based Formulas

Buron, Fanny; Hadj-Aissa, Aoumer; Dubourg, Laurence; More

Transplantation . 92(9):1005-1011, November 15, 2011.

Editor Comment

Monitoring of renal function after solid organ transplantation is of obvious importance not only for renal transplantation but also for other solid organs as renal impairment, renal failure and need for renal replacement is becoming an increasing concern. Most clinicians are well aware of the limitations of estimating renal function by simply assessing serum creatinine or urea but a move towards more direct measurement of renal function by measurement of clearance of EDTA, inulin or other markers has been hampered not only by the expense but also by the logistics. To achieve a complete urine collection is an achievement whether as inpatient or outpatient and is, at best, a nuisance for the patient. The use of indirect markers ofGFR using formulae such as Cockcroft-Gault or Modification of Diet in Renal disease is increasing although most clinicians are aware that these are substitutes with their own limitations. The Lyon group compared 4 standard formulae with inulin clearance and showed that MDRD correlated most closely with inulin measurements, both overall and in sub-groups but there is a worrying number of outliers. These findings are broadly consistent with those from other studies and offer clinicians an easier approach to estimating renal function in a practical way. The increasing use of IT enables easy automatic calculation of eGFR and so should alert the clinician to changes that merit further action, however, clinicians need to be aware of the limitations of these surrogate markers of renal function and simplicity and ease should continue to bear the limitations in mind.

Clinical Utility of Molecular Surveillance for Cytomegalovirus After Antiviral Prophylaxis in High-Risk Solid Organ Transplant Recipients

Lisboa, Luiz F.; Preiksaitis, Jutta K.; Humar, Atul; More

Transplantation . 92(9):1063-1068, November 15, 2011.

Editor Comment

CMV infection and disease remains a significant problem after solid organ transplantation. Most centres adopt a strategy of 3 months prophylaxis in those at risk, mainly donor positive recipient negative. While this approach is effective in reducing the early CMV disease that was seen not uncommonly, later infection is being increasingly recognised. While later infections are often milder and possibly associated with fewer sequelae, the optimal approach to monitoring and management of high risk patients after the prophylaxis period is uncertain. In this manuscript the Alberta group have done a retrospective chart review assessing their approach of 3 months (for most recipients) prophylaxis of D+/R- transplants and 8 weeks’ monitoring with a PCR based assay. Results were available within 24 hours and treatment suggested above 25000copies/ml plasma or if the recipient was symptomatic. About half the episodes of viremia were detected during the 8 week post prophylaxis period and just over half had symptomatic CMV at the end of the 8 week period. And in only 3 of the 19 patients had successful pre-emptive treatment. Close monitoring of CMV using molecular markers is expensive and intrusive for the recipient. This study does suggest that such monitoring is not fully justified and recipients may be better served by being fully instructed to report any symptoms suggestive of CMV infection with subsequent rapid diagnosis and prompt treatment.

Effect of Smoking on Kidney Transplant Outcomes: Analysis of the United States Renal Data System

Hurst, Frank P.; Altieri, Maria; Patel, Purav P.; More

Transplantation . 92(10):1101-1107, November 27, 2011.

Editor Comment

Solid organ transplant recipients are at increased risk of both cerebro- and cardiovascular disease and some malignancies. Smoking is a major and preventable factor that increases both complications and is avoidable. Indeed, some units will not take on patients who either continue to smoke or fail to engage in smoking cessation programmes. This is a retrospective study of over 40000 primary renal transplant recipients and the authors report that 10% had smoked prior to transplantation and just under 5% started smoking after transplantation. Some of the factors associated with new smoking are not unexpected (such as male gender and a history of alcohol or drug use, but a history of COPD was also associated. Smoking was associated with an increased risk of graft loss and death. These observations are not unexpected and re-emphasise the greater need for avoiding smoking in the transplant population. These data will provide added strength to the arguments that transplant recipients should stop smoking but I suspect is unlikely to have a major impact: smokers are already aware of the risks of smoking and, if anything, over-estimate the risks of smoking. Clearly, education alone is insufficient so clinicians will just have to work harder and more consistently to encourage recipients to stop and, when stopped, remain smoke-free.

Total Lymphoid Irradiation in Heart Transplantation: Long-Term Efficacy and Survival—An 18-Year Experience

Tallaj, José A.; Pamboukian, Salpy V.; George, James F.; More

Transplantation . 92(10):1159-1164, November 27, 2011.

Editor Comment

TLI has a long history in organ transplantation both in the prevention and treatment of rejection but with the advent of more powerful and specific approaches to the treatment of rejection, its use may be falling although, as the authors confirm, one fifth of units claim to use this approach in selected cases. In this manuscript, the group from Boston report their experience in 73 heart recipients. They showed that use of TLI was effective in reducing the short term risk of rejection but had little impact in the longer term and possibly an increased risk of other complications. As would be anticipated, those having TLI are a selected population and have a greater risk in the longer term of rejection and rejection-related deaths. Only 55 were able to receive 80% or more of the prescribed radiation and other side-effects are common. Given all the caveats with such a retrospective study with relatively few patients, I would predict that TLI is likely to fall out of use and newer agents and approaches will be increasingly used to prevent and treat allograft rejection.

Reversal of Diabetes by the Creation of Neo-Islet Tissues Into a Subcutaneous Site Using Islet Cell Sheets

Saito, Takahiro; Ohashi, Kazuo; Utoh, Rie; More

Transplantation . 92(11):1231-1236, December 15, 2011.

Editor Comment

Reversal of Diabetes by the Creation of neo-islet tissues diabetes mellitus is increasing in prevalence and continues to places an increasing burden on both patients and health-care providers; treatment, with diet or medication (oral, subcutaneous, inhaled or other) is largely effective in controlling the disease and reducing complications but still provides palliation. Transplantation of pancreas or islets can be effective but has its limitations. In part because of the scarcity of donated and usable pancreases, transplantation remains an option for a tiny fraction of those who might benefit from the procedure and for those in whom transplantation does remain an option. The benefit is sometimes transitory. There have been a variety of approaches adopted to increase the longevity of translated islets and these include using different systems in extra-hepatic sites. Of the various sites evaluated, subcutaneous implantation clearly offers many benefits but remains subject to many structural restrictions. Takahiro and the group from Fukushima and Tokyo have developed the production of cell sheets in which functional cells are formed on a monolayer. In this report, they provide data on the functional outcome in mice of subcutaneous implantation of islets using their cell sheet technology. Islets were prepared from rats and, after preparation, given to SCID mice rendered diabetic with streptozotocin. The treatment was found to be effective, rendering the diabetic mice euglycemic for over 100 days. These findings are exciting and of significant clinical importance. Of course the model used cannot be readily extrapolated to the human situation, the numbers of islets transplanted relatively few and follow-up relatively short, yet they do offer another potential approach to the management of what will become an increasing challenge.

Association Between Age and Graft Failure Rates in Young Kidney Transplant Recipients

Foster, Bethany J.; Dahhou, Mourad; Zhang, Xun; More

Transplantation . 92(11):1237-1243, December 15, 2011.

Editor Comment

Association between age and graft failure rates Graft failure places an extra burden on already limited transplant resource; there are, of course, many causes of graft failure including technical, infective, recurrence and immunological. Failure to comply with immunosuppression remains a major and largely avoidable cause of graft loss: there have been many studies looking at risk factors that are associated with non-compliance (or non-concordance) as shown by a recent Forum in this journal. This large scale retrospective registry-based study confirms both clinical impression and published data that older adolescent and younger adults are at greatest risk of graft loss, irrespective of when they were transplanted; although these findings will not come as any surprise, the strength of the observations make this an important study that should inform practice. If the assumption that non-compliance with medication is a major contributory factor to graft loss, on approach, still adopted by some clinicians, is to postpone transplantation and leave the potential transplant candidate on renal support until there is a stronger likelihood of compliance. While this approach is understandable and may help the overall recipient pool, it seems to this editor, not the right way. Life with organ failure is tough and so is life as a teenager: the combination seems very hard. These data do lend increasing emphasis on the need of the health-care professionals and the families and friends to find more effective ways of ensuring that those who are fortunate enough to receive a kidney graft, will comply and take advice. There have been improvements but it seems that there is still a long way to go.

Renal Protection From Prolonged Cold Ischemia and Warm Reperfusion in Hibernating Squirrels

Jani, Alkesh; Epperson, Elaine; Martin, Jessica; More

Transplantation . 92(11):1215-1221, December 15, 2011.

Editor Comment

The inclusion of a manuscript involving squirrels in the journal cannot go unremarked in Editors' Picks. The current practice of hypothermic perfusion of retrieved organs and associated schema/reperfusion injury, remains a clinical challenge. The attraction of studying the natural homeostatic responses to the physiological cooling during hibernation is an attractive piece of lateral thinking that will provide further insight of this clinical challenge and may translate, in time, to clinical practice.

Early Changes in Kidney Function Predict Long-Term Chronic Kidney Disease and Mortality in Patients After Liver Transplantation

Cantarovich, Marcelo; Tchervenkov, Jean; Paraskevas, Steven; More

Transplantation . 92(12):1358-1363, December 27, 2011.

Editor Comment

Liver transplant recipients, as other solid organ recipients, usually have a reduced survival compared with age and gender matched healthy controls. Reasons for the reduction in survival are well described and include technical problems, rejection, recurrent disease, and an increased mortality from cardio and cerebrovascular complications, some cancers and some infections. Renal failure itself is well recognised and is associated with a four fold increased risk of death. Since the seminal paper by Ojo over one decade ago, clinicians have recognised that renal failure is a significant cause of morbidity and mortality that is, at least in part presentable. This paper from Canada confirms other studies that the scene for late renal failure is set within the first few months of transplantation. This should allow for interventions to reduce the impact of renal failure on mortality. The role of drugs, especially the calcineurin inhibitors (CNI) is well recognised and several different approaches have been adopted to reduce the impact of these and other modifiable factors (such as better control of blood pressure and diabetes): delayed introduction, lower doses or avoidance of CNI have all been advocated and, to varying degrees, assessed in studies. This study is a useful reminder that prevention is better than treatment and focus on avoidance is more effective than remedies to mitigate established renal impairment. While there is ongoing discussion about the best way to assess renal function, such debate should not divert attention from the need to take early action in the first year rather than wait for evidence of renal damage.

Quality of Life in Adult Survivors of Pediatric Kidney Transplantation

Haavisto, Anu; Jalanko, Hannu; Sintonen, Harri; More

Transplantation . 92(12):1322-1326, December 27, 2011.

Editor Comment

Childhood for normal individuals is not easy, so it is scarcely surprising that those with renal failure or following a transplant will have additional challenges. This study from Finland emphasises that the quality of life for such long-term adult survivors of paediatric kidney transplants is slightly reduced, that the educational outcome was similar irrespective of cerebral ischemic changes in childhood and the scores in childhood predicted scores in adulthood. The authors acknowledge the limitations of the study, namely the relatively small numbers and single centre, but a small well conducted study is often more constructive than a larger and less well done study. It would have been of interest to compare the outcomes of those who had undergone transplantation with those who had continued with dialysis. In non-renal transplant recipients, children often seem to perform less well than their healthy peers, yet it is often hard to unpick the impact of the transplant and its attendant complications (physical and other) and stress for not only the child but for the family from the impact of the disease process. Adult transplant clinicians are often envious of the additional resources that paediatric recipients are able to attract but studies such as these reinforce the need for support to be in place to allow children to reach their full potential.

Intestinal Retransplantation: Analysis of Organ Procurement and Transplantation Network Database

Desai, Chirag S.; Khan, Khalid M.; Gruessner, Angelika C.; More

Transplantation . 93(1):120-125, January 15, 2012.

Editor Comment

Intestinal transplantation has only relatively recently come of age but the procedure remains with a number of significant challenges. Graft failure and the consequences of the necessary immunosuppression continue to pose a threat to the recipient. This study based on analysis of the UNOS registry concludes that both graft and patient survival after a paediatric intestinal re-transplant remains poor. Of course the study can be criticised on the grounds that is an analysis of a registry, that it is based on relatively small numbers and on historical data. Yet this study provides the best data available. What does this mean for the clinician faced with a youngster with a failing intestinal graft? In the editor’s view, it would be wrong to withhold consideration from re-graft just on the basis of this useful study. To use these conclusions to deny access to a potential life-saving treatment would run counter to the stimulus to progress and overcome the problems that this and other studies have identified. There is not such a shortage of grafts that use of these precious organs would deny others access to transplantation. No surgeon or parent would wish to subject any child to ineffective surgery, but provided the parents are given the information and believe that further surgery is in the best interest of the child and that the surgeons and transplant team adopt an approach that might overcome the challenges of a re-graft, then such procedures should be undertaken. Therapeutic nihilism is a significant inhibitor of progress.

Splenectomy Does Not Offer Immunological Benefits in ABO-Incompatible Liver Transplantation With a Preoperative Rituximab

Raut, Vikram; Mori, Akira; Kaido, Toshimi; More

Transplantation . 93(1):99-105, January 15, 2012.

Editor Comment

The shortage of livers for transplantation has acted as a spur to surgeons and others to look at making the most effective and equitable use of a limited donor pool. The current practice is in most centres to allocate donated livers, whether from deceased or living donors, according to the blood transfusion rules. This has led to inequity of access, with some transplant candidates waiting longer and with a greater risk of death than others, purely because the blood group distribution of donated livers does not seem to correspond well to that of recipients. Most studies have shown that transplantation across ABO groups is associated with a reduced graft survival. A number of different approaches have been adopted to overcome the ABO restriction, especially in the field of living donor transplantation. Here the Kyoto group report their findings in 37 ABO incompatible liver transplants done over a 3 year period and suggest that use of Rituximab and plasma exchange reduced the antibody load and splenectomy has little additional benefit. Are these data strong enough to alter practice? Certainly splenectomy is associated with short and long term risks and consequences and more information is required. Nonetheless, if these findings are confirmed, then these findings offer greater benefit to those with a limited access to either deceased or living donor grafts.

Sotrastaurin (AEB071) Alone and in Combination With Cyclosporine A Prolongs Survival Times of Non-Human Primate Recipients of Life-Supporting Kidney Allografts

Bigaud, Marc; Wieczorek, Grazyna; Beerli, Christian; More

Transplantation . 93(2):156-164, January 27, 2012.

Editor Comment

The outlook after organ transplantation has been revolutionised by the increasing array of immunosuppressive agents. The well recognised toxicity profile of the calcineurin inibitors and inhibitors of mammalian target of rapamycin has further spurred the drive to develop more effective and less toxic agents. There is a variety of new agents that are being evaluated in animals and humans and amongst these is Sotrastaurin, an inhibitor of protein kinase C. This agent, which can be given orally, inhibits T cell activation and may allow reduction of CNI dose. In this study, Bigaud and colleagues have evaluated the impact of sotrastaurin alone and in combination in cynomolgus monkeys undergoing a life-saving kidney transplant. They showed that both as monotherapy and at lower doses in combination with ciclosporin improved graft survival. These data provide encouraging data for human studies and reinforce the potential of this new agent. Extrapolation from non-human primates to humans is of course to be done with caution but nonetheless, this should stimulate further work on this more recent approach to immunosuppression.

First Human Face Transplantation: 5 Years Outcomes

Petruzzo, Palmina; Testelin, Sylvie; Kanitakis, Jean; More

Transplantation . 93(2):236-240, January 27, 2012.

Editor Comment

Face transplants have attracted more publicity in recent years than other forms of transplantation and sometimes the scientific and medical developments have been obfuscated by the media interest. Indeed, sometimes public prurience exceeds interest. Initially medical enthusiasm for this advance was limited and there were many valid reasons for these concerns. Hence a formal assessment of one of the long standing survivor is of medical value. The recipient was a 38 year old female: she made a good recovery from the surgery and has regained many but not all of the normal functions of the face. Initial reservations included concerns about rejection and its impact on the individual; one other recipient did lose his graft as a consequence of non-compliance. Two episodes of rejection have responded to treatment but at the expense of the side-effects of immunosuppression such as hypertension. The authors mention she did develop carcinoma in situ of the cervix but this is not necessarily a consequence of immunosuppression. It is hazardous to extrapolate from an individual case but this study reinforces the argument that face transplantation is an effective treatment for a highly selected group of recipients, that immunological factors can be overcome but there is a need not only for careful selection on psychological grounds as well as medical ones but also full support for all those involved.

A Simplified Donor Risk Index for Predicting Outcome After Deceased Donor Kidney Transplantation

Watson, Christopher J. E.; Johnson, Rachel J.; Birch, Rhiannon; More

Transplantation . 93(3):314-318, February 15, 2012.

Editor Comment

There is a clear benefit for both patients and clinicians in providing some assessment of outcome after transplantation. It has been clear for many years that donor, transplant and recipient factors all contribute to the outcome. The development of validated models will not only provide practical information but will also identify prognostic factors. The model developed in the UK for renal transplant recipients is relatively simple with only 5 factors: it is of interest that donation after circulatory death was not associated with a poor outcome. These conclusions must be treated with some caution:the c-statistic was only 0.62 (which is similar o better than in other models) they are, inevitably, based on retrospective data and so may not take into account new developments; furthermore, the matching of donor and recipient is not random and, although there is in the UK a national allocation scheme, a significant proportion of preferred offers are declined. It must also be recognised that the prognostic model looked at outcomes at a relatively short interval after transplantation. Thus, the impact of donor age decreases with time after transplantation, whereas the impact of donor weight increases with time. These concerns notwithstanding, a simple model predicting outcomes for an individual will benefit patients and allow an improved allocation system.

Ibandronate and Calcitriol Reduces Fracture Risk, Reverses Bone Loss, and Normalizes Bone Turnover After lTX

Wagner, Doris; Amrein, Karin; Dimai, Hans Peter; More

Transplantation . 93(3):331-336, February 15, 2012.

Editor Comment

As liver transplant recipients live longer, clinicians have started to focus more on non-graft diseases such as cardiovascular disease and bone disease. Bone disease is important in that the progression of bone loss is relatively less dramatic and is largely sub-clinical until it presents with a fracture or other complication. many patients will have some degree of bone loss pre-transplant and the impact of bed rest, poor diet and corticosteroids will further exacerbate the bone loss. While drug treatment plays an important role in preventing graft loss or reducing its rate, other factors such as a healthy life style are important. this study from Graz gives important and useful information on the impact of parenteral ibandronate and calcitriol with calcium and vitamin D supplementation.Those treated with ibandronate had a significant increase in bone density at the femoral neck and trochanteric region compared with a small loss in the control group and ibandronate treatment was associated with a lower risk of fractures. Bisphosphonates are not indicated in all patients and choice of agent remains uncertain. Use of parenteral agents does mean added inconvenience to patients but will allow greater knowledge of adherence. This study clearly demonstrates the benefits of intervention and that calcium and vitamin D alone may not be sufficient and should ensure that the transplant clinician considers bone health as a routine part of clinical follow-up.

Impact of Donor and Recipient Race on Survival After Hepatitis C-Related Liver Transplantation

Layden, Jennifer E.; Cotler, Scott J.; Grim, Shellee A.; More

Transplantation . 93(4):444-449, February 27, 2012.

Editor Comment

Hepatitis C virus recurrence has a major impact on patient and graft survival. Attempts to reduce the impact of hepatitis C virus recurrence by choice of immunosuppressive regime, avoidance of acute rejection (and the need for its treatment) and giving a graft from a younger donor may help reduce the impact of recurrence. Treatment of the recipient, either before or after transplant, is effective in a small minority although newer agents may give some additional benefit. The impact of racial disparities between donor and recipient on graft outcomes has been studied in transplantation and HCV. As the authors discuss, in the US, at two years after liver transplant, Hispanics had a higher survival and black recipients had a lower survival compared with white recipients. This study, based on the UNOS database, shows a significant association between recipient and donor race and outcomes after liver transplantation for HCV. The authors found that black recipients with white donors had a higher mortality than white recipients of a white donor liver whereas Hispanic recipients of white donor livers had a lower mortality. these observations, which are not readily explained, raise concerns about equity of access. the better outcomes seen in a black recipient of a liver from a black donor should encourage further efforts to increase donation amongst all communities and encourage clinicians to work harder to ensure that outcomes are excellent for all, regardless of race.

Perceived Discrimination Predicts Longer Time to Be Accepted for Kidney Transplant

Myaskovsky, Larissa; Almario Doebler, Donna; Posluszny, Donna M.; More

Transplantation . 93(4):423-429, February 27, 2012.

Editor Comment

This study from Pittsburgh reports a longitudinal study on afro-American and white patients with end-stage kidney disease undergoing assessment for kidney transplantation to look at non-medical factors that are associated with time to acceptance. This was done in a relatively small number (127) and based on two telephone interviews. Nonetheless, the authors found that afro-American patients had a higher level of cultural factors (such as perceived racism, medical mistrust. After adjustment for demographic, psychosocial and cultural factors, race was not associated with a longer waiting time. This timely study will enable transplant teams to modify their approach to assessment to provide an approach that meets the needs of all those who require a kidney graft.

Everolimus as Primary Immunosuppression in Kidney Transplantation: Experience in Conversion From Calcineurin Inhibitors

Sánchez-Fructuoso, Ana I.; Ruiz, Juan C.; Calvo, Natividad; More

Transplantation . 93(4):398-405, February 27, 2012.

Editor Comment

The addition of mTOR inhibitors to the armamentarium of drugs to prevent rejection is welcome but the role of sirolimus and everolimus remains uncertain. Here the authors report their retrospective analysis of 220 kidney allograft recipients converted from a calcineurin inhibitor to everolimus. After conversion, creatinine clearance improved marginally and proteinuria increased significantly. Risk factors for proteinuria included a lower creatinine clearance, later conversion and a greater baseline level of proteinuria. This is not a randomised study and reasons for conversion were varied, including tumours and IFTA in one third each. Interestingly, the authors stated that generalised vascular disease was an indication for conversion in about 10%. There was a low rate of rejection (4%) and this was usually mild. One third of patients had everolimus discontinued, usually in the first year and the indications were as expected: pneumonitis, proteinuria skin eruptions and renal impairment. This study confirms that everolimus is another useful option in the treatment of allograft recipients but choice of immunosuppression remains complex and most recipients will require modification with time.

Effect of Everolimus on Left Ventricular Hypertrophy of De Novo Kidney Transplant Recipients: A 1 Year, Randomized, Controlled Trial

Paoletti, Ernesto; Marsano, Luigina; Bellino, Diego; More

Transplantation . 93(5):503-508, March 15, 2012.

Editor Comment

With the better matching of donors and recipient and the increasing range of immunosuppressive agents, prevention and treatment of rejection is less of an issue and attention of clinicians is focussed on the longer term outcomes of allograft recipients. Cardiovascular problems remain a significant cause of morbidity and mortality after transplantation, despite increasing recognition and earlier and more effective interventions. Most of the currently used immunosuppressive agents have adverse effects on cardiovascular risk factors; mTOR inhibitors, often used as a calcineurin inhibitor-sparing agent, have adverse effects on blood lipids. The study by Paoletti and colleagues from Genoa is therefore of interest. In an analysis of a prospective randomised study comparing everolimus and low-dose ciclosporin with standard ciclosporin in 30 consecutive non-diabetic first-time renal allograft recipients and showed that everolimus and low-dose ciclosporin were associated with a reduction in left ventricular hypertrophy, irrespective of blood pressure. The study is intriguing: with limitations of relatively small numbers, limited follow-up and lack of correlation with clinical events, the significance of the conclusions must be treated with caution. Furthermore, it is not clear whether the effect on LVH is due to the lower dose of ciclosporin or the use of everolimus. There is no clear mechanistic hypothesis even though these findings are consistent with animal data and raise the intriguing question about the overall risks and benefits of mTOR on cardiovascular risks.

Interleukin-22: Implications for Liver Ischemia-Reperfusion Injury

Chestovich, Paul J.; Uchida, Yoichiro; Chang, William; More

Transplantation . 93(5):485-492, March 15, 2012.

Editor Comment

Ischemia/reperfusion (I/R) injury after transplantation remains a significant cause of both morbidity and mortality. Several factors have been identified to define those at risk of I/R and many studies have begun to identify the mechanisms, both prevention and treatment remains largely empirical. Involvement of immune mechanisms in the pathogenesis of I/R injury has been established for many years but translation of this understanding into therapeutic intervention has remained elusive. In this paper from UCLA, Chestovich and colleagues have evaluated the effect of IL-22 on warm I/R injury in mice and have shown clearly that IL-22 protein has a hepatoprotective effect mediated by STAT-3 activation and offers an opportunity for therapeutic intervention. I/R is a complex process and several processes are in play. Furthermore, extrapolation of data from animals to man is hazardous: nonetheless, not only do these studies shed further light on a significant cause of graft injury but offers the hope of what might be a safe and effective therapeutic intervention.

Minimal Hepatic Encephalopathy: Follow-Up 10 Years After Successful Liver Transplantation

Mattarozzi, Katia; Cretella, Lucia; Guarino, Maria; More

Transplantation . 93(6):639-643, March 27, 2012.

Editor Comment

Chronic hepatic encephalopathy (HE) is not uncommon in liver transplant candidates and, in a small number of patients, may be the main indication for transplant, even if associated with a low MELD score. Depending on the extent that the clinicians look for evidence of HE, the incidence may be high. In the cirrhotic, consequences of hepatic encephalopathy may not be reversible. Furthermore, neurological sequelae of transplantation are multi-factorial and the role of ischemia and the neurotoxicity of drugs may play a role. So this study of the long-term outcomes of patients with minimal HE is of importance. Although there were only twelve patients in this study, nearly all showed significant improvement in cognitive function. It is reassuring that liver transplantation is effective and appropriate in such patients.

Hepatitis E Virus and the Kidney in Solid-Organ Transplant Patients

Kamar, Nassim; Weclawiak, Hugo; Guilbeau-Frugier, Céline; More

Transplantation . 93(6):617-623, March 27, 2012.

Editor Comment

Hepatitis E viral (HEV) infection is usually considered a mild and self-limiting infection, rather akin to Hepatitis A. In the liver transplant recipients, it is becoming increasingly recognised that HEV can give rise to a chronic hepatitic illness and now can affect other solid organ recipients. In this paper, Kamar and colleagues from Toulouse, describe 51 patients with HEV infection post-transplant, of whom 37 had received a kidney graft. Just under half cleared the infection within 6 months and the remainder developed a chronic hepatitis. During the HEV infection, there was a significant decrease in estimated GFR and histology of the kidney showed a membrano-proliferative glomerulonephritis and relapses in IgA nephropathy. After HEV clearance, renal function improved, proteinuria reduced and the cryoglobulinemia resolved. This study should remind clinicians that one of the many causes of renal impairment and hepatitis that should be considered in HEV infection. Diagnosis is usually straightforward by measuring HEV RNA: treatment with ribavirin may be helpful although it is potentially toxic. The extent of this infection in the allograft recipient remains uncertain and this infection provides yet another challenge to clinicians faced with a patient with unexplained liver or renal dysfunction.

A Score Predicting Survival After Liver Retransplantation for Hepatitis C Virus Cirrhosis

Andres, Axel; Gerstel, Eric; Combescure, Christophe; More

Transplantation . 93(7):717-722, April 15, 2012.

Editor Comment

Liver transplantation for Hepatitis C is common but bedevilled by the impact of graft re-infection. Strategies to reduce the impact, whether by pre- or post-transplant anti-viral treatment or better choice of donor or immunosuppression have only partly mitigated the problem. Thus many patients grafted for HCV come to graft failure and may require a re-graft, putting further pressure on a limited resource. To predict survival after re-graft would therefore help clinicians decide access to donated livers. The model is based on those parameters that would be anticipated, such as donor and recipient age and liver function. The main challenge is to what use would the model be used? If validated, would clinicians be happy to use such a model to allow or deny access to a life-saving transplant? While models are of value in providing guidance and also identifying significant variables, their use in clinical practice is fraught with challenges. Confidence intervals are wide and models reflect past practice and cannot take into account new developments and are based on collected data and not necessarily the most relevant ones. So, while these models are relevant and of value, their use is perhaps not as great as would be hoped.

Primary Lung Transplantation After Bridge With Extracorporeal Membrane Oxygenation: A Plea for a Shift in Our Paradigms for Indications

Lang, György; Taghavi, Shahrokh; Aigner, Clemens; More

Transplantation . 93(7):729-736, April 15, 2012.

Editor Comment

Allocation of life-saving and scarce organs remains a challenge: scoring systems provide an objective and transparent approach and takes some of the burden from the surgeon, although the surgeon still has to make the final decision whether or not to accept the organ. In contrast, organ allocation to a center allows the surgeon to make a decision but the rationale is necessarily complex and not usually transparent. In the US, lungs are allocated on the basis of a lung allocation score whereas in Austria, lungs are allocated to the center, thus providing an opportunity for a retrospective analysis of ECMO as a bridge to transplantation. The 38 patients included had a vaiety of indications and a mixture of approaches to bridging. Although the authors state that the survival of those grafted on ECMO were no worse than the comparison group was no worse statistically, the outcomes were inferior (5 year survival conditional on 3 months survival were 63% and 72%) in the ECMO group. Allocation of organs is difficult and these data to help provide some insight as to how scarce organs can be allocated most effectively.

Influence of Induction Modality on the Outcome of Deceased Donor Kidney Transplant Recipients Discharged on Steroid-Free Maintenance Immunosuppression

Sureshkumar, Kalathil K.; Thai, Ngoc L.; Hussain, Sabiha M.; More

Transplantation . 93(8):799-805, April 27, 2012.

Editor Comment

Despite the wish to reduce the immunosuppressive burden on allograft recipients, many units appear to be moving in the opposite direction with the use of induction agents as well as more potent immunosuppressive agents. Greater understanding of the immune mechanisms involved in the response to the graft and advances in biotechnology have provided clinicians with a number of potent induction agents. Many of these have gained widespread use in transplantation and their benefits and side-effects becoming well defined. In this paper, the authors have used the US database to look at the outcomes of deceased donor kidney transplants in patients who received induction therapy with ATG, IL2R blocker or alemtuzumab and were maintained on calcineurin inhibitor and mycophenolate. The conclusions were broadly that ATG is associated with a superior outcome in this group of patients and compares with other prospective studies. Side-effects are not discussed in detail and this remains of concern. Should centers move to ATG if induction therapy is needed. Large databases have huge strengths but also weaknesses including questions about the completeness and accuracy of data but, although questions remain based on non-randomised trials, the results are challenging and must encourage units to question their own regimens.

Long-Term (5 Years) Efficacy and Safety of Pancreas Transplantation Alone in Type 1 Diabetic Patients

Boggi, Ugo; Vistoli, Fabio; Amorese, Gabriella; More

Transplantation . 93(8):842-846, April 27, 2012.

Editor Comment

Pancreas transplantation has come of age; here the Pisa unit presents their own experience. Of 71 patients who underwent pancreas alone transplantation for type I diabetes. The outcomes, which are consistent with other reports are encouraging with good 5 year patient and graft survival. Overall, the clinical outcomes are good with improvements in most aspects of diabetes. Pancreas replacement does seem a fairly draconian approach to a major problem.

Hypothermic Reconditioning of Porcine Kidney Grafts by Short-Term Preimplantation Machine Perfusion

Gallinat, Anja; Paul, Andreas; Efferz, Patrik; More

Transplantation . 93(8):787-793, April 27, 2012.

Editor Comment

Donor organs are becoming increasingly high risk: attempts to improve both donors and organs are increasing organ viability. The provision of machine perfusion of organs has been variably associated with better graft function but provision of this support nationally poses a major clinical and logistical challenge. In this report, the team from Essen have studied a model of renal transplantation in pigs and suggest that conditioning after short-term cold storage is as effective as continuous hypothermic machine perfusion. This study, with obvious caveats, is encouraging and suggests that a clinical study should be undertaken. This seems logical but the costs, (and not only the financial ones) are challenges are great and the outcome should be not only graft function but also whether such interventions allows more organs to be used for transplantation.

Anogenital Malignancies in Women After Renal Transplantation Over 40 Years in a Single Center

Meeuwis, Kim A.P.; Melchers, Willem J.G.; Bouten, Hanneke; More

Transplantation . 93(9):914-922, May 15, 2012.

Editor Comment

Malignancies are a recognised complication of organ transplantation and immunosuppression. Studies have now evolved from merely looking at number and types of cancers recorded post transplant to looking at the increased risk, expressed by various measures such as standardised incidence ration. Thus while the absolute numbers of de novo cancers is greatest in the older recipient, the SIRs are greater in younger patients. UK studies have shown that, for example, there is no increase in cancers of the breast. Some malignancies are related to viral infections and these include those associated with HPV. This study from the Netherlands reports on 16 ano-genital malignancies that developed in just over one thousand female renal transplant recipients. In nearly all patients, the malignancy was associated with high risk HPV, usually subtype 16. While these malignancies are uncommon, the report not only highlights the need for appropriate surveillance but also the potential for targeting immunosuppression and the potential benefits from vaccination.

Repeat True Surveillance Biopsies in Kidney Transplantation

Buchmann, Thomas N.; Wolff, Thomas; Bachmann, Alexander; More

Transplantation . 93(9):908-913, May 15, 2012.

Editor Comment

Allograft biopsy may be for cause or protocol; the latter are done at fixed time points after transplantation. No biopsy is totally free of risk and therefore there needs to be a clear benefit from such a procedure. Although some (including myself) argue that protocol biopsies can be justified on purely academic grounds but, in that case, the biopsy needs to be done under appropriate control measures, with properly informed consent and, ideally, in the context of a prospective research study. Others argue that assessment of graft function though routine monitoring of serological or urine analytes is inadequate to detect pathological changes in the graft and histological findings, complemented by appropriate immunological and nucleic acid monitoring may allow not only early detection of pathological changes but will also allow for earlier intervention and so prolong graft survival and function. On the other hand, others will argue that information from such biopsies is rarely useful and does little to improve patient or graft function and the risks and costs (not only financial) are not justified by the benefits. The study from Basel goes some way to help resolve this controversy. This study largely confirms other studies that abnormalities, not suspected by routine monitoring, are relatively common and may help predict graft function in the longer term. Nearly one third had a therapeutic intervention as a consequence of the findings. It still remains unclear whether all units should consider protocol biopsies of the graft and at what time points. Furthermore, it is not clear what features should merit intervention but it is only by gathering information that a rational base for management can be made.

Community Attitudes to Deceased Organ Donation: A Focus Group Study

Irving, Michelle J.; Tong, Allison; Jan, Stephen; More

Transplantation . 93(10):1064-1069, May 27, 2012.

Editor Comment

Much of the clinical research in transplantation has focussed on the events following retrieval, yet transplantation cannot proceed without donors. The widespread improvement in health care and reduction of deaths from events such as road accidents has resulted, in almost all jurisdictions, in a donor pool that is shrinking and becoming higher risk, because of increasing age and obesity. It is therefore of increasing importance to identify all potential organ donors and ensure that donation occurs whenever it is appropriate. There have been many manuscripts looking at reasons for family consent or refusal but most of these have focussed on either those who have consented to donation or healthy individuals. Qualitative research is often employed and, while such techniques are potentially very powerful, they have a limited impact because they are done badly. This study from Australia looked at the views on organ donation in over 100 Australian adults. Of interest, they identified several areas where measures could be taken to improve consent and donation: improved confidence in the donation process, media coverage and clear information on the stances adopted by various religions. The last one has been well covered but disentangling religious from cultural beliefs is, inevitably, complex. The extent to which these conclusions are generalisable is uncertain but it is worth remembering that one of the conclusions of the Spanish model is that a constant stream of positive stories will enhance consent rates and this should be remembered by the relevant administrations . Journalists need to be aware of the wider impact of ‘bad news’ stories but clinicians will need to ensure that such an impact is not used as a cover-up for error.

Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

Kitchens, William H.; Haridas, Divya; Wagener, Maylene E.; More

Transplantation . 93(10):997-1005, May 27, 2012.

Editor Comment

The potential for co-stimulatory blockade to impact on allograft survival has been well documented in several trials in renal transplants; although there were concerns about some side-effects including allograft rejection, the ability to move away from calcineurin-based regimens is attractive. Alloreactive memory T cells may arise not only from events such as pregnancy or transfusion but also in transplant recipients. Based on observations that alloreactive memory T cells may play a role in mediating the costimulatory-blockade-resistant rejection and that memory T cells have a lower costimulatory threshold than naïve T cells, the authors evaluated the use of antibodies to integrins can impact on rejection; using an allogeneic murine model, they showed that by coupling anti-LFA-1 with co-stimulatory blockade the barrier posed by heterologous immunity could be surmounted. Both agents are clinically available (even if not all are licenced for transplantation) and so could lead to clinical trials. It is clearly a big stem from such animal studies to human trials, but should this work be extended and confirmed, it leads the way for novel approaches to managing immunosuppression and reducing the burden of the currently available drugs.

Discovery and Validation of a Molecular Signature for the Noninvasive Diagnosis of Human Renal Allograft Fibrosis

Anglicheau, Dany; Muthukumar, Thangamani; Hummel, Aurélie; More

Transplantation . 93(11):1136-1146, June 15, 2012.

Editor Comment

With increasing success of solid organ transplantation, clinicians are focussing increasingly on the long-term function of the graft. Assessment of graft function and structure is usually crude, using mainly serological and urinary analytes and imaging. Histological assessment is usually required for full assessment of the graft since visualisation of the graft will allow assessment of many aspects of the graft, including structure, damage, infiltrating cells and so on. Although such histologic assessment is usually considered the gold standard, the procedure has costs and risks as well as discomfort for the patient. Indirect assessment of graft structure will allow not only the potential for better patient care and longer graft function but may also inform the clinician as to the mechanism of graft damage and so, potentially, lead to better treatment. . Assessment of urine measurement of mRNA has been described over the last decade in this manuscript, the authors have taken this approach further and measured mRNA levels in urinary cells in kidney allograft recipients of whom just under half had graft fibrosis. They found that a model incorporating 4 genes was reasonably sensitive and specific for allograft fibrosis. Not only it is a bit surprising (to this author at least!) that such genes are expressed in urinary cells but that the model is robust. It would be of value to know more, to look at other series, in other cases of allograft damage, the impact of different immunosuppressive and other drugs, see how the model develops over time and how it correlates with rates of allograft fibrosis progression. Nonetheless, non-invasive measures of kidney allograft fibrosis are informative not only for understanding of the mechanism but can lead to better management and so longer graft survival.

Using Donor-Specific Antibodies to Monitor the Need for Immunosuppression

Hoshino, Junichi; Kaneku, Hugo; Everly, Matthew J.; More

Transplantation . 93(11):1173-1178, June 15, 2012.

Editor Comment

Despite the great advantages made in the understanding of the mechanisms of allograft rejection and the availability of more immunosuppressive agents, developing the most appropriate immunosuppressive regime for allograft recipients has remained elusive. Maintaining the dynamic balance between over-immunosuppression (and so putting the patient at unnecessary risk of drug-specific side effects and non-specific effects such as increased susceptibility to infection and cancer) and too little immunosuppression (so leading to graft damage and even loss) has remained a challenge and many laboratories have looked at a global measure of immunosuppression. Here the authors have looked at a prospective cohort of 72 living donor kidney recipients, treated with clonal deletion therapy and what is described as ‘lower dose’ immunosuppression. Donor specific antigens (DSA) were measured every 2 months using mixed or single antigen beads. DSA increased over time and proved a robust measure of re-emergence of an immune response. Is measurement of DSA the way to monitor immunosuppression? Although the report is encouraging and intriguing, more work needs to be done to establish this approach as a routine approach to monitoring graft function but clearly a useful step in what may prove a long path.

Face Transplantation Program in France: A Cost Analysis of Five Patients

Rüegg, Eva Meia; Hivelin, Mikael; Hemery, François; More

Transplantation . 93(11):1166-1172, June 15, 2012.

Editor Comment

Face transplants are not directly life saving but do have the potential for making huge improvements in quality of life for the recipient. Although few face transplants have been done, they have attracted enormous world-wide interest and continued media and public interest have, if anything, hampered progress. This manuscript, from one of the pioneering units, have looked at the costs of such a transplant and suggest that the overall costs for the operation and subsequent hospitalisation ranges from just over €100k to €170k. This is slightly lower than that reported by the Cleveland Clinic. Most of the costs relate to surgery, hospitalisation and nursing. While it is always difficult to make meaningful sense of costs and distinguish costs and charges, this does place the procedure in context with other solid organ transplants. Kidney transplants are not only the cheapest but also the most cost-effective (if for no other reason than there is a relatively expensive alternative): all costs are less. Liver and heart are somewhat less expensive. This study shows some of the additional challenges of face transplantation but also emphasises the need for not only more cost benefit studies of different types of transplantation but also the assess cost and quality of life years gained of such expensive procedures.

Immunosuppression With 4SC-101, a Novel Inhibitor of Dihydroorotate Dehydrogenase, in a Rat Model of Renal Transplantation

Rusai, Krisztina; Schmaderer, Christoph; Baumann, Marcus; More

Transplantation . 93(11):1101-1107, June 15, 2012.

Editor Comment

Leflunomide is currently used in some patients with arthritis and was used in transplantation but its routine use was discontinued because of side-effects although it remains used in polyoma associated nephropathy. This study, from Hungary, of kidney transplantation in rats, suggests that another dihydro-orotate inhibitor and blocker of IL-17, may be an effective alternate. Extrapolation of conclusions from short term animal experiments to humans is fraught with risk but this work does raise against the potential of this class of immunosuppressive agent.

Transfusion Rate for 500 Consecutive Liver Transplantations: Experience of One Liver Transplantation Center

Massicotte, Luc; Denault, André Y.; Beaulieu, Danielle; More

Transplantation . 93(12):1276-1281, June 27, 2012.

Editor Comment

This editor remembers the early days of liver transplantation when to conclude a liver transplant operation with less than 100 units was considered a great success by the surgeon and a relief by the transfusion service. The unenviable record is well over 1000 units for one procedure. It is a huge tribute to the skills of surgeons, anaesthetists and others, that many transplant units will now have a median of no blood useage during the operation. There are many factors that have led to this dramatic change, including technical skills of the surgeon, new approaches to haemostasis, including use of plasma, anti-fibrinolytic agents and cell savers, better anaesthesiology and technology. In this editor’s experience, many patients will require blood or blood product after surgery, and return from theatre with a lower haemoglobin concentration, but this will be of potential benefit as this will reduce the risk of early hepatic artery thrombosis and potential graft loss. Of course, more blood use is associated with a worse outcome but this may well be that blood loss (and so blood usage) will reflect the higher risk patient rather than being a cause. This reports, which reflects most units’ experience, can be considered yet another triumph is modern transplantation.

The Role of Liver Transplantation for Congenital Extrahepatic Portosystemic Shunt

Sakamoto, Seisuke; Shigeta, Takanobu; Fukuda, Akinari; More

Transplantation . 93(12):1282-1287, June 27, 2012.

Editor Comment

Indications for liver transplantation are increasing and contra-indications decreasing, in part because of the improvements in surgical and aneasthetic techniques; the failure of donation to keep pace with the need has meant that clinicians have to restrict access to deceased donor livers and, for those potential recipients with a living donor, clinicians must balance the risks to the donor (which are independent of the clinical state of the recipient) and the benefits to the recipient. Congenital extra-hepatic portal hypertension may be associated with intrinsic liver disease (such as biliary atresia) or with a structurally normal liver. In both cases, there may be associated extra-hepatic disease such as hepatic encephalopathy and pulmonary hypertension.Does liver transplantation have any role in those with good intrinsic liver function or those who could be treated by other and potentially less invasive interventions? Certainly, liver replacement has been advocated for those with portal hypertension not perfusing the liver through the portal vein.This study reviews 34 children and adults who underwent liver transplantation. As would be expected, two thirds had associated abnormalities, mainly cardiac defects; indications for transplantation were encephalopathy and pulmonary complications in about one third each although the severity of these is not clear. Just over one half had a living donor graft and three had auxilliary transplant.Three died, one after a re-graft. These are good results and show that, despite the technical complexity, liver transplantation can be done but the question remains should it be done? With the limited availability of donor livers and the long-term consequences of immunosuppression, the long term outcome, both in terns of length and quality of survival, the selection of recipients is a challenge. This study shows that the technical problems can be overcome by careful pre-operative imaging and careful planning and now puts the uncertainty back in to the optimal management of these challenging group of patients.

Hypothermic Oxygenated Machine Perfusion in Porcine Donation After Circulatory Determination of Death Liver Transplant

Fondevila, Constantino; Hessheimer, Amelia J.; Maathuis, Mark-Hugo J.; More

Transplantation . 94(1):22-29, July 15, 2012.

Editor Comment

As the traditional donor pool becomes smaller and those donors of greater risk, surgeons have to work harder to maximise the donor potential. This includes not only searching for new sources of donors (such as donors after circulatory death in Emergency Departments or elsewhere) but also trying to improve the quality of retrieved organs both to improve the function of those that are traditionally retrieved and also to make useable those organs that might otherwise be discarded. The challenge is further exacerbated by the lack of robust markers to define those organs that are safe to use. While donor optimisation will be of help, techniques such as ischemic preconditioning have really failed as yet to show a significant improvement. For lungs, ex vivo lung perfusion appears to be of benefit. In this paper, the authors from Spain and the Netherlands have used a pig model of donation after circulatory death: retrieved livers were preserved with either conventional static storage at 4ºC or subjected to hypothermic, oxygenated machine perfusion before being implanted. Follow-up was relatively short (5 days) and while those livers that were treated with hypothermic perfusion did show greater early restoration of liver cell function but did develop endothelial and Kupffer cell injury leading to death in all but one of the five pigs. While extrapolation of these experiments to the human situation is uncertain, they do suggest that if hypothemic perfusion does offer an opportunity to improve the quality and number of livers that can be retrieved from human donors after circulatory death, more work will need to be done to develop better techniques or else investigators will need to look at alternatives such as normothermic perfusion.

A Cardiovascular Risk Calculator for Renal Transplant Recipients

Soveri, Inga; Holme, Ingar; Holdaas, Hallvard; More

Transplantation . 94(1):57-62, July 15, 2012.

Editor Comment

It has long been recognised that renal transplant recipients, as with other solid organ recipients, have an increased risk of cardiovascular and cerebrovascular death. As clinicians focus their attention on long term outcomes, greater attention is being focussed on such complications, with ever tighter control of risk factors such as blood pressure, diabetes and blood lipids. Here, the authors have used data collected from the ALERT Study (Assessment of Lescol in renal transplantation) to develop and validate a risk score for cardiovascular disease in kidney transplant recipients. Seven factors were included in the model for cardiovascular death and six for death. Risk factors included age, the presence of coronary heart disease, smoking history, creatinine, number of transplants diabetes, serum LDL and, for mortality, total time of renal replacement therapy. Given the relatively good ROC, this model is likely to be helpful and is simpler than others. However, like all models there are weaknesses: data were derived from a study which, like all such studies, does not necessarily represent the ‘real world’ as there are entry criteria and follow-up is usually more focussed; analysis is also, inevitably, based on historical data and so may not reflect changes in practice or treatments, such as novel immunosuppressive agents. The model, like others, is also a static model and real life if course has a time-dependence. Models are of value for many reasons: they do provide a guide for patients and a stimulus for life changing patterns of behaviour where indicated as well as identification of prognostically (but not necessarily mechanistically) relevant factors and do identify high risk patients where interventions can be focussed and so reduce the non-transplant death rates and improve quality of life.

In Vitro Effects of Cyclosporine A and Tacrolimus on Regulatory T-Cell Proliferation and Function

Miroux, Céline; Morales, Olivier; Ghazal, Khaldoun; More

Transplantation . 94(2):123-131, July 27, 2012.

Editor Comment

Many factors have been associated with the impact of hepatitis c virus (HCV) infection of the liver graft. While many studies have shown that a bolus of high-dose steroids to treat allograft rejection is associated not only with an increase in viral load but also in graft damage. The role of other immunosuppressive agents has been raised with some studies suggesting an adverse impact of mycophenolate. There has long been a debate about the effect of calcineurin inhibitors on HCV replication and graft damage: in vitro studies, some using a replicon system, have suggested that HCV replication is inhibited by ciclosporin but not by tacrolimus. However, clinical evidence for a differential effect is lacking. This may be explained by the design of most studies (such as their retrospective nature) but also the lack of control of variables that might impact on recurrence, such as viral load and genotype, donor and recipient IL28B genotype, donor factors such as age and steatosis, episodes of rejection and so on. In this study, the authors from Paris evaluated the in vitro effect of ciclosporin and tacrolimus on normal human T regulatory cell function and activity and found that low dose ciclosporin inhibited T reg activity and this effect was independent on the calcineurin pathway. If conclusions from these studies can be extrapolated to the clinical situation, then it would seem that there is a paradox that lower dose ciclosporin may inhibit HCV replication and so reduce graft damage but tacrolimus may have a greater impact on preventing acute rejection and so obviate the need for treatment with high dose steroids that would themselves increase viral replication and graft damage. This possibility is certainly compatible with in vivo observations and, together with the in vitro studies, may lead to a more effective approach to immunosuppression in this challenging group of patients.

  • Video

The Course of Posttransplant Hepatitis C Infection: Comparative Impact of Donor and Recipient Source of the Favorable IL28B Genotype and Other Variables

Duarte-Rojo, Andres; Veldt, Bart J.; Goldstein, David D.; More

Transplantation . 94(2):197-203, July 27, 2012.

Editor Comment

Hepatitis C viral (HCV) infection is a major indication for liver transplantation and may complicate other solid organ transplants. In liver transplantation, infection of the graft is almost universal and may lead to fibrosis, cirrhosis and graft loss in up to half the patients. The progression of HCV infection in the graft is accelerated compared to that in the native liver and several risk factors are identified, including genotype, age of donor and treatment for rejection. Although the newer protease inhibitors may result in more effective and less toxic treatment, conventional treatment with pegylated interferon and ribavirin, whether pre- or post-transplantation, is usually toxic and relatively ineffective. Relatively recently, the variations in the genotype of IL28B have been linked to responsiveness as well as spontaneous viral clearance. In this study, the authors have evaluated the role of the IL28B in 272 consecutive liver transplants for HCV and found that the recipient CC genotype was associated with less graft inflammation and fibrosis and a lower viral load compared with the non-CC genotype; in contrast, the opposite was found for donor CC genotype. The best response was when both donor and recipient had CC and then a sustained viral response to treatment was seen in 90%. This study, which confirms the findings from others, does shed some light not only on the mechanism of response but allows personalised treatment. While in an ideal world, it would be nice if donors could be genotyped and those grafts with a favourable profile allocated to recipients with HCV but, given the challenges to divert livers from younger donors to such patients, such an approach is unlikely to be introduced for IL28; nonetheless, such analysis could help with selection of living donors.

Mycophenolate Versus Azathioprine for Kidney Transplantation: A 15-Year Follow-Up of a Randomized Trial

Clayton, Philip A.; McDonald, Stephen P.; Chapman, Jeremy R.; More

Transplantation . 94(2):152-158, July 27, 2012.

Editor Comment

Despite the absence of overwhelming evidence, mycophenolate has, in many centres, replaced azathioprine as the main anti-metabolite in immunosuppressive regimens. Mycophenolate is more expensive and more teratogenic but is probably more effective as an immunosuppressive and may allow for lower doses of calcineurin inhibitors. Is it more effective in prolonging graft survival? This study, from Australia, looked at 15 year outcomes of kidney grafts in patients entered into a randomised study comparing mycophenolate and azathioprine when used with ciclosporin and corticosteroids and showed little benefit of mycophenolate. Numbers are small and the management of immunosuppression has changed and this is a sub-group analysis but this study does raise again the value of using mycophenolate as a standard of care.

  • Video

The Implications of Acute Rejection and Reduced Allograft Function on Health Care Expenditures in Contemporary US Kidney Transplantation

Gheorghian, Adrian; Schnitzler, Mark A.; Axelrod, David A.; More

Transplantation . 94(3):241-249, August 15, 2012.

Editor Comment

Acute rejection after renal transplantation usually responds to treatment with additional steroids and, where necessary, antibody therapy, but this adds to the financial costs of transplantation. In this issue Gheorghian and colleagues examine in detail the economic implications of acute rejection. Their analysis is based on a very large patient population using data from the United States Renal Data System. Biopsy information was not available and it was not possible to differentiae between cellular and humoral rejection. Notwithstanding these limitations, they show that the incremental marginal cost for acute rejection is very considerable at over $22,000 in the first year if antibody treatment was required and over $14,000 when antibody treatment was not needed. Acute rejection, therefore, adds substantially to individual patient transplant costs, although these costs remain a relatively low proportion of the overall treatment costs for the entire transplant population given that rejection occurs in a minority of patients, and of course transplantation is less expensive than dialysis.

Attitudes Among Surgeons Towards Live-Donor Nephrectomy: A European Update

Klop, Karel W.J.; Dols, Leonienke F.C.; Kok, Niels F.M.; More

Transplantation . 94(3):263-268, August 15, 2012.

Editor Comment

Surveying surgical practice often reveals interesting differences between centres. The survey of attitudes towards live donor nephrectomy by surgeons in different European centres reported by Klop and colleagues in this issue is no exception. Perhaps surprisingly, thirty one (32%) of the 96 transplant centres surveyed reported that they still undertook donor nephrectomy exclusively by open surgery and of these 9 still used a classic lumbotomy. The most commonly stated reason for using open rather than laparoscopic nephrectomy was a lack of evidence that laparoscopic nephrectomy was superior. This highlights the need for further educational programmes since there is now clear published evidence that laparoscopic live donor nephrectomy is as safe as open nephrectomy and is associated with improved post-operative recovery and faster return to normal activity. Several other interesting findings emerged from the survey, but the most alarming was that nine of the centres surveyed reported using self locking clips for control of the renal artery, even though it is now clearly documented that such clips may compromise the safety of the procedure.

Prospective Evaluation of the Toxicity Profile of Proteasome Inhibitor–Based Therapy in Renal Transplant Candidates and Recipients

Schmidt, Nicole; Alloway, Rita R.; Walsh, R. Carlin; More

Transplantation . 94(4):352-361, August 27, 2012.

Editor Comment

Bortezomib is a small molecule proteasome inhibitor licensed for treatment of multiple myeloma. Because of its potent immunomodulatory effects, that include apoptosis of plasma cells, it has attracted considerable attention as a potential treatment for antibody-mediated graft rejection and to aid desensitisation prior to transplantation. Bortezomib toxicity has been well characterised in patients with myeloma and the side effect profile includes gastrointestinal symptoms, peripheral neuropathy and haematological toxicity. However, its toxicity in the context of renal transplantation is not well described. In this issue, Schmidt and colleagues prospectively evaluated the side effects of bortezomib in 51 patients undergoing treatment for antibody-mediated rejection and 19 patients undergoing desensitisation prior to transplantation. In this large experience, the toxicity observed was broadly similar to that seen in myeloma patients. Anaemia and peripheral neuropathy were significant toxicities and the former appeared more common in patients treated for antibody mediated rejection and the latter on those undergoing desensitisation. Peripheral neuropathy was mostly mild in nature it was reversible in all but one case. The authors conclude that bortezomib toxicity in the context of renal transplantation is relatively low in incidence and severity if well managed.

  • Video

The Implications of Acute Rejection for Allograft Survival in Contemporary U.S. Kidney Transplantation

Lentine, Krista L.; Gheorghian, Adrian; Axelrod, David; More

Transplantation . 94(4):369-376, August 27, 2012.

Editor Comment

Although the incidence of acute rejection after renal transplant has declined it remains an important cause of morbidity. In this issue, Lentine and colleagues report the clinical implications of acute rejection in a large and contemporary patient population. Their analysis included data from over 48,000 renal transplants (performed between 2000 and 2007) held on the United States Renal Data System. They examined the clinical impact of acute rejection occurring in different 6 month epochs after transplantation (up to three years) and one of the principal observations was that acute rejection that occurred later after transplantation was associated with poorer graft survival. This may in part reflect less intensive monitoring and delayed treatment of late acute rejection. Irrespective of when acute rejection occurred, graft loss was highest in first 3 months after diagnosis. While the study has a number of limitations by virtue of its dependence on registry data, including the lack of histological data on rejection, it clearly highlights the need for non-invasive monitoring of grafts to allow early recognition and prompt treatment of acute rejection.

Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation: 3-Year Follow-Up of the ATLAS Trial

Krämer, Bernhard K.; Klinger, Marian; Vítko, Štefan; More

Transplantation . 94(5):492-498, September 15, 2012.

Editor Comment

Long-term use of corticosteroids is associated with significant cardiovascular and metabolic complications after renal transplantation and there is a substantial literature on the successful use of steroid avoidance regimens. In this issue of Transplantation, Kramer and colleagues provide further evidence that steroid-free regimens are feasible and effective, at least in recipients at relatively low immunological risk. They report the three year follow up of an open-label, randomised multi-centre European study showing that recipients randomised to steroid free regimens (tacrolimus monotherapy or tacrolimus plus MMF) had more acute rejection episodes than those randomised to triple therapy (tacrolimus and MMF and steroids) but showed no difference in patient or graft survival which was good in all three groups. A majority (64% or more) of patients in the steroid free regimens remained corticosteroid free at 3-years and those given tacrolimus monotherapy showed a trend towards an improved cardiovascular and metabolic risk profile.

Randomized Clinical Trial of Transversus Abdominis Plane Block Versus Placebo Control in Live-Donor Nephrectomy

Hosgood, Sarah A.; Thiyagarajan, Umasanker M.; Nicholson, Harriet F.L.; More

Transplantation . 94(5):520-525, September 15, 2012.

Editor Comment

Laparoscopic live donor nephrectomy has now replaced open nephrectomy in most centres and has led to a less painful and more rapid recovery of the donor. Nevertheless many patients undergoing laparoscopic nephrectomy still require parental opiates for pain relief and these may cause side effects. In this issue Hosgood and colleagues report the results of a randomised double-blind clinical trial in which live donors received a posterior transversus abdominal plane (TAP) block with Bupivacaine or were given saline placebo. Those given Bupivacaine experienced less wound pain on days one and two and required 42% less morphine in the first 6 hours, although total morphine use was similar in both groups. Recovery and hospital stay were also similar in both groups. While promising, these findings need to be extended to include the use of TAP catheters that provide continuous infusions that prolong the analgesic effects beyond the 6 to 8 hours provided by a single injection of Bupivacaine.

NK Cells are Required for Costimulatory Blockade Induced Tolerance to Vascularized Allografts

van der Touw, William; Burrell, Bryna; Lal, Girdhari; More

Transplantation . 94(6):575-584, September 27, 2012.

Editor Comment

The role of Natural killer (NK) cells in transplantation has until recently centred mainly on their potential as cellular effectors of graft rejection. It is becoming clear, however, that there may be a more desirable side to NK cells. The findings of Van der Touw and colleagues in this issue add to the increasing evidence that NK cells may contribute to the development of transplant tolerance. In a mouse cardiac allograft model, where donor specific transplant tolerance can be successfully induced by pre-treatment with donor splenocytes and co-stimulatory blockade (anti-CD40L), Van der Touw et al show that depletion of NK cells before transplantation prevents tolerance induction and leads to acute cellular rejection. Their experimental studies further suggest that the beneficial effects of NK cells in this model of tolerance may, at least in part, be dependent on the ability of NK cells to regulate macrophage activation and infiltration into allografts. These findings are of interest because better understanding of the regulatory role of NK cells on adoptive alloimmunity may lead to novel therapeutic approaches in transplantation.

  • Video

Concurrent Acute Cellular Rejection Is an Independent Risk Factor for Renal Allograft Failure in Patients With C4d-Positive Antibody-Mediated Rejection

Matignon, Marie; Muthukumar, Thangamani; Seshan, Surya V.; More

Transplantation . 94(6):603-611, September 27, 2012.

Editor Comment

Improved methods for detecting donor specific alloantibodies, along with routine staining of graft biopsies for the presence of C4d deposition, has led to the realization that acute antibody-mediated rejection (AMR) is more common than previously thought and may have a worse prognosis for graft survival than acute T cell-mediated rejection. In this issue, Matignon and colleagues report that concurrent acute antibody-mediated and cellular rejection carries a particularly unfavorable prognosis. In a single centre retrospective analysis they identified 87 patients whose renal transplant biopsies showed AMR. Of these 18 had a combination of T-cell mediated and AMR and this combination of humoral and cellular rejection was shown to be an independent risk factor for allograft loss, with a hazard ration of 2.59. Inferior graft function at the time of biopsy was also an independent predictor of subsequent graft loss. Whether this finding has therapeutic implications is not clear but the treatment of AMR is a rapidly evolving area and identification of high risk sub-groups may have implications for treatment.

High Transplant Rates of Highly Sensitized Recipients With Virtual Crossmatching in Kidney Paired Donation

Ferrari, Paolo; Fidler, Samantha; Holdsworth, Rhonda; More

Transplantation . 94(7):744-749, October 15, 2012.

Editor Comment

Paired and pooled kidney exchange programs give recipients who have an HLA or ABO blood group antibody incompatible live donor the chance to receive a kidney transplant. Successful exchange schemes have now been established at a national or regional level in several countries. In this issue Ferrari et al report the early results from the recently established Australian paired kidney exchange scheme. The great majority of pairs listed (90%) were enrolled because of HLA antibody incompatibility although 40% were both HLA and ABO antibody incompatible. Notable features of the programme were that ABO incompatible matching was allowed for recipients with low blood-group specific antibody titres, virtual cross matching using Luminex to exclude incompatible HLA mismatches (MFI>2000) was employed, and both 2-way and 3-way exchanges were allowed with unlimited chain length with altruistic donors. A total of 20 (38%) of recipients listed in the first year of the programme received a kidney transplant, many of who were highly sensitised to HLA antigens. Despite the limited size of the programme to date it has clearly proven its success in enabling a relative high number of sensitised patients to receive a living donor kidney transplant.

Independent of Nephrectomy, Weaning Immunosuppression Leads to Late Sensitization After Kidney Transplant Failure

Augustine, Joshua J.; Woodside, Kenneth J.; Padiyar, Aparna; More

Transplantation . 94(7):738-743, October 15, 2012.

Editor Comment

Around 20% of patients listed for renal transplantation have already had a previous failed transplant and many of these have, as a result, developed HLA antibodies that may limit their chance of finding an immunologically compatible kidney. In this issue Augustine et al provide a timely warning that weaning patients from immunosuppression after their transplant has failed is likely to lead to the emergence of antibodies against HLA antigens expressed by the failed graft. In their large single centre study they show clearly that those recipients who were maintained on immunosuppression developed minimal sensitisation after graft failure whereas in those who stopped immunosuppression the percentage of highly sensitised patients increased from 21% to 68%. The two strategies for reducing the risk of de novo HLA antibodies developing for those patients seeking a further transplant are continuing with immunosuppression after graft failure or early graft nephrectomy while recipients are still on immunosuppression. As the authors point out prospective studies are now required to determine which of these two alternatives is most safe and effective.

Early Corticosteroid Withdrawal in Recipients of Renal Allografts: A Single-Center Report of Ethnically Diverse Recipients and Recipients of Marginal Deceased-Donor Kidneys

Aull, Meredith J.; Dadhania, Darshana; Afaneh, Cheguevara; More

Transplantation . 94(8):837-844, October 27, 2012.

Editor Comment

The long-term use of corticosteroids after renal transplantation may be associated with adverse metabolic and cardiovascular effects and their early discontinuation has been shown in large-scale clinical studies to be a safe and potentially beneficial option. However, such trials often exclude recipients of expanded criteria donor kidneys, those with delayed graft function and those receiving kidneys from old donors. In this issue Aull et al describe their large single centre experience of early steroid withdrawal in an ethically diverse recipient population many of whom received marginal deceased donor kidneys. In other words the type of transplant population that makes up a sizable proportion of activity in most centres. They show that a regime comprising ATG induction and tacrolimus plus mycophenolate maintenance therapy allows steroids to be safely withdrawn 5 days after transplantation. They obtained excellent patient and graft survival in the medium to long-term despite the high rate of risk factors for poor transplant outcomes.

The Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients—A Systematic Review

Roberts, Darren M.; Jiang, Simon H.; Chadban, Steven J.

Transplantation . 94(8):775-783, October 27, 2012.

Editor Comment

In contrast to acute cellular rejection, acute antibody-mediated rejection (AMR) after renal transplantation often responds poorly to treatment with corticosteroids alone. Various additional treatment options are available, including plasmapheresis, immununoadsorption, IVIG, depleting antibody preparations such as rituximab, and drugs such as bortezomib. In this issue Roberts et al report the first systematic review of the evidence for these alternative treatments. Perhaps not surprisingly their analysis shows that relatively little high-level evidence for any of the possible treatments exists. Their conclusion, which is important though, is that the optimal treatment for AMR, particularly in terms of cost, inconvenience and associated side effects remains unclear. The obvious take home message is that there is a need for good quality randomised trials to determine the efficacy of treatments for acute antibody-mediated renal allograft rejection.

Implantable Continuous Doppler Monitoring Device for Detection of Hepatic Artery Thrombosis After Liver Transplantation

de Jong, Koert P.; Bekker, Jasper; van Laarhoven, Stijn; More

Transplantation . 94(9):958-964, November 15, 2012.

Editor Comment

Early hepatic artery thrombosis (eHAT) is a serious complication in patients undergoing liver transplantation. Diagnosis is often delayed and urgent re-transplantation is invariably necessary. Percutaneous Doppler ultrasound examination is widely used to screen for eHAT but is problematic and often gives rise to false positive results. Consequently there is a need for a more reliable approach to screen for eHAT when reversal of the problem may be a treatment option. In this issue de Jong et al report their early experience of using a miniature Doppler ultrasound probe that is implanted alongside the hepatic artery at the time of liver transplantation and allows "continuous" monitoring of blood flow for several days during the early post-transplant period. The safety and efficacy of the device was evaluated in cohort of 102 patients (23 children and 79 adults) undergoing liver transplantation. The implantable probe did not lead to any specific complications and allowed regular monitoring of HAT patency during the ten-day study period. Its use was found to reduce the high false positive rate of eHAT resulting from percutaneos ultrasound examination, thereby decreasing the need for additional imaging investigations. However, it failed to detect two of the five cases of eHAT that occurred. Clearly this false negative rate is too high to recommend use of this approach in its current state of development, but the authors suggest that refining the positioning of the probe and improving the sensitivity of the device may lead to improved performance that may make it more reliable. If they are correct it could in the future find a role in helping to reduce early graft loss after liver transplantation.

Identification and Characterization of Kidney Transplants With Good Glomerular Filtration Rate at 1 Year But Subsequent Progressive Loss of Renal Function

Park, Walter D.; Larson, Timothy S.; Griffin, Matthew D.; More

Transplantation . 94(9):931-939, November 15, 2012.

Editor Comment

Poor graft function during the first year following renal transplantation is associated with inferior long-term graft survival. However, a single early GFR estimate may not be a very good predictor of longer-term graft loss. In contrast, longitudinal analysis of serial eGFR measurements identifies a group of recipients whose grafts initially functioned well during the first year, but that subsequently go on to lose their grafts over subsequent years. This is the principal conclusion from an observational cohort study reported in this issue by Park et al. They studied a cohort of 788 recipients who received a kidney transplant at the Mayo Clinic and found that a subset of grafts that had good function at one-year (eGFR of >= 40 ml/min) showed a progressive decline in eGFR over the next few years. Of those, 41% suffered graft failure during the follow-up period and they accounted for 69% of all graft failures after 2.5 years post-transplant. These observations have important implications. First, for clinical trials, the use of sequential eGFR values between one and five years following transplantation to create an "eGFR slope" provides a better surrogate end-point for long-term graft survival than a single measure of early graft function. Second, improved identification and understanding of the modifiable causes of graft failure in those kidneys with initial good graft function is required so that appropriate interventions can be introduced.

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Impact of Depression on Long-Term Outcome After Renal Transplantation: A Prospective Cohort Study

Zelle, Dorien M.; Dorland, Heleen F.; Rosmalen, Judith G. M.; More

Transplantation . 94(10):1033-1040, November 27, 2012.

Editor Comment

For many patients with end-stage renal disease, transplantation promises a markedly improved quality of life compared to dialysis. The report by Zelle et al in this issue is, however, a salutary reminder that even after transplantation many recipients continue to experience depression. In their prospective cohort study a disappointingly high number (31%) of transplant recipients experienced depression. The strongest independent variable associated with depression was being "medically unfit for work", although of course this could to some extent be self-fulfilling, since depression can lead to poorer physical health and reduce the ability to work. Proteinuria, lower physical activity level and increased duration of dialysis were also associated with depression. Depression was found to be strongly associated with increased risk of cardiovascular and all-cause mortality, and while the reasons are unclear, this may relate to a less healthy life style and poorer compliance with medical therapy. Although this study has a number of limitations, including the lack of data on depression status prior to transplantation, it makes a very important point and more attention clearly needs to be given to the diagnosis and treatment of depression in transplant recipients.

Reconditioning Lungs Donated After Cardiac Death Using Short-Term Hypothermic Machine Perfusion

Nakajima, Daisuke; Chen, Fengshi; Okita, Kenji; More

Transplantation . 94(10):999-1004, November 27, 2012.

Editor Comment

The use of lungs from uncontrolled circulatory death (DCD) donors has the potential to increase lung transplant numbers but such organs suffer significant ischemic injury making them more likely to experience primary graft failure after transplantation. In this issue Nakajima et al provide evidence, from a canine model, that lungs from "uncontrolled" circulatory death donors can be "reconditioned" by a short period of hypothermic machine perfusion before transplantation. In their study, donor lungs were first subjected to four hours of warm ischemia, to mimic uncontrolled donation after circulatory death, and then stored by simple cold storage alone or by simple cold storage and then two hours of cold machine perfusion. Lungs subjected to machine perfusion showed better physiological function and reduced ischemia reperfusion injury after transplantation, with higher ATP levels in the lung tissue and lower levels of pro-inflammatory cytokines in bronchiolar lavage fluid. While the period of evaluation after lung transplantation in this study was limited to four hours, the findings suggest that a period of cold machine perfusion helps protect uncontrolled DCD donor lungs from ischemia reperfusion injury.

Effects of HLA-Matched Blood Transfusion for Patients Awaiting Renal Transplantation

Magee, Bernadette A.; Martin, Jeanie; Cole, Miceal P.; More

Transplantation . 94(11):1111-1116, December 15, 2012.

Editor Comment

Avoiding unnecessary sensitisation to HLA in patients awaiting renal transplantation is highly desirable since sensitisation may prejudice access to transplantation and transplant outcome. Blood transfusion frequently leads to HLA sensitisation, even when leucodepleted blood is used. In this issue Magee et al show that the use of blood from donors selected so that there is either no HLA mismatch (or minimal mismatch) at HLA-A and HLA-B markedly reduces the risk of provoking HLA specific alloantibodies. None of the patients in this report that were given HLA matched blood (sourced from blood donors on the British Bone Marrow Registry and therefore of known HLA type) showed a change in their HLA sensitisation status whereas 23% of those given randomly selected blood showed either a significant increase in panel reactive alloantibodies or developed de novo HLA-specific antibodies. Although this is a small-scale single-centre study it clearly demonstrates the feasibility and potential advantage of using HLA matched blood in renal transplant candidates who require blood transfusion. This approach may be particularly relevant to children and young adults who are likely to require multiple transplants over their life-time.

MicroRNA Sequence Profiles of Human Kidney Allografts With or Without Tubulointerstitial Fibrosis

Ben-Dov, Iddo Z.; Muthukumar, Thangamani; Morozov, Pavel; More

Transplantation . 94(11):1086-1094, December 15, 2012.

Editor Comment

Kidney allografts that fail beyond the first year commonly display interstitial fibrosis and tubular atrophy (IFTA) but the underlying pathological mechanisms are poorly understood and management options are limited. Certain fibrogenic proteins have been implicated in IFTA and the genes encoding these proteins are regulated, at least in part, by small RNA molecules (miRNAs). Over 500 different miRNAs have now been identified and knowledge of those that contribute to IFTA is potentially very important. In this issue Ben-Dov et al show that human kidney allografts with IFTA display an altered intragraft miRNA expression profile that is distinct from that seen in kidney allografts without fibrosis. In their proof of concept study, a novel barcoded (multiplexed) miRNA sequencing approach was used to characterise the miRNA transcriptome. Their study is important because it demonstrates for the first time the feasibility and practicality of the highly informative technique used to sequence the miRNA transcriptome in kidney allografts, and provides preliminary data linking miRNA expression levels and kidney allograft outcome. Further studies are now needed to evaluate the utility of miRNAs as diagnostic and prognostic biomarkers following renal transplantation.

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Cancer Transmission From Organ Donors—Unavoidable But Low Risk

Desai, Rajeev; Collett, Dave; Watson, Christopher J.; More

Transplantation . 94(12):1200-1207, December 27, 2012.

Editor Comment

The inadvertent transmission of cancer from organ donor to recipient by transplantation is a feared complication and as the age of organ donors rises so too does concern about cancer transmission. As with all risks, it is important to try and quantify them to inform decision-making. In this issue, Desai et al report the results of a UK wide survey that attempts to do just that. During the ten-year period of the study, over thirty thousand solid organ transplants were performed using organs from nearly fifteen thousand donors, none of who were known to have cancer at the time of organ donation. Only 15 recipients (0.05%) developed a donor transmitted cancer and 6 of these were renal cell cancers identified incidentally early after renal transplantation. Despite the comprehensive nature of this study it remains possible that the incidence of donor-transmitted cancer has been underestimated though probably not by very much. The message is clear and is that while all possible precautions to detect previously unrecognised cancer in organ donors should be made, cancer transmission will still occur and prospective recipients should be made aware of this but fortunately it is a rare and often treatable problem.

Is Cytomegalovirus Prophylaxis Dispensable in Patients Receiving an mTOR Inhibitor–Based Immunosuppression? A Systematic Review and Meta-Analysis

Andrassy, Joachim; Hoffmann, Verena S.; Rentsch, Markus; More

Transplantation . 94(12):1208-1217, December 27, 2012.

Editor Comment

CMV prophylaxis is widely used in patients undergoing organ transplantation, particularly in those deemed at highest risk of CMV infection. However, such prophylaxis is not without problems. In this issue, Andrassy et al report the results of metanalyses showing that mTOR-inhibitor-based immunosupression is associated with fewer problems from CMV than when calcineurin-inhibitor-based immunosuppression is used. The combination of mTOR and calcineurin inhibitors is also associated with a lower incidence of CMV infection. The possible biological mechanisms underlying the inhibitory properties of mTOR blockade on CMV are discussed and include direct effects on viral replication, as well as influence on innate and adaptive immunity. On the basis of these findings the authors suggest that CMV prophylaxis may be safely replaced by a pre-emptive CMV strategy when mTOR inhibitors are used, but they also highlight the need for a prospective trial to confirm the safety and efficacy of this approach.

Preformed Complement-Activating Low-Level Donor-Specific Antibody Predicts Early Antibody-Mediated Rejection in Renal Allografts

Lawrence, Christopher; Willicombe, Michelle; Brookes, Paul A.; More

Transplantation . 95(2):341-346, January 27, 2013.

Editor Comment

The use of solid phase assays that allow accurate and sensitive screening for donor-specific antibodies has demonstrated that even relatively low levels of pre-formed donor specific antibodies (DSA) may be associated with inferior outcome after renal transplantation. It would be helpful if those with low levels of donor-specific antibodies could be further stratified to determine their immunological risk profile and in this issue Lawrence et al provide evidence that this is possible using a modified single antigen fluorescent bead assay that detects the ability of DSA to trigger fixation of the complement fragment CD4d. They show in a retrospective single centre analysis that 19% of patients with low levels of pre-formed DSA had complement fixing antibodies and that this group had a significantly higher incidence of biopsy-proven antibody-mediated rejection compared to those with non-complement fixing DSA (70% versus 19%). Further studies are now needed to determine whether this type of approach can be used to guide intervention in terms of modified organ allocation policy or immunosuppressive strategy in high-risk recipients.

Donor-Specific Antibodies to Class II Antigens Are Associated With Accelerated Cardiac Allograft Vasculopathy: A Three-Dimensional Volumetric Intravascular Ultrasound Study

Topilsky, Yan; Gandhi, Manish J.; Hasin, Tal; More

Transplantation . 95(2):389-396, January 27, 2013.

Editor Comment

Donor specific antibodies (DSA) directed against HLA Class II are associated with inferior outcome following renal transplantation but their significance in cardiac transplantation is much less clear. In this issue Topilsky et al demonstrate a significant association between the presence of pre-formed DSA to HLA Class II and accelerated cardiac allograft vasculopathy. The presence of allograft vasculopathy was assessed comprehensively by both coronary angiography and 3-dimensional intravascular ultrasound examination at baseline and one year after transplantation. The study is relatively small and included only 51 patients, 11 of who had pre-transplant HLA class II DSA. The authors highlight the preliminary nature of the study and the need for larger observational studies to validate their findings. However, it does look as though the situation with respect to DSA for heart transplantation is similar to that in kidney transplantation.

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Blood Group Antigen-Targeting Peptide Suppresses Anti-Blood Group Antibody Binding to Antigen in Renal Glomerular Capillaries After ABO-Incompatible Blood Reperfusion

Yoneyama, Tohru; Hatakeyama, Shingo; Tobisawa, Yuki; More

Transplantation . 95(3):418-425, February 15, 2013.

Editor Comment

ABO incompatible organ transplantation is commonly undertaken in carefully selected recipients with appropriate pre-transplant preparatory treatment and, where necessary, increased post-transplant immunosuppressive therapy. However, complications relating to immunosuppression and antibody-mediated rejection remain a concern and in some potential recipients high ABO antibody levels may preclude transplantation altogether. In this issue, Yoneyama et al have sought to develop a novel approach that targets ABO antigens expressed by target tissue and prevents antibody binding. By screening a peptide library they identified an ABO blood group antigen-binding peptide (BATP). They show that the 7 amino acid peptide is able to suppress haemagglutination of red cells by anti-ABO antibodies in vitro and that ex vivo perfusion of human kidneys with BATP partially blocks antibody deposition on renal glomerular capillaries. Based on these preliminary findings, BATP shows promise as a potential novel intervention for helping to facilitate ABO incompatible transplantation.

Donor Smoking History and Age in Lung Transplantation: A Revisit

Shigemura, Norihisa; Toyoda, Yoshiya; Bhama, Jay K.; More

Transplantation . 95(3):513-518, February 15, 2013.

Editor Comment

When selecting deceased donor lungs for transplantation those from donors who do not have a history of smoking are regarded as more desirable than those from smokers. The findings reported by Toyoda et al in this issue suggest that a history of smoking by the donor may not necessarily be such a problem, at least for lungs from donors who are not "heavy smokers". In a large retrospective single-centre cohort study of over 500 lung transplants, it was found that five-year survival was no worse for those receiving lungs from the 55% of donors with a history of smoking. In fact, overall survival was significantly better in those receiving lungs from smokers. Subgroup analysis of the donors who were heavy smokers (>40 packs /year) showed, however, that they had a worse outcome than those receiving lungs from those who smoked less. Surprisingly, recipients of lungs from teenage donors with no history of smoking fared worse than those given adult lungs from non-smokers. These results should be interpreted with caution, given the retrospective nature of the study and the possibility of bias but the report certainly raises some intriguing questions.

Ten-Year Results of a Randomized Trial Comparing Tacrolimus Versus Cyclosporine A in Combination With Mycophenolate Mofetil After Heart Transplantation

Guethoff, Sonja; Meiser, Bruno M.; Groetzner, Jan; More

Transplantation . 95(4):629-634, February 27, 2013.

Editor Comment

Most heart transplant recipients now receive tacrolimus rather than cyclosporine based therapy but the evidence base for this is limited. Guethoff et al report the ten-year results of prospective randomized trials comparing triple immunosuppressive strategies combining either tacrolimus or cyclosporine with mycophenolate mofetil and steroids after heart transplantation. Recipients randomised to the tacrolimus arm had a lower rate of both acute rejection and chronic allograft vasculopathy. Transplant survival at ten-years was not significantly different between the two study groups (73% tacrolimus versus 67% cyclosporine) but the small study size (60 patients in total) means the trial is probably insufficiently powered to detect any such difference.

Acute Rejection Characteristics From a Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial of Early Corticosteroid Withdrawal

Gaber, A. Osama; Moore, Linda W.; Alloway, Rita R.; More

Transplantation . 95(4):573-579, February 27, 2013.

Editor Comment

Safe reduction of corticosteroids in transplant recipients is a desirable goal and Gaber et al report a post-hoc analysis of a 5-year prospective, multicenter, randomized, double-blind trial of early corticosteroid withdrawal in kidney transplant recipients. They previously reported no overall differences in the composite primary end-point for the trial (death, graft loss, and acute rejection requiring anti-lymphocyte antibody therapy) or any of its components. Now they report that biopsy confirmed acute rejection, for which the criteria were broadened to include borderline changes of rejection, occurred more frequently in recipients randomised to corticosteroid withdrawal (22% versus 13%), particularly for non-African American recipients. This adds to evidence that steroid withdrawal is feasible in many recipients but may lead to problems in some.

Risks and Benefits of Preemptive Second Kidney Transplantation

Johnston, Olwyn; Rose, Caren L.; Gill, Jagbir S.; More

Transplantation . 95(5):705-710, March 15, 2013.

Editor Comment

Although kidney allograft survival is increasing over time, grafts do have a limited survival. With the increasing pressures to use more marginal grafts, the impact of better care and more appropriate use of a growing armamentarium of immunosuppressive agents is being inhibited. The consequence is that the number of kidney allograft recipients developing graft failure is increasing and, for many, the best therapeutic option is a re-graft. While it is generally accepted that pre-emptive renal transplantation is associated with better outcomes than transplantation after dialysis in the first kidney transplant (whatever the explanation), the benefit of pre-emptive second transplants has not been clearly established. In this paper, Johnston and colleagues have used the US Renal Data System to compare outcomes of pre-emptive and non-pre-emptive second kidney transplants.

HIV-Infected Kidney Graft Recipients Managed With an Early Corticosteroid Withdrawal Protocol: Clinical Outcomes and Messenger RNA Profiles

Muthukumar, Thangamani; Afaneh, Cheguevara; Ding, Ruchuang; More

Transplantation . 95(5):711-720, March 15, 2013.

Editor Comment

Despite the increasing organ shortage, clinicians and scientists are constantly stretching the boundaries of what can be achieved. The advent of effective HAART for those infected with HIV has allowed this cohort of people access to organ transplantation. Those with HIV who need a liver transplant (often because of associated Hepatitis C viral infection) do well after transplantation although the impact of HCV remains a concern. Management is a challenge, primarily because of the need to manage immunosuppression safely. Here Muthukumar reports on the outcome of 11 kidney allograft recipients treated a novel regimen of ATG with maintenance with tacrolimus and mycophenolate; corticosteroids were given for just 4 days. With this regimen, all 11 recipients have done well, both from the graft and the HIV infection. Outcomes are early but it is clear that, with experienced follow-up, those suitable people with HIV can now claim equal access to this scarce resource. It seems sensible to restrict transplantation and follow-up to those centres which have adequate experience not only to manage these recipients but also to publish outcomes using a protocol-based follow-up. We await longer term outcomes with interest.

Systematic Comparison of Four Cell- and Luminex-Based Methods for Assessment of Complement-Activating HLA Antibodies

Lachmann, Nils; Todorova, Kremena; Schulze, Harald; More

Transplantation . 95(5):694-700, March 15, 2013.

Editor Comment

The advances that newer technology brings undoubted benefits but also challenges. The ability to detect, characterise and quantify anti-HLA antibodies has allowed better matching of donors and recipients but has also brought uncertainty about the significance of some of the findings. In many countries, laboratories use different technologies for the detection of these antibodies and different reporting systems. In this paper from Berlin, the authors have compared the standard CDC assay with three Luminex assays (C1q, C4d and IgG) to assess or predict complement-binding capability of HLA IgG antibodies in sera from 45 highly sensitised sera and show that their in-house C1q and C4d assays show increased sensitivity and specificity compared with CDC. The next question is how to interpret these findings and how best to use such findings to improve allocation and outcomes of solid organ grafts.

Monitoring for HHV-6 Infection After Renal Transplantation: Evaluation of Risk Factors for Sustained Viral Replication

Luiz, Claudia R.; Machado, Clarisse M.; Canto, Cynthia L.M.; More

Transplantation . 95(6):842-846, March 27, 2013.

Editor Comment

Long-term immunosuppression, necessary to maintain good graft function, is associated with, amongst other features, chronic viral replication which sometimes have significant adverse consequences for the patient: these range from asymptomatic infection to malignancy. As many of the early problems associated with transplantation have been overcome, attention has focussed on the long term consequences and, for example, chronic Hepatitis E infection is now well recognised as a significant, if still rare, cause of graft hepatitis. Another virus that has attracted attention is the Human herpes virus 6 (HHV-6) which may, in the immunosuppressed, cause hepatitis, encephalitis, pneumonitis and bone marrow suppression. Luiz and colleagues followed prospectively a small number of kidney allograft recipients and evaluated HHV-6 DNA levels for in the early post-transplant follow-up. As might be anticipated in this Brazilian population, HHV-6 sero-positivity was common in both donors and recipients pre-transplant. Post transplant, just over one quarter developed active infection at a mean time of 4 weeks with a mean duration of 3 weeks: of these only one developed symptoms of an upper respiratory tract infection. Risk factors for viremia included transplant from a live donor, recipients with IgM antibodies pre-transplant and a higher viral load pre-transplant. Although this short term study does not give rise to concerns or suggest a change in practice, it does highlight the need for clinicians to bear in mind chronic viral infections and their consequences; with the use of what may be more aggressive induction therapies, these infections may take on a greater significance.

Effect of Peripheral Vascular Disease on Kidney Allograft Outcomes: A Study of U.S. Renal Data System

Brar, Amarpali; Jindal, Rahul M.; Elster, Eric A.; More

Transplantation . 95(6):810-815, March 27, 2013.

Editor Comment

Vascular disease is not uncommon in kidney allognenerraft candidates and recipients so Brar and colleagues used data in the US Renal Database System to test what impact asymptomatic peripheral vascular disease had on outcomes after kidney transplantation and found that peripheral vascular disease was associated with lower death-censored graft survival and a higher all-cause mortality. While these findings are scarcely surprising, it is useful to have some evidence to support clinical expectations as this will not only allow better information for recipients (and living donors where appropriate) but may also allow better allocation. Differences in survival, while statistically significant, do not support the exclusion of those with peripheral vascular disease from listing. Furthermore, these findings also reinforce the need to look for and actively treat those risk factors that may lead to peripheral vascular disease in those with chronic kidney disease, although it remains to be shown that such a policy would have any beneficial impact of post-transplant outcomes. An additional feature of the study was the impact of race: renal allograft outcomes in those with no peripheral vascular disease were worse in Afro-Americans compared to non-Afro-Americans but this difference was not apparent when comparing those two groups with vascular disease. Reasons for this are not apparent from the analysis but the authors speculate that one explanation may be that Afro-Americans with significant peripheral vascular disease have a lower chance of being listed for transplantation. As seen in many other spheres of medicine, this study raises issues about equitable access to medicine for all.