Peter A. Andrews

Summary of the British Transplantation Society/Renal Association UK Guidelines for Living Donor Kidney Transplantation

The third edition of the joint British Transplantation Society/Renal Association guidelines for living donor kidney transplantation was published in May 2011. The guideline has been extensively revised since the previous edition in 2005 and has used the GRADE system to rate the strength of evidence and recommendations. This article summarizes the statements of recommendation contained in the guideline, which provide a framework for the delivery of living kidney donation in the United Kingdom and may be of wide international interest. It is recommended that the full guideline document is consulted for details of the relevant references and evidence base. This may be accessed at http://www.bts.org.uk/transplantation/standards-and-guidelines/ and http://www.renal.org/clinical/OtherGuidelines.aspx (transplantation is welcome to add a web link in this article to/through its own Web site to increase traffic).

Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation

The third edition of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease after Solid Organ Transplantation was published in March 2011. This article summarizes the important changes and advances in management in this rapidly evolving field. The pros and cons of universal, or targeted anti-cytomegalovirus (CMV) prophylaxis, and pre-emptive anti-CMV therapy are discussed, especially with respect to advances in CMV polymerase chain reaction monitoring. The evidence for oral anti-CMV prophylaxis using valganciclovir is presented, together with a summary of the treatment of CMV disease and emerging fields such as CMV vaccination, CMV genotyping, and drug resistance.

MOLECULAR ANALYSIS OF C3 ALLOTYPES RELATED TO TRANSPLANT OUTCOME IN HUMAN RENAL ALLOGRAFTS

The third component of complement (C3) exists in two main allotypic forms, C3S and C3F, which can be distinguished at the molecular level using a variation of the polymerase chain reaction. An increased frequency of the C3F allele has been noted in a number of autoimmune and inflammatory conditions affecting the kidney, including systemic vasculitis, IgA nephropathy, and type II mesangiocapillary nephritis. Recently, in an unrelated study, we found (with small numbers) an increased incidence of graft loss associated with the presence of the C3F allele. To further assess this, we analyzed the S/F polymorphism in 183 donor-recipient pairs of patients undergoing renal transplantation. Forty-one of 183 grafts were lost, but graft loss was not associated with the C3F allele over 14-month follow-up. However, the presence of the C3F allele predicted an increased risk of graft dysfunction (defined as serum creatinine >150

Tissue synthesis of complement as an immune regulator

mUmol/L): 61/105 versus 36/78, with a relative risk of 1.4 (P<0.05). The C3F allele predisposed toward graft dysfunction when present in either donor or recipient. The presence of two C3F alleles gave a relative risk for graft dysfunction of 1.8, suggesting a dose-dependent effect, although numbers were small. The presence of the C3F allele was not significantly correlated with the number of rejection episodes, serum creatinine, or duration of primary nonfunction. These findings suggest that C3F may be a susceptibility allele for allograft injury. Possible mechanisms for this association are discussed.

Rhesus immunization after renal transplantation.

Evidence is accumulating that a variety of tissues produce complement components, and that production in each tissue is differentially regulated by inflammatory cytokines. This locally produced complement could have protective or injurious actions, depending upon local circumstances. Techniques for analysing separately the contributions of local complement synthesis and complement derived from the circulation are now becoming available. We argue that an appreciation of the role of local complement synthesis may help to explain many features of organ- and tissue-specific immunological disease.

Summary of the British Transplantation Society guidelines for transplantation from donors after deceased circulatory death.

Previous reports, before the advent of cyclosporine, suggest that the small amount of blood transplanted with a kidney can result in rhesus D (RhD) antibody production. We looked for retrospective and current evidence of primary RhD antibody production following renal transplantation in RhD-negative recipients of an RhD-positive kidney. Of 42 patients, all on triple immunosuppressive therapy, 2 (5%) were found to have an RhD antibody identified for the first time after transplantation. As the number of pregnancies in transplant recipients increases, the small risk of primary immunization and subsequent risk of hemolytic disease of the newborn will become more important. Therefore, we recommend that all RhD-negative women of child-bearing age receiving an RhD-positive solid organ transplant are given a prophylactic dose of 500 IU of anti-D immunoglobulin intramuscularly at the time of transplantation.

Review of living kidney donor guidelines is out of date before publication.

The second edition of the British Transplantation Society Guidelines for Transplantation from Donors after Deceased Circulatory Death was published in June 2013. The guideline has been extensively revised since the previous edition in 2004 and has used the GRADE system to rate the strength of evidence and recommendations. This article summarizes the Statements of Recommendation contained in the guideline, which provide a framework for transplantation after deceased circulatory death in the U.K. and may be of wide international interest. It is recommended that the full guideline document is consulted for details of the relevant references and evidence base. This may be accessed at: http://www.bts.org.uk/MBR/Clinical/Guidelines/Current/Member/Clinical/Current_Guidelines.aspx.

Medications to reduce cardiovascular risk after kidney transplantation.

The British Transplantation Society (BTS) applauds the attempt by Tong et al. (1) to critically assess the guidelines for living kidney donor transplantation. It is important that national guidelines are, whenever possible, consistent and that their production is both transparent and evidence-based. However, it is unfortunate that the article is out of date even at the time of publication. The article reviews the second edition of the BTS/Renal Association United Kingdom Guidelines for Living Kidney Donor Transplantation, published in 2005 (2). Subsequently, a comprehensively updated third edition of the UK guidelines was published in May 2011, which currently represents the most up-to-date guideline in this field (3). Much has changed in the new edition. Most importantly, the revised guideline has been produced to a higher standard of evidence, reflecting the move from opinion-based to evidencebased guidelines over this period, and now uses an internationally recognized grading system to rate both the quality of the evidence and the strength of the recommendations (4). It has been produced following the institution of a rigorous guideline development policy, which has adhered to the quality standards set by National Health Service Evidence (5). The BTS agrees that efforts to improve the consistency of guidelines are of value and indeed is contributing to the development of European guidelines in this field. Best practice requires that guidelines do not unnecessarily duplicate; are updated at regular intervals; are produced in an open and transparent fashion; are evidence based; and are not unnecessarily proscriptive. However, it should be recognized that there are variations in legal, ethical, and medical practice that will require the parallel development of guidelines that match the needs of different health environments and that there will always be a need to individualize patient care.

HLA matching: still important despite modern immunosuppression.

Cardiovascular disease (CVD) accounts for a substantial proportion of deaths after transplantation. Traditional cardiovascular (CV) risk factors including diabetes, hypertension, and cigarette smoking predict risk of CV events in transplant patients (1– 4). Similarly, reduced kidney function is associated with increased CV risk in both the general population and in those with kidney transplants (5, 6). There are, however, a number of CV risk factors that are unique to the transplant population (2– 4) (Table 1). These are not insignificant, and some attribute transplant-associated risk factors, particularly those relating to kidney function, as potentially more potent predictors of CV risk than conventional ones (7). In this issue of Transplantation, Pilmore et al. (8) from the Auckland City Hospital report the findings from a retrospective analysis of data from the Patient Outcomes in Renal Transplantation (PORT) study on the use of CVD medications after renal transplantation and the relationship of medication use to coronary heart disease. The study collected medication data on 15,410 transplant patients from 10 centers. It demonstrated an increase in the use of CVD medications in the first 4 months posttransplantation, with a leveling off of medication use after this time. A total of 36.3% of patients were taking Ace inhibitors and 39.6% were taking statins at 5 years after transplantation. There was a 4-fold increase in the use of any CVD medication, with the exception of diuretics, and a 12-fold increase in the use of statins between 1990 and 1994 and 2000 and 2006. The observed increase in medication since 2000 has occurred in the absence of any trial evidence or evidence-based guidelines to support the use of CVD medication in renal transplant recipients. Indeed, what evidence is available is not encouraging. Data from large trials in hemodialysis patients have consistently failed to demonstrate CV or mortality benefits for quite rational treatment strategies, such as increasing hemoglobin levels, increasing dose of dialysis, and the use of statins to lower cholesterol (9 –12). This may reflect the different CV risk profile and disease pattern in the general and renal populations. In renal transplantation, specifically, there have been few high-quality trials that have addressed interventions to reduce the burden of CVD. Observational studies support the stopping of smoking (13, 14). Antiplatelet agent use has been associated with improved allograft survival in previous studies and with a reduction in adverse cardiac events in the current PORT study (8, 15). However, there have been no randomized control trials looking at blood pressure targets or specific antihypertensive agents after transplantation. The role of statin therapy is equally unclear. Although frequently misrepresented as a positive result, the one large randomized controlled trial of statin therapy in renal transplant recipients found no benefit in the prespecified cardiac endpoints (16). Despite the aforementioned paucity of evidence, the UK Renal Association has recently produced guidelines on the Postoperative Care of the Kidney Transplant Recipient (available in draft form), which suggest that individuals should stop smoking, that clinic blood pressure should be less than 130/80 mm Hg, and that those at increased primary or secondary CV risk should receive statin therapy (17). In addition, the guideline suggests that diabetics and individuals with prior CV events should be managed according to standard diabetic practice. In the United States, National Kidney Foundation Kidney Disease Outcomes Quality Initiative have also issued a commentary on the care of the kidney transplant patient but has not issued guidelines, presumably due to a lack of high-quality evidence in this patient group (18). There is no substitution for appropriate trial evidence in the appropriate setting. At present, we do not have sufficient evidence to recommend specific therapies for CV risk reduction in renal transplant patients. Perhaps naturally, there is a regression to the recommendations made for the general population. This may or may not be appropriate: but where trial evidence does not support the use of drugs used in the nontransplant population, there is no logical rationale for their use. In practice, the relatively low use of ACEI/ARB, antiplatelet, and lipid-lowering agents found in the PORT study is notable, even in patients with diabetes. It is possible that this low rate of medication uptake reflects a tension, with the careful physician reluctant to extrapolate data from studies in different populations, balancing this judgment against the pressures from the pharmacologic industry, peers, and nonevidence-based guidelines. Pending the results of the study of heart and renal protection, expected shortly, cliniThe authors declare no conflict of interest. SW Thames Renal and Transplantation Unit, St Helier Hospital, Carshalton, Surrey, United Kingdom. Address correspondence to: Peter A. Andrews, F.R.C.P., SW Thames Renal and Transplantation Unit, St Helier Hospital, Carshalton, Surrey SM5 1AA, United Kingdom. E-mail: peter.andrews@esth.nhs.uk Received 19 November 2010. Accepted 27 November 2010. Copyright

Expression and tissue localization of donor-specific complement C3 synthesized in human renal allografts

Registry reports and most single-center studies have historically shown a significant positive association between the number of human leukocyte antigen (HLA) mismatches and increased graft loss (1). Thus, most organ allocation systems have incorporated HLA matching as an important, and often the predominant, determinant of kidney allocation. In recent years, an argument has emerged that HLA matching has become less important with modern immunosuppressive protocols, especially after the introduction of anti-interleukin (IL)-2 receptor antibodies for induction immunosuppression. In support, large registry studies have highlighted that there have been reductions in the incidence of acute rejection and improvements in graft survival in association with the progressive introduction of calcineurin inhibitors, mycophenolate mofetil, and antiIL2 receptor antibodies. For example, Su and coworkers analyzed the United Network for Organ Sharing data, and reported a reduction in the influence of HLA matching on graft survival for more recent kidney transplants (2). They suggested that, based on this, organ allocation algorithms might need to be revised. In contrast, a recent analysis of the Collaborative Transplant Study (CTS) database highlighted that HLA mismatching retained the same relative risk of graft loss in very recent cohorts of recipients (2000 – 2004) compared with earlier cohorts (1985–1994) (3). The authors of this report argued that HLA matching remained important even with modern immunosuppression, which was likely to include anti-IL2 receptor antibodies. Registry studies such as these contribute to hypothesis generation and to debate, but by their nature lack the precision, control, and uniformity of single-center experiences or randomized controlled trials. For instance, immunosuppressive policies may differ across the different participating centers, as will the stringency of HLA typing, whereas the CTS database incorporates data from 363 centers in three different continents, many utilizing different models for organ allocation. It is not surprising that seemingly contradictory conclusions may emerge. Given the above, the study by Wissing et al. in this issue of Transplantation is a welcome addition to the literature (4). The authors report a retrospective single-center experience of 208 consecutive patients who received a kidney transplant and induction immunosuppression with an anti-IL2 receptor antibody, calcineurin inhibitor, mycophenolate mofetil, and steroids. Multivariable logistic regression modeling was performed to assess risk factors for acute rejection within the first year and subsequent graft survival. Protocol biopsies were not undertaken. They identified that a progressively higher number of HLA mismatches remained an independent predictor of acute rejection, with each unit increase in HLA-A, -B, and -DR mismatches conferring an odds ratio for acute rejection of 1.65 (P 0.007). In multivariate analysis, the only other factor that remained an independent risk factor for acute rejection was a prolonged period ( 4 years) of dialysis prior to transplantation. In concordance with the published literature (5), the authors found that acute rejection within the first year remained associated with a significant reduction in overall and death-censored graft survival at 5 years posttransplantation. They suggest a causal link between episodes of rejection in the first year and subsequent graft loss. In support of this assertion, they observed that 11 of the 27 patients who experienced acute rejection suffered either permanent reduction in graft function or early graft loss. Clearly, as a single-center report, the number of patients in this paper is relatively small. Hence, the power of this study is limited and other confounding influences cannot be excluded. However, this is the first study that has specifically investigated the role of HLA matching in patients receiving quadruple induction immunosuppression including an antiIL2 receptor antibody. In an era when acute rejection rates of less than 15% within the first year are routinely reported, we should not be complacent about immunological factors and their significant contribution towards graft loss.