With the increasing number of kidney transplant recipients (KTRs), it is inevitable that, despite improvements in graft survival, failing grafts will become progressively more common. Although some patients will be retransplanted, increasing age and comorbidity means that most KTRs whose transplants fail will never return to the transplant list. It is estimated that patients with failed transplants currently constitute approximately 4% of the incident dialysis population (1).
Alongside this increase in the absolute number of failing grafts, there is evidence that KTRs with poor graft function receive suboptimal care when compared to patients with native renal disease (2). Possibly unrelated, but a subject of concern, is the observation that poor allograft function is associated with an increased risk of death that increases as the need for dialysis approaches (3). This risk mainly results from higher rates of cardiovascular and infective death. Returning to dialysis after graft failure is an especially risky time, with mortality rates significantly greater than those of patients with poorly functioning allografts (4).
As a result of these findings, a number of centers in the United Kingdom have set up specialist transplant advanced kidney care (low clearance) services. Other units currently manage failing transplants in low clearance clinics, or in standard transplant clinics with additional input from low clearance teams as required. Whatever the set up, the increasing numbers and significant excess morbidity associated with graft failure means that guidelines for the management of the failing kidney graft are overdue.
This article summarizes the first national guidelines on this subject published by the British Transplantation Society (BTS). The guideline aims to provide a comprehensive summary of all aspects of the management of the failing kidney transplant, including outcome data. Guidelines for the management of patients with failing grafts are inevitably similar in many respects to those for general KTRs which have been previously published (5, 6). The document should be read in conjunction with these existing guidelines, but focuses on areas with special relevance to KTRs with poor renal function.
The method used for producing these guidelines is detailed in the guideline and the BTS Guideline Development Policy is available at http://www.bts.org.uk/. In brief, a systematic review of the relevant literature and synthesis of the available evidence was undertaken by selected relevant clinical experts. This was followed by peer group appraisal and expert review. Draft proposals were amended by an editorial committee and the appropriate levels of evidence added to recommendations. Wider consultation with the transplant community was undertaken by a presentation to the British Renal Society in May 2013, and through subsequent e-mail commentary. The penultimate draft of the document was placed on the BTS website in April 2014 for an additional period of open consultation, to which patient and transplant groups were actively encouraged to contribute.
The guideline has used the GRADE system to rate the strength of evidence and the strength of recommendations (Table 1) (2). This approach is consistent with that adopted by the Kidney Disease: Improving Global Outcomes foundation, and also with guidelines from the European Best Practice Committee (3, 4). It is recognized that the evidence base in this area of clinical practice is weak, and the grading of the recommendations reflects this. The guidelines are designed to indicate areas of agreement where they exist and to suggest good practice where they do not. As such, it is hoped that they will stimulate debate audit, research, and changes in practice, as well as a providing a reference point to current clinical practice.
The guideline represents the current U.K. perspective and the most up-to-date synthesis of the evidence in this field. Initial commissioning to the publication of the final document was achieved within 15 months. The guideline comprises seven chapters and 70 pages, and is freely available at http://www.bts.org.uk/MBR/Clinical/Guidelines/Current/Member/Clinical/Current_Guidelines.aspx. Given the lack of a consistent evidence base and the range of practice encountered, the guideline does not attempt to be proscriptive or to define a standard of care. However, to be of value, it must indicate areas where the evidence or consensus of opinion is strong. Therefore, each section of the guideline is prefaced by one or several “statements of recommendation,” which are explained and referenced in the subsequent text.
This article summarizes the statements of recommendation in the BTS guideline and in so doing represents a short reference summary of the full guideline. For further details and references, the reader is directed to the main guideline document.
STATEMENTS OF RECOMMENDATION
Principles of Management of the Failing Graft
We suggest that:
- Patients with failing grafts have ready access to the advanced kidney care (low clearance) multidisciplinary team. (2C)
- Joint transplant or advanced kidney care be initiated at least 6 to 12 months before the anticipated need for dialysis or retransplantation, or when graft estimated glomerular filtration rate (eGFR) falls below 20 mL per min. (2C)
- Where appropriate, retransplantation be undertaken when the eGFR of the recipient with a failing kidney transplant (RFKT) has fallen to 10 to 15 mL per min. (2C)
- Given the increased morbidity seen in the RFKT, special care be paid to the attainment of cardiovascular and other targets. (2C)
- Immunosuppression be reduced in the late stages of graft dysfunction, with reduction of target tacrolimus or ciclosporin blood concentrations or complete withdrawal of these agents. (2C)
- Given the possibility of immunological damage following reduction of immunosuppression, transplant biopsy be considered before deciding on the preferred course of action. (2D)
Management of Immunosuppression
We recommend that:
- Consideration be given to the relative risk of maintaining recipient immunosuppression after return to dialysis and relisting for a repeat kidney transplant, the clinical benefit of immunosuppressive drug tapering or withdrawal, and the risk of de novo allosensitization that may preclude options for future kidney transplantation. This is particularly relevant for pediatric recipients and young adults who are likely to require retransplantation within their lifetime. (1D)
- All immunosuppression apart from steroids be stopped immediately after transplant nephrectomy, with subsequent gradual withdrawal of steroids. (1D)
- In the event of severe acute rejection after withdrawal of immunosuppression, we recommend that steroid therapy be restarted, followed by transplant nephrectomy when acute inflammation has settled. (1D)
- For patients relisted for transplantation, that the clinical team notify the histocompatibility laboratory of significant changes in immunosuppression and that additional serum samples be obtained for human leukocyte antigen–specific antibody screening 4 weeks after any such changes. (1C)
We suggest that:
- Immunosuppressive therapy be continued to avoid immunologic sensitization if a living kidney donor is available and there is the prospect of retransplantation preemptively or within 1 year of starting dialysis. (2C)
- Immunosuppressive treatment be withdrawn after graft failure when there are immunosuppression-related complications such as skin cancer and an anticipated delay in retransplantation. (2C)
Cardiovascular and Other Risk Factor Management
We recommend that:
- Smoking be actively discouraged in RFKTs. (1B)
- RFKTs be vaccinated with inactivated viruses as per the normal population, except for hepatitis B virus. (1D)
- RFKTs receive annual influenza vaccination unless contraindicated. (1C)
- RFKTs are thoroughly assessed for the cause of their graft failure and counselled appropriately regarding future transplantation. (1D)
We suggest that:
- Blood pressure be recorded at each clinic visit and maintained lower than 130/80 mm Hg (125/75 mm Hg if urine PCR >50 or ACR >35 mg/mmol). (2C)
- There is no evidence to support the use of any particular antihypertensive agent. The focus is to achieve absolute blood pressure targets rather than the use of individual agents. (2D)
- Inhibitors of the renin-angiotensin system may be more effective in reducing proteinuria but may worsen anaemia. (2C)
- Resistant hypertension is often caused by salt and water retention and should be addressed by dietary measures and the use of diuretics. (2D)
- Treatment of dyslipidemia in RFKTs is the same as treatment in KTRs. Pravastatin and fluvastatin are preferred statins. Fibrates are contraindicated. (2C)
- Nicotinic acid compounds and ezetimibe may be safely used in RFKTs. (2B)
- Low level consumption of alcohol is safe in RFKTs. (2D)
- Control of diabetes can be erratic as renal function deteriorates and is improved by monitoring in specialist clinics. (2C)
- RFKTs be counselled regarding diet, weight loss and exercise. (2D)
- Anemia is common and can be treated according to existing guidelines. (2C)
- RFKTs have their skin examined at 1 to 3 yearly intervals by a trained healthcare professional. (2C)
- Sirolimus may be considered in RFKTs with previous squamous cell carcinoma. (2B)
- Acitretin can be safely used in RFKTs. (2B)
- There is no evidence to support aggressive immunosuppression in RFKTs with late recurrent disease. (2D)
- RFKT have HBsAb levels rechecked annually and be revaccinated if antibody titres fall below 10 U/mL (2D); do not receive live attenuated vaccines (2C); and receive pneumococcal vaccine and one booster after 5 years. (2D)
Surgical Issues in the Management of the Failing Renal transplant
- Widely accepted indications for graft nephrectomy include:
- ○ localizing symptoms (pain, infection, bleeding) that are resistant to medical therapy in a failed graft;
- ○ to create space for retransplantation;
- ○ to enable complete withdrawal of immunosuppression;
- ○ risk of graft rupture;
- ○ graft malignancy;
- ○ refractory anaemia with raised C-reactive protein (Not graded).
We suggest that:
- In the absence of prospective data, decisions on whether to remove a failed or failing graft be made on perceived benefits and risks and on a case-by-case basis. (2B)
- The surgical technique used for graft nephrectomy is dependent on timing after transplantation and operator preference. There is no compelling evidence favoring the intracapsular or extracapsular approach in the late phase posttransplantation. (2C)
- The role of percutaneous embolization of the failing or failed renal allograft is uncertain. At present, it is reserved for patients at high operative risk where malignancy is not a consideration. (2D)
- Data on outcomes after graft nephrectomy in the pediatric group are limited. Local and regional specialist opinion should be followed. (2D)
Patient Education and Options for Renal Replacement Therapy
We recommend that:
- Although there are some important transplant-specific issues, the decision-making process and management of end-stage kidney disease are largely the same as for patients with chronic kidney disease and are covered by the Renal Association Guideline ‘Planning, Initiating and Withdrawal of Renal Replacement Therapy’. (1C)
- Preemptive retransplantation in suitable candidates is the best option for ongoing renal replacement therapy, and should ideally occur when eGFR is 10 to 15 mL per min. (1D)
- If the patient is returning to a local center for dialysis or conservative care, the transfer of care be completed in time (at least 6 months before graft failure) to ensure that patients are adequately prepared. (1D)
- Appropriately skilled psychological support be made available to patients with failing transplants, with ongoing support on return to dialysis or conservative management. (Not graded)
- Patients with squamous cell carcinoma have all current lesions resected before retransplantation and be clear of metastatic disease. However, there is no requirement to wait for a disease-free interval before retransplantation. (1C)
- Patients with graft loss because of BK nephropathy be considered for retransplantation, but preferably avoiding highly potent immunosuppressive regimens. (1C)
- Potential nonconcordance is not an absolute contraindication to retransplantation. However, there will clearly be cases where the clinical team assesses the risk of nonconcordance to be unacceptably high. (1D)
Outcomes Following Return to Dialysis or Retransplantation
We recommend that:
- After graft failure, repeat transplantation offers the best survival and quality of life. This is particularly true for preemptive repeat transplantation. (1A)
- Patients suitable for retransplantation be evaluated for repeat transplantation when graft survival is anticipated to be less than 1 year. (1B)
- The optimum kidney for retransplantation comes from a well-matched living donor. (1A)
The authors wish to thank those who contributed to or commented on this Guideline, and the Council of the BTS for permission to produce this summary. Authors of this guideline were as follows (asterisk denotes member of the editorial committee): P Andrews* (Surrey), R Baker (Leeds), L Burnapp* (NHSBT), C Callaghan (London), C Eggeling (Surrey), S Fuggle (Oxford), D Manas* (Newcastle), I MacPhee (London), C Taylor (Cambridge), C Watson (Cambridge).
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