Guidelines for kidney transplantation in patients with HIV disease*

III=meta-analysis or randomised controlled trial (RCT) III=other good-quality trial III=observational studies/case reports IV=expert opinion Any patient with end-stage renal disease with a life expectancy of at least 5 years is considered appropriate for transplantation (III). With the advent of HAART, there has been a considerable improvement in the prognosis of patients with HIV disease [1,2]. End-stage renal disease (ESRD) is common in the context of HIV infection [3] and is multifactorial. Diseases unrelated to HIV infection directly, including immune complex and HCV-associated glomerulonephritis, diabetes mellitus, polycystic kidneys and obstructive nephropathy, may be encountered. However, HIV-associated nephropathy (HIVAN) is the commonest cause of ESRD in HIV-infected patients [4,5] and is the third commonest cause of ESRD in black patients in the USA [5]. As a consequence of widespread and increasing use of HAART in the developed world, the incidence of HIVAN may be decreasing, but the number of patients on dialysis programmes both in the USA and across Europe [3] is on the increase. In the pre-HAART era, haemodialysis was associated with reduced survival [6]. In the era of HAART, although overall survival and morbidity for HIV-positive patients on dialysis have improved, they are much worse than for patients not on dialysis programmes [7]. This, coupled with the complexities of antiretroviral therapy dosing in patients with reduced renal clearance and dialysis, has prompted consideration of renal transplantation for this group of patients. Until recently, HIV infection was considered an absolute contraindication to renal transplantation across the majority of transplant centres in the USA [8]. The European Best Practice Guidelines document also considered HIV infection as an absolute contraindication to renal transplantation [9]. The earlier concerns about additional immunosuppression and its effect on HIV replication and risk of further opportunistic infections have been allayed with increasing experience from a number of centres offering renal and liver transplants to stable HIV-positive patients [10]. Results from a number of published studies suggest graft and patient survival comparable to those for non-HIV-infected recipients of both cadaveric and live-related donor kidney transplants [11–17]. Recent guidelines from UK Transplant do not consider HIV infection an absolute contraindication [18]. There are still a number of issues that need addressing, including the long-term survival of grafts and recipients, the long-term impact of immunosuppression on HIV reservoirs and CD4 cells, and the pharmacokinetic interactions between antiretroviral and immunosuppressant therapies. Many of these questions will be answered with increasing experience and well-designed studies [10,19]. These guidelines have been developed to reflect previous experience of renal transplantation in HIV-positive patients and to maximize patient and graft survival. We acknowledge the influence of Professor PG Stock, Dr ME Roland and the National Institutes of Health (NIH) solid-organ transplant study in developing these guidelines [13,14,19]. As we gain in experience, it is likely that these guidelines will be updated. In order to make the learning curve as steep as possible it is essential that a national network and registry are set up to develop clinically useful protocols in the shortest space of time. The indications for renal transplantations in HIV-positive patients are broadly the same as in non-HIV-infected patients, that is, any patient with end-stage renal disease is eligible for transplantation [9,18], if medically sufficiently fit. A life expectancy of at least 5 years is considered appropriate before embarking on transplantation. The following subsections clarify what is meant by medically fit. There are specific conditions that the patient must meet, in terms of their HIV disease. These are based on previous experiences with renal transplantation in HIV-positive patients in the pre-HAART [11] and HAART [14,16,17] eras and include the following. It has become increasingly evident that there is an increased mortality associated with accelerated progression to end-stage liver disease in post-renal transplantation in patients with HCV [20] and HBV [21] coinfection. Patients with replicating HBV (>400 IU/L HBV DNA in blood) should be treated with nucleoside/nucleotide reverse transcriptase inhibitors (lamivudine/emtricitabine and tenofovir), which must be part of, or additional to, the HAART regimen to render them aviraemic (HBV DNA<400 IU/L) prior to transplantation and with continued suppressive therapy post-transplantation. Doses need to be adjusted for renal function. In the context of HCV, evidence of replicating HCV (HCV RNA positive by RT-PCR in blood) should prompt a liver biopsy, irrespective of liver enzymes. HCV-associated hepatic fibrosis or inflammation of any stage is considered a contraindication for renal transplantation. HCV treatment with pegylated interferons and ribavirin should be considered in such patients. Patients who have achieved a sustained virological response (negative HCV RNA by RT-PCR 24 weeks after the end of treatment) would be eligible for transplantation. Many of the general criteria applicable to non-HIV renal transplant waiting lists also apply. Infectious complications following solid-organ transplantation are common [22] and often life- or graft-threatening. Reactivation following immune suppression may occur with previously indolent infections, and therefore many of the infections listed below are considered contraindications to listing patients on solid-organ transplant lists [19]. As cardiovascular disease is the main cause of mortality after transplantation, it is mandatory to detect and treat asymptomatic coronary artery disease, congestive cardiac failure resulting from valvular disease or cardiomyopathy, and constrictive pericarditis [23]. Patients with advanced cardiopulmonary disease should be excluded. Solid-organ transplant recipients are at high risk of occurrence of cancers including human papilloma virus-associated cervical and anal carcinomas [24]. For treated solid-organ cancers, a variable period of recurrence-free survival is required before listing. Recommendations and advice may be obtained from the IPTTR (http://www.ipittr.uc.edu/Publications/public.cfm). The following should be considered absolute contraindications. Although prophylaxis is available for many of the common infections resulting from immune suppression, there are certain infections such as HHV8 and JC virus for which this is not an option. Early evidence from a pilot transplant programme suggests progression of aggressive KS only in patients with pre-existing extracutaneous disease [25]. Patients with low CD4 counts, persistently detectable HIV viraemia and patients with continued non-adherence to antiretroviral therapy and multiresistant HIV infection are unlikely to benefit from transplantation. Live donation (whether related or unrelated) is preferable to cadaver donation. However, live donors must always be informed that this is an ‘experimental’ or ‘new’ procedure and that the prognosis for graft and patient survival may be significantly worse than average. Although individual units and ethics committees may differ in their views, many would currently consider that the donor be fully informed that the recipient is HIV-infected. If this is the case at your centre, the consent form needs to be adapted accordingly. Thus, if felt appropriate and according to local guidelines, then it is the responsibility of the recipient rather than the medical team fully to inform the donor of their HIV status. UK guidelines [26] will be adhered to in the assessment of all living donors. HIV-positive patients awaiting transplantation may be blood group B or of black descent, and as such well-matched kidneys may not become available. Nevertheless, patients should be listed for a DR identical graft. Until experience has increased with transplantation in HIV-positive recipients, extended criteria donors should not be used. Because of the increased risk of infectious complications post-transplant we would recommend the following minimal vaccinations (if previously unvaccinated) and assessments for pre-transplant immunity. Note that vaccine response may be reduced and therefore in some cases extra doses or double doses may be required. Pre-transplant assessments should include the following. Early experience from the USA suggests higher than expected episodes of acute rejection in HIV-positive renal transplant recipients [14]. Moreover, there are clinically important interactions between the CNIs and PIs and the NNRTI efavirenz [27]. MMF may increase intracellular levels of abacavir, didanosine and tenofovir and could result in enhanced toxicity [27]. In the presence of PIs a major dose reduction of CNIs may be required [28]. Episodes of acute graft rejection should be treated as per local guidelines. If acute rejection occurs, bolus therapy with high-dose methylprednisolone needs to be used. Current advice suggests that the treatment of two or more acute rejections is associated with a greatly increased complication rate. Under these circumstances consideration needs to be given to abandoning the graft. In view of the complexities of transplantation in HIV infection, all episodes of graft dysfunction should be assessed with a renal transplant biopsy if a diagnosis is not established following the usual work-up to exclude extrarenal causes of graft dysfuntion. In general, graft monitoring will follow local protocols. Kidney transplantation in HIV-positive patients is still experimental, although experience is growing. There is the risk that immunosuppression to prevent rejection of the transplant will encourage HIV growth and may increase the risk of tumours and infections. The drugs required to control HIV and to prevent transplant rejection have complex and sometimes unpredictable interactions. In order for transplantation to be successful, it will be necessary to administer a complex drug regimen and to monitor all aspects of treatment and progress carefully. Extra blood tests, X-rays and scans will be required. Once you are discharged from hospital, out-patient visits will be required 2–3 times a week for the first 3 months. If transplant rejection is not easily controlled or if serious infections occur, the doctors looking after you may recommend removal of the transplanted kidney and return to dialysis. In view of the complex nature of the treatment and uncertainties about drug interactions, a transplant biopsy will be required on several occasions. At a minimum a biopsy will be performed at 1, 6 and 12 months. It may be necessary at other times if kidney function deteriorates. From the current literature it would appear that the success rate is about 80% at 1 year but the mortality rate may be as high as 5%. This has to be balanced by the risks and complications of long-term dialysis. Optional according to local guidelines – (In the event of a living donor, I agree to the donor being informed that I am HIV positive.) I have read the above and agree to kidney transplantation.