Kidney Transplantation: Challenging the Future

For the vast majority of the 54 years since the first kidney transplant, T cell–mediated inflammation was believed to be the central process in allograft rejection. The therapies to prevent and treat allograft rejection consequently have been directed primarily against T cells. The improvements in these drugs have led to greatly improve rates of acute cellular rejection and 1-yr graft survival; however, acute rejection does still occur, as does long-term chronic rejection. It was the development of the immunohistochemical process for visualization of complement split product C4d in graft tissue that provides concrete evidence linking antibody binding and complement activation in renal allografts to the mechanism by which damage occurs in this setting. We now recognize that alloantibodies play a role in rejections that do not respond to T cell therapies and, indeed, require targeted therapies that address the various mechanisms by which they exert their effects. Newer, more sensitive technologies for serum antibody screening are allowing for clearer delineation of the relationship between antibodies and acute and/or chronic allograft pathologies and their attendant clinical outcomes. This chapter tries to clarify the antigenic targets of the humoral alloimmune response, the mechanism of antibody generation, the pathophysiology of antibody-mediated cell damage, the phenomenon of accommodation, the mechanisms of allorecognition, the T cell-mediated rejection and overview of the current understanding and classification of antibody-mediated syndromes. In addition two new aspects of allograft rejection are discussed: the roles of chemokines and Toll-Like Receptors pathway involvement in allograft rejections.

The clinical evaluation of the renal transplant candidate is a complex medical procedure. Its final goal is to select the patients in whom renal transplantation is likely to improve the clinical outcome. Potential candidate should be referred to the transplant center within six months from the onset of dialysis. The first step of the evaluation is to identify those conditions such as active alcohol or drug abuse, cancer, infections which may represent a major barrier to a successful transplant. If present, they should be removed before any further step in the evaluation process. Special attention should be focused on the detection of any active neoplastic disease and an adequate disease free interval, generally between 2 and 5 years, should be allowed prior to transplant. Similarly, careful evaluation and treatment of any active infectious disease should be undertaken prior to transplant. Cardiovascular diseases represent the major cause of death in patients with renal failure as well as in transplant recipients. Their detection and treatment in the evaluation process greatly improve the clinical outcome of the transplant recipients.

Renal transplantation among high-risk transplant recipients is becoming more and more common. As the incidence of end-stage renal disease is increasing the need for organ donors is also increasing, and with the shortage of organs the use of marginal donors has increased. All these factors impact patient and graft survival. As time has progressed the incidence of acute rejection has decreased significantly due to improvements in immunosuppressive medications. However, even though rates of acute rejection have decreased significantly overall patient and graft survival has not changed much over the years. In order to fully understand the stratification of “high-risk” renal transplantation many donor, recipient and allograft variables need to be considered.

In an effort to overcome the severe organ shortage, ABO-incompatible kidney transplantation has been carried out in many transplant centers worldwide over the last decade. In the 1980s, ABOincompatible kidney transplantation was electively performed in Europe and Japan and the early results were acceptable though short-term results were significantly poorer than those of ABO-compatible kidney transplantation (80% vs. 95% at one year, 79% vs. 92% at three years in ABO-incompatible vs. ABOcompatible transplantations, respectively). The original preconditioning regimens included splenectomy, plasmapheresis, and immunosuppression with ciclosporin, azathioprine and steroids.

Early in this century, many potent immunosuppressive agents, such as tacrolimus, mycophenolate mofetil, rituximab, basiliximab, thymoglobulin and daclizimab were introduced in the field of clinical kidney transplantation. With these potent immunosuppressive agents, the outcomes of ABO-incompatible kidney transplantation improved significantly. Currently, in most transplant programs, preconditioning and immunosuppressive regimens typically include a rituximab injection, plasmapheresis or immunoadsorption and immunosuppression with tacrolimus, mycophenolate mofetil and steroids. The latter is a mild regimen comparable to those for ABO-compatible kidney transplantation. Recently, one year graft survival in most ABO-incompatible programs has exceeded 90-95%. Furthermore, the incidence of rejection is less than 10% in most reports of ABO-incompatible kidney transplantation.

ABO-incompatible kidney transplantation has become a safe, excellent treatment option for renal failure patients.

The increased discrepancy between the number of patients on the waiting list and the kidney graft availability has prompted most of the transplant centers to expand their suitability criteria for deceased donor kidneys. However, these grafts have a potential lower graft functionality and must be properly allocated to ensure the best outcome. Histopathological pre-transplant evaluation has progressively assumed as the best prognostic factor for graft function in kidney transplantation from older donors. However, there is not consensus about the best strategy of scoring the bioptic samples and there are no clinical trials comparing the best allocation strategy of these kidneys. In this chapter will be reviewed the recent acquisition on pre-transplant histopathologic examination with a brief overview on the role of kidney biopsy in living kidney donors.

Due to the increased demand in transplantable organs, the gap between kidney graft and supply grows. The organ shortage continues despite the fact that surgeons have liberalized their acceptance criteria for suitable deceased donor organs, have exploited the use of ABO-incompatible and marginal ‘expanded criteria donors (ECD)’. However, kidneys from ECD donors come with their relative risk of graft failure of 1.7 compared with a reference group. Therefore, selection of kidneys from ECD donors remains extremely important to guarantee an adequate kidney function and graft survival for long-term. Some ECD donor kidneys are not accepted by many centers due to their extreme age and additional risk factors such as hypertension, diabetes mellitus of the donor. A comprehensive assessment of the ECD kidney is mandatory and long-term graft survival and kidney function need to be assured.

The increasing demand of organ donors to supply the increasing number of patients on kidney waiting list, has led most of the transplant centers to develop protocols that allow safe utilization from donors with special clinical situation, which heretofore were regarded as contraindication. Deceased donors with previous hepatitis may represent a safe resource to expand the donor pool. When allocated to serology-matched recipients, kidney transplantation from donors with hepatitis may result in excellent short term outcome. However, many concerns may arise in the long term outcome, and studies must be addressed to the evaluation of the progression of liver disease and to the rate of reactivation of liver disease in the recipients. An accurate selection of both donor and recipient is mandatory to achieve a satisfactory long term outcome.

Acute kidney injury in the critically ill patient represents a serious danger for the patients’ survival, and is probably one of the most challenging fields for ICU physicians, as renal physiology is very well known and different drugs and molecules are available to try to perform an effective nephroprotection.

The main goals to achieve before any pharmacological attempt for nephroprotection are represented by fluid balance optimization and by hemodynamic sustain, which, together with the internal renal hemodynamic and oxygen imbalance of nephrons and tubules, represent the target of any available or potential nephroprotective strategy: most of the studies support many different nephroprotective drugs, including dopamine, dopexamine, N-Acetyl-Cisteine (NAC), prostaglandins and fenoldopam.

This chapter is devoted to the analysis of all potential nephroprotective strategies, focusing on the different phases in the field of kidney transplantation.

A variety of surgical techniques are currently available for live donor nephrectomy (LDN). The surge of laparoscopic LDN (LLDN) has promoted the reduction of the invasiveness of open donor nephrectomy (ODN). Overall, LDN is a safe operation, the risk of donor death being 0.03%. Long-term complications are rare, and actually live renal donors have a lower risk of end-stage renal failure and live longer as compared with aged-matched individuals who do not donate.

Advantages of LLDN are mostly faster recovery, shorter sick leave, reduced incidence of wound-related complications, and improved cosmetic result. On the other hand, safety is the main advantage of ODN. No donor death has been reported since 1991 following ODN. LLDN increases operative costs, especially when combined with hand assistance, but decreases overall hospital costs and indirect costs.

Bleeding, mostly caused by failure of methods used to seal renal vessel, remains the main surgical complication of LDN. Transfixion ligature is currently recommended for renal arteries, while the use of any type of clips, including locking clips, is banished by the manufacturers themselves. Effective postoperative analgesia also plays an important role since it reduces the arising of hypertensive peaks. Awareness of the risk of massive hemorrhage after LDN is fundamental to reduce the risk of this dramatic complication.

Overall, based on current information no technique of LDN is definitely superior. Transplant surgeons should therefore be familiar with multiple methods of LDN in order to be able to select the one that best fits the needs of each individual donor.

This chapter presents a critical overview of the relationship which transplant medicine has had with the market as a source of organs for transplantation. It has three parts. The first two parts discuss the increasing appeal of the market option in practice and theory against the backdrop of the worsening organ crisis and the intensification of pro-transplant interests. The emerging trend suggests that the recent achievements in the struggle against international organ trafficking do not herald the abolition of the organ market but rather presage its reconfiguration in deglobalized, more or less regulated, forms. The third part rephrases the market question. It concludes that the struggle against a market in organs could make sense, let alone stand a chance, only as part of a general struggle against the conditions that have made it so appealing in the first place.

Renal transplantation is the treatment of choice for children with end-stage renal disease as it results in better survival rates and quality of life compared to dialysis. The pediatric transplant population represents a unique population whereby patients undergo rapid phases of growth and development, not only physically but also mentally and psychologically. This chapter provides an overview of the current trends and issues pertaining to pediatric renal transplantation. These issues include the discrepancy in size between the young recipient and the large adult-sized kidney, variations in the development of the immune response, specific pediatric considerations in immunosuppressive regimens, non-adherence in adolescence, and the greater propensity for infections and viral-driven lymphoproliferative disorders, growth failure and longterm cardiovascular disease. Recurrence of the primary renal disease, especially focal segmental glomerulosclerosis, is a significant concern in pediatric renal transplantation, as this often results in graft loss. Patients with abnormal urinary tracts will need evaluation and often surgical correction prior to transplant. Advances in immunosuppression regimens and surgical techniques in the last two decades have dramatically improved short and medium-term patient and graft survival outcomes in pediatric renal transplantation. Long-term graft survival, however, remains suboptimal, due to calcineurin inhibitor toxicity, cardiovascular disease, infections and non-adherence. Therefore the current challenge in pediatric renal transplantation will be to improve long-term graft survival by minimizing the side effects of immunosuppression while preventing rejections. There are trends towards steroid and/or calcineurin inhibitor-sparing immunosuppressive regimens, with the use of non-depleting or depleting monoclonal and polyclonal antibodies as induction therapy.

The growing success of renal transplantation around the world in the treatment of chronic renal failure has increased the significance of imaging in evaluating the transplanted kidney. Accurate interpretation of imaging studies plays a crucial role in the evaluation of renal grafts, the monitoring of developing pathology and the treatment of complications. Ultrasound, in particular, has proven to be an integral part of the burgeoning success of renal transplantation and subsequent monitoring. The role of imaging, especially ultrasound in detecting and evaluating complications of the parenchyma, vasculature, collecting system and ureter are discussed here with special attention to percutaneous transplant biopsy.

One-year graft survival of renal grafts increased progressively in the last two decades and can be now considered excellent, but long-term outcomes has not improved proportionally in the last years. Indeed, chronic allograft dysfunction is a growing problem among renal transplant recipients and together with death from cardiovascular disease, infection and malignancy is the leading cause of graft failure.

The goal of immunosuppressive therapy is to balance the beneficial effects of reducing acute rejection while minimizing adverse effects from over-immunosuppression such as infections, malignancy, and cardiovascular disease. Current immunosuppressive protocols use combinations of immunosuppressive drugs with different mechanisms of action to maximize efficacy and minimize the toxicity of each drug. During the past decade, there has been a increasing interest in identifying regimens that may allow the minimization of immunosuppressive drugs characterized by significant side effects, including nephrotoxicity and metabolic dysregulation. The emergence of new immunosuppressive agents and tolerance protocols appears promising as a means to deliver immunosuppression without long-term toxicity. Ultimately, the goal of “future” immunosuppression is to move from an empiric therapy to a personalized treatment.

In an effort to reduce the long-term toxicities of immunosuppressant drugs, corticosteroid and calcineurin inhibitor-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. The use of induction antibody therapy and potent residual immunosuppressants have increased the safety of steroid-free regimens, resulting in a paradigm shift towards earlier elimination of steroids after kidney transplantation. However, even in the modern era, results of randomized trials generally indicate that steroid elimination increases the risk of rejection compared to maintenance steroid therapy. Among calcineurin inhibitor-sparing strategies, withdrawal of these agents after their initial use in stable patients, or conversion to either mycophenolate mofetil or sirolimus in patients with renal dysfunction appears to yield the greatest benefit in preserving renal function. The outcomes of calcineurin inhibitor avoidance protocols have been mixed but have fallen into disfavor. The benefits of minimizing immunosuppression in kidney transplant recipients must be weighed against the risks of precipitating acute rejection or chronic allograft dysfunction. Additional research is needed to identify clinical and immune parameters that will enable selection of patients for whom the benefits outweigh the risks. In addition, the transplant community is in need of newer agents that can potently prevent rejection without the need for corticosteroids or calcineurin inhibitors.

Protocol biopsies in renal transplant patients are those that are obtained at preimplantation and at predetermined times post-transplant, even in the absence of renal dysfunction. These biopsies have been invaluable for the study of the “natural history” of allograft histopathology, and have indeed revealed unexpected acute and chronic lesions in well-functioning grafts. Many centres, including ours, are attempting to develop non-invasive biomarkers of early graft injury. However, it is our view that until such tests have been developed and validated, the protocol biopsy will remain a useful tool for the management of renal transplant patients.

This literature review summarizes the research on quality of life (QoL) in kidney transplant recipients. After clarification and discussion of conceptual issues in view of QoL, the following topics are reviewed: comparisons of QoL pre- to post-transplant, post-transplant QoL of kidney transplant recipients to that of other chronically ill patients and of healthy subjects, correlates of QoL, and interventions designed to enhance QoL in kidney transplantation. Gaps in the state-of-the-art evidence, from conceptual, content, and methodological perspectives, are highlighted, and directions for future research are discussed.

Transplanted organs can transmit infectious diseases to recipients with varying consequences depending on the pathogen, the infection status of the recipient and the effectiveness of treatment (curative and/or preventive). In this non-exhaustive review, we detailed the classical diseases transmitted by the transplanted kidney which can be easily detected in the deceased donor with the last recommendations of treatment, but also emerging infectious diseases due to the increasing mobility of populations (conventional tourism , transplant tourism, immigration .). New challenge in this field, is the earliest possible detection of infectious agents from the donor to guide the decision of organ harvesting and direct matching D/R . Pending the use of Nucleic Acid Testing in routine, it remains essential, in addition to conventional serological tests, to achieve a very specific examination, paying particular attention to record the countries visited by the donor, as well as performing systematic bacteriological and mycological analysis of preservation solution.

Improved immunosuppressive therapies for organ transplantation have reduced the incidence of allograft rejection while increasing susceptibility to opportunistic infections and virally mediated malignancies. Renal transplant recipients are susceptible to a broad range of infectious pathogens and infections often progress rapidly. Improved microbiologic diagnostic tools are used in the routine management of common infections and have allowed the definition of new clinical syndromes and of donor-derived infections. However, invasive diagnostic procedures are often required for accurate and timely diagnosis and are justified by the high morbidity and mortality of infection in this population. Early and specific microbiologic diagnosis is essential for guiding treatment and minimizing nonessential drug therapy.

After polyomavirus BK was recognized as a pathogen causing severe nephropathy in transplant recipients, infections in renal transplant patients receiving more potent immunosuppressive medication have raised increasing concern. As no effective treatment of BK-virus nephropathy is available, the prevention of this condition, which often leads to graft loss, is of outmost importance. Recently, new data of the pathogenesis of replication and immune responses to BK virus have been reported. In addition to the well-characterized direct effects caused by clinical CMV infections, also multiple indirect immunomodulatory effects of CMV have been postulated. Experimental data of the indirect effect of CMV have associated CMV with acute and chronic injury of the kidney graft, but in the recent years, also some clinical evidence has associated persistent CMV infection of the transplant with detrimental long-term effects.

The aim of this chapter is to review the pathophysiology of the effect of viruses to the kidney allograft, with special emphasis on the two probably most important viruses challenging the survival of the graft, namely polyomavirus BK and cytomegalovirus.

Kidney transplantation (KT) is an increasingly used medical procedure for treating otherwise fatal end stage renal diseases (ESRD); this success was obtained with the use of potent immunosuppressive agents able to reduce the risk of rejection of transplanted organs, but exposing patients to an increased risk of opportunistic diseases such infections or cancers, this latter representing nowadays the second major cause of morbidity and mortality after KT. KT recipients (KTR) experience a 2- to 4-fold increase of de novo post-transplant malignancies (PTM) when compared to the general population, particularly skin cancers, urological malignancies and virus-related cancers such as non- Hodgkin lymphoma (NHL) or Kaposi’s sarcoma (KS) with up to 100-fold augmented risk when compared to the general population. Given the improved graft and patient survival that have lengthened the observation period for the natural history of immunosuppressed recipients and their increasing age, we can expect that over the next decades mortality from malignancy may represents the leading cause of death in transplanted patients. As the immunosuppression per se and various potentially oncogenic viruses play a major role in cancer development after transplant, a better definition of this phenomenon can lead to the adoption of preventive measure to reduce the risk of PTM or the implementation of better screening protocols to earlier detect malignancies. This chapter examines, from an epidemiological point of view, the incidence, etiology and prognosis of malignancies after kidney transplantation with a focus on those associated with viral infections..

Increasing success in organ transplantation, longer graft and patient survival malignancies are becoming a major burden in transplantation medicine.

There is now convincing evidence to confirm a 3- to 5-fold increase in overall cancer incidence.

Duration and intensity of immunosuppression have been linked to the increased incidence of malignancies and the choice of immunosuppressive therapy could also play a role in the development of cancer.

It is mandatory to understand how and when the tumoral process began and if a screening program could be established. Considering the poor outcome of transplanted patients that develop a tumour process, immunosuppression dose reduction or withdrawal is sometimes necessary to control the progression of life-threatening malignancies maintaining, when possible, graft function.

A conversion from CNI to PSI, although is not curative, could be potentially helpful to prolong survival in some patients. Transplant recipients with evidence of cancer should be offered the best medical and surgical oncology treatment in addition to the choice of immunosuppressive therapy.

Those patients in whom the neoplastic process is advanced and life expectance is really poor probably could not have any clinical advantage reducing or stopping immunosuppressive therapy, adding at cancer disease the risk of acute rejection and graft loss.

Cardiovascular disease in renal transplant recipients is a major cause of graft loss and patient mortality. It is only in recent years that it has become understood that the mechanisms underlying coronary events in these patients differ from the general population. Patients with renal disease are more likely to suffer a fatal cardiovascular event than a non-fatal event and simply addressing conventional risk factors, which relate to atheromatous coronary artery disease, is insufficient in this population, where uraemic cardiomyopathy and graft specific factors uniquely increase risk. We discuss known epidemiological data relating to cardiovascular risk in these patients, consider traditional risk factors such as smoking, hypertension, diabetes and lipids, as well as graft-specific factors such as immunosuppressive therapies, and graft dysfunction. Management of cardiovascular risk in renal transplant recipients is necessarily multi-factorial but strong prospective evidence is lacking.

The prevalence, impact and main clinicopathological aspects of recurrent and de novo glomerulonephritis are reviewed, with the use of unpublished data of the authors. The prevalence in Hungarian recipients was investigated in 697 biopsies obtained for cause and analyzed by light microscopy and an expanded panel of immunofluorescence. Electron microscopy was performed if there were symptoms of glomerular disease or the histological alterations or immunfluorescent findings indicated. Glomerular disease was recorded in 199 biopsies (28.5%): chronic rejection-induced transplant glomerulopathy in 155 biopsies (22.2%), post-transplantation glomerulonephritis (recurrent, de novo or undetermined) in 39 (5.5%) biopsies, and systemic disease affecting the glomeruli in 8 biopsies (1.1%). Membranous nephropathy (17), IgA nephritis (9), focal-segmental glomerulosclerosis (8), mesangial proliferative glomerulonephritis, (3) IgM nephropathy (1) and type I membranoproliferative glomerulonephritis (1) were identified. Transplant glomerulopathy frequently coincided with membranous nephropathy. Unusual combinations of histological patterns and/or immunofluorescent findings were occasionally observed, such as mesangial proliferation with mesangial and peripheral immune deposits, or epimembranous and mesangial deposits, or mesangial proliferation and subperimesangial deposits of solely IgM. Post-transplantation GN, more frequent in males, unfavorably influenced graft survival. Our results and the literature data indicate that posttransplantation glomerulonephritis relatively rarely involves the white race. Male gender, non-white ethnicity, younger age and biopsy-proven glomerulonephritis in the native kidney are predictors of posttransplantation glomerulonephritis. Post-transplantation glomerulonephritis contributes significantly to late allograft loss; through elevated serum creatinine levels and proteinuria, it precipitates the cardiovascular mortality and morbidity of the recipient. Limited evidence is available on the management of post-transplantation glomerulonephritis.

Chronic allograft nephropathy (CAN) and death with graft function have been the leading causes of late kidney graft loss in the last 20 years. The term CAN substituted the old term “chronic allograft rejection” and designs a poorly understood condition characterized by a progressive decline of graft function often associated with hypertension and proteinuria and non-specific histologic changes affecting all kidney compartments. As CAN includes many specific chronic diseases caused by different etiopathogenic mechanisms, workers attending the 8^th Banff Conference on Allograft Nephropathy decided to eliminate and to replace the term CAN by “interstitial fibrosis and tubular atrophy without evidence of any specific etiology”. The implications of this change in the future could probably be of paramount importance and contribute to a better understanding and treatment of the different entities included in the term CAN. In the present chapter, the different conditions associated with a progressive decline of graft function such as interstitial fibrosis and tubular atrophy, transplant glomerulopathy, chronic T-cell mediated rejection and calcineurin inhibitor toxicity are described, with special emphasis on the clinical course, the possible etiopathogenic mechanism, the diagnostic criteria and the different therapeutical options.

The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the outcomes of pregnancies in female transplant recipients as well as pregnancies fathered by male transplant recipients. Data from the NTPR along with publications of smaller experiences have endorsed the concepts that successful pregnancies are possible in the solid-organ transplant population. The largest cohort among the organ transplant population studied by the NTPR continues to be the kidney transplant recipient group. Data collected over the last twenty years by the NTPR have addressed a myriad of issues, thus providing a variety of additional information for healthcare providers in caring for transplant recipients of childbearing age. Preconception guidelines proposed in 1976 have undergone some refinement over the years, however most remain applicable today. Outcomes of the children of transplant recipients have been encouraging with few negative effects identified, but ongoing surveillance is still important. This article will provide a review of the historical literature regarding pregnancy in the kidney transplant population, recent studies conducted by the NTPR, and a brief review of the current literature regarding pregnancy after kidney transplantation.

Induction of donor specific tolerance has been the ultimate goal in organ transplantation. Recent application of approaches to the induction of allograft tolerance in human kidney transplant recipients has been based upon preclinical studies in nonhuman primates, including 1) profound T cell depletion by powerful anti-T cell antibodies, 2) use of total lymphoid irradiation, 3) costimulatory blockade, 4) infusion of anergic cells 5) donor bone marrow (DBM) infusion without anticipation of engraftment and 6) DBM transplantation leading to Mixed Chimerism. Mixed Chimerism following DBM transplantation has to date been the most successful approach for induction of renal allograft tolerance in clinical kidney transplantation trials.

Xenotransplantation using pig organs as source for transplant has the potential to overcome the severe shortage of human donor organs. Wide utilization of genetically-engineered pigs is enabling progress to be made in pig-to-nonhuman primate experimental models. Novel, non-nephrotoxic immunosuppressive regimens have largely overcome T cell rejection and a T cell-dependent elicited antibody response. Recent advances in understanding of the biology of xenograft rejection and zoonotic infections and the generation of alpha1,3-galactosyltransferase-gene knockout pigs have moved this approach closer to the clinical application. However, inter-species coagulation dysregulation is proving a major hurdle. Progress in islet xenotransplantation has been more encouraging controlling diabetes in nonhuman primates up to 6 months, though this has usually been achieved using immunosuppressive protocols that might not be clinically applicable. Further advances are required to overcome the remaining barriers.