I. Long-Term Survival after Kidney Transplantation

TYPE OF ARTICLE:
Review Article
LEVEL OF EVIDENCE:
Level V: Evidence from systematic reviews of descriptive and qualitative studies (meta-synthesis).

‘’The data reported here for all kidney transplants from living 
and deceased donors, as well as the survival analyses, have been supplied by the Hennepin Healthcare Research Institute as contractor for the Scientific Registry of Transplant Recipients (SRTR)’. 

SUMMARY:
This article emphasized the importance and crucialness of long term graft survival for Researchers, Clinicians and Patients as It reflects the overall survival of kidney transplantation over long term dialysis treatment.This review summarizes the evolution of survival rates, demographic characteristics, and risk variables since the mid-1990s. 

Graft and patient survival have improved over time for kidneys from deceased donors,This improvement has occurred despite increases in the recipients’ age, body-mass index (BMI), frequency of diabetes, and length of time undergoing dialysis, as well as a higher proportion of recipients with a previous kidney transplant. The improvement has also occurred despite increases in the age of donors, in the percentage of donations after circulatory death, and in the degree of HLA presensitization, expressed as calculated panel-reactive antibody levels.In addition, a survival advantage of transplantation has been noted even when kidney transplants have higher scores on the Kidney Donor Profile Index, a measure of organ quality and has been observed among older and frailer recipients as well as those with diabetes and obesity. 

Long-term survival rates reported in the United States are lower than those reported by non-U.S(Australia,New Zealand,Europe & Canada. registries. A tri-continental analysis of 379,257 recipients of first kidney transplants revealed a higher graft failure rate among recipients in the United States than among those in the United Kingdom, Australia, and New Zealand.The decline in survival rate among US recipients starting 3 years post transplantation has been attributed to and coincides with the discontinuations of insurance coverage for long term immunosuppressive medications ,a point that contributed largely for the release of the long awaited Immunosuppressive Drug Coverage for Kidney Transplant Patients Act (Immuno Bill, H.R. 5534), which stipulates lifelong coverage for immunosuppressive drugs for kidney transplant recipients, was approved by the U.S. Congress and became law in December 2020. 

The observed improvement in long-term out- 
comes has been ascribed to a decline in rates of clinical acute rejection, better pretransplantation cross-matching techniques, prudent use of paired- exchange transplants for candidates with incompatible living donors, surveillance for viral infections, and effective antiviral prophylaxis. Another contributing factor is improved medical manage- ment of acute rejection, viral infections, hypertension, lipidemia, cardiovascular disease, and post-transplantation cancer.

The leading causes of transplant failure, excluding death, are alloimmune injury and recurrent glomerulonephritis. During the first year after transplantation, most graft losses were due to technical issues and vascular complications (41% of graft losses), followed by acute rejection (17%) and glomerulonephritis (3%).Beyond 1 year, most graft losses were due to chronic rejection (63%) and glomerulonephritis (6%). 

The primary causes of death with a functioning graft during the first year after transplantation were cardiovascular disease (31% of deaths), infection (31%), and cancer (7%). After the first year, the primary causes of death were cancer (29%), cardiovascular disease (23%), and infection (12%). 
IMMUNOSUPPRESSION PROTOCOL:

• A combination of immunosuppressive medications targeting T cells is required to prevent kidney rejection and graft loss. 
• ATG & anti-CD25 monoclonal antibody basiliximab are the most commonly used induction agents in the United States. 
• Most patients receive a calcineurin inhibitor (cyclosporine or tacrolimus), typically in combination with an antimetabolite (azathioprine, mycophenolate mofetil, or mycophenolic acid) and a glucocorticoid. 
• Mycophenolate mofetil has largely replaced azathioprine; however, azathioprine can be substituted during pregnancy, when mycophenolate mofetil is contraindicated, or if gastrointestinal intolerance of mycophenolate mofetil develops. 
• The use of the mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) and the costimulatory blocker belatacept has remained limited. 
• Calcineurin inhibitors are highly effective in preventing acute rejection but are inherently nephrotoxic, yet immunosuppressive regimens that are free of calcineurin inhibitors (i.e., mycophenolate mofetil and mTOR inhibitors) have been associated with high rates of acute rejection.
• Long-term use of mTOR inhibitors, with or without a calcineurin inhibitor, has been associated with an increased incidence of acute rejection, worsening renal function, and increased long- term mortality. 
• Use of a combination of mycophenolate mofetil and belatacept has been limited because of high rates of acute rejection,high cost, concerns about post-transplantation lymphoma, and the logistics of the required monthly belatacept infusions.
• However, in patients who do not have early acute rejection but do have side effects from calcineurin inhibitors, a switch to belatacept is an option. 
• Rapid glucocorticoid withdrawal has been associated with a slightly increased incidence of acute rejection and has not been universally adopted. 
• The combination of mycophenolate mofetil, tacrolimus, and low-dose prednisone remains the most common immunosuppressive regimen for kidney transplant recipients worldwide. 

Post-Transplantation Events That Affect Long-Term Survival :
1-Delayed Graft Function 

• Defined as a requirement for dialysis in the first week after transplantation. 
• Graft function is delayed in more than 25% of recipients of transplants from deceased donors. 
• Delayed graft function augments graft inflammation and fibrosis and may accelerate graft dysfunction and lead to premature failure. 
• Rates of delayed graft function can be reduced by the use of hypothermic pulsatile machine perfusion of kidneys from deceased donors. Use of mild hypothermia in brain-dead donors has been reported to reduce rates of delayed graft function, but has not been adopted in clinical practice. 
• Long- term graft survival of kidneys from deceased donors can be improved by reducing the severity of perfusion injury with a shorter cold ischemia time, especially for kidneys with high scores on the Kidney Donor Profile Index.

2-Acute Rejection 

• Episodes of acute rejection, typically confirmed by kidney biopsy, are common after kidney transplantation. 
• Rejection episodes may be T-cell– mediated, antibody-mediated, or both and are graded on the basis of the widely accepted Banff classification .
• Banff classification is a classification that involves an integration of histologic features of the transplanted kidney with serologic and molecular diagnostic techniques; it also provides a consensus- based reporting system that offers precise composite scores and accurate diagnosis of allograft dysfunction and rejection. 
• Histologic diagnosis of acute rejection is descriptive and is graded according to the extent of lymphocytic infiltrates, an approach that is limited by sample size and variations in interpretation. 
• Acute rejection, when discovered because of renal dysfunction, is referred to as clinical acute rejection, and subclinical rejection is diagnosed on the basis of surveillance biopsy. 
• The inicidence of clinical acute rejection and subclinical rejection during the first year after transplantation ranges from 10 to 15% and from 5 to 15%, respectively. 
• Up to 40% of transplant recipients may have subclinical inflammation (borderline changes suggestive of rejection) during the first year after transplantation, which falls below the threshold for the diagnosis of rejection (T-Cell mediated rejection, grade IA) in the Banff classification.
• Acute rejection negatively affects long- term survival.
• In accordance with the severity, persistence, and histologic type of rejection, and acute rejection that occurs more than 3 months after transplantation has a worse prognosis than acute rejection occurring earlier.
• Acute rejection in the first year after transplantation is primarily T-cell–mediated rejection, with fewer cases of antibody-mediated rejection.
• After the first year, acute rejection is often a combination of antibody-mediated and T-cell–mediated rejection.
• Confirmation of antibody-mediated rejection is provided by histologic evidence of capillaritis, defined as an accumulation of inflammatory cells in graft capillaries, the presence of complement fraction C4d in peritubular capillaries, and circulating donor- specific antibody against donor HLA antigens. 
• Antibody-mediated rejection in the absence of donor-specific antibodies reflects either an inability to detect HLA antibodies with current platforms or mediation by non-HLA antibodies.
• Acute rejection is the result of suboptimal immunosuppressive therapy, particularly in transplant recipients at high immunologic risk; non- adherence to immunosuppressive therapy; or a reduction in immunosuppressive medications because of infections or cancers. 

Noninvasive Screening for Acute Rejection 

• The search for reliable biomarkers to diagnose acute rejection noninvasively is ongoing.
• Donor- specific antibodies against donor HLA antigens may be detected concurrently with histologic diagnosis of antibody-mediated rejection or may follow T-cell–mediated rejection.
• Donor-specific antibodies appearing early after transplantation represent a preformed or “memory” response causing antibody-mediated rejection. 
• De novo donor-specific antibodies that develop late usually occur with mixed rejection. 
• Patients with donor-specific antibodies that are persistent, preformed or complement-fixing (C1q+)and class II, with T-cell–mediated rejection, have poorer outcomes. 
• The diagnosis of acute rejection has been correlated with urinary FOXP3 messenger RNA (mRNA); a urinary signature of CD3ε mRNA, interferon-inducible protein 10 mRNA, and 18S ribosomal RNA; transcriptomic signatures in blood; transitional B-cell cytokines in blood; and a urinary exosome mRNA signature.
• Transcriptional analysis of biopsy specimens at 1 year after transplantation revealed that a set of 13 genes predicted graft scarring and poor survival.
• A gene microarray from graft biopsies has been analyzed in an attempt to develop a “molecular microscope” that can aid in the diagnosis of acute rejection, risk stratification, and prediction of graft loss.
• The measurement of circulating cell-free DNA (cfDNA) and multigene expressions is approved by the Food and Drug Administration for the diagnosis of acute rejection. However, the sensitivity of cfDNA for the diagnosis is only 59%. Circulating cfDNA can be used to identify anti- body-mediated rejection but not to differentiate Banff grade 1A rejection from borderline rejection. The place of cfDNA measurement in clinical practice has yet to be established by randomized clinical trials. 
• A multicenter trial identified a circulating 57-gene biomarker profile that correlates with acute rejection, including subclinical inflammation, as determined by surveillance biopsies. The sensitivity for acute rejection was 48%, and the specificity was about 80%.
• The available biomarkers are inflammatory, injury, and genetic markers; none are specific for alloimmune injury. Moreover, these biomarkers do not differentiate among grades of T-cell– mediated rejection; they also do not differentiate between acute and chronic T-cell–mediated rejection.
• Instead of providing the basis for a specific diagnosis of acute rejection, noninvasive biomarkers may serve to determine graft quiescence (the absence of graft rejection) and permit more precise immunosuppression, with the goal of preventing infections, tumors, and acute rejection .
• At present, immunosuppressive therapy should not be modified on the basis of biomarker tests alone. 

Treatment of Acute Rejection 

• Prevention of acute rejection remains the key to achieving long-term graft survival . 
• Adequate tacrolimus exposure (trough levels of 7 to 12 ng per milliliter during the first year after transplantation and >5 ng per milliliter after the first year), with low-dose glucocorticoids and an antimetabolite, is central to the prevention of early acute rejection and the development of de novo donorspecific antibodies.
• Strategies such as performing transplantation in recipients with two HLA-DR matches, matching at the amino acid level (eplet matching) as opposed to the whole-molecule level, and improving immunosuppression for those with a high eplet mismatch have been shown to decrease the risk of de novo donor-specific antibody formation and acute rejection and to improve long-term survival.
• Patients with lower grades of T-cell–mediated rejection are treated with glucocorticoids, where- as those with higher grades receive antithymocyte globulin. 
• Costimulatory blockers such as belatacept can control the alloimmune response and prevent the formation of donor-specific anti- bodies.
• Costimulatory blockers do not reduce the incidence of donor-specific antibodies, as compared with tacrolimus. 
• Early antibody- mediated rejection is treated with glucocorticoids, plasmapheresis, and intravenous immune globulin. Other therapies (anti-CD20 antibodies,proteasome inhibitors, and anticomplement therapy are being investigated. 
• Late antibody-mediated rejection may be treated by augmenting maintenance immunosuppressive therapy, but the benefit of plasmapheresis with intravenous immune globulin, proteasome inhibitors, and anti-CD20 antibodies remains questionable.
• Therapies to block interleukin-6 (tocilizumab and clazakizumab) are under investigation. 
• The combination of a proteasome inhibitor and costimulatory blocker has the theoretical advantage of blocking donorspecific antibody formation at multiple levels and may be valuable for treating antibody-mediated rejection.
• Trials of immune-cell therapies involving donor regulatory T cells and studies of donor-derived regulatory dendritic cells for the prevention and treatment of acute rejection are under way.
• Although immune-cell therapies appear to have few side effects, prevention of acute rejection remains the best approach. 

3-Infections 

• Vaccination status must be assessed and vaccinations administered before transplantation. Only inactivated vaccines should be given after transplantation. 
• Cytomegalovirus (CMV) infection is the most common opportunistic infection after transplantation. CMV-seronegative patients are at increased risk for CMV infection if they receive a kidney from a seropositive donor.In addition, CMV infection is a risk factor for acute rejection and graft failure.Prevention, early recognition, and treatment of CMV infection are essential. Fortunately, effective antiviral treatment is available in the form of valganciclovir.Resistant CMV infections are usually characterized by UL97 (kinase) and UL54 (DNA polymerase) mutations. Patients with UL97 mutations can be treated with foscarnet, and those with UL54 mutations can be given cidofovir. Potential alternatives to valganciclovir (letermovir, maribavir, and neutralizing monoclonal antibodies) are under investigation. 
• BK virus infection is common in immunosuppressed kidney transplant recipients.BK virus infection starts as viruria, progresses to viremia, and if unchecked, leads to nephropathy and transplant failure. BK virus nephropathy is characterized histologically by a plasma-cell and lymphocytic-rich interstitial nephritis that may be difficult to distinguish from acute rejection unless viral inclusions are recognized. Such differentiation is critical, because successful treatment of BK virus infection requires early recognition and reduction of immunosuppressive therapy. Switching of immunosuppressive agents and the addition of leflunomide, cidofovir, fluoroquinolones, and intravenous immune globulin have not proved effective as treatment. In the absence of an effective antiviral agent, the key to prevention of BK virus nephropathy is aggressive screening for viremia, with early reduction of immunosuppressive therapy.
• Influenza infections are common among kidney transplant recipients. Currently, however, the coronavirus disease 2019 (Covid-19) pandemic represents a serious threat to patients who have undergone kidney transplantation. Immunosuppression, advanced age, hypertension, diabetes, obesity, and chronic kidney disease put many transplant recipients at grave risk. A Covid-19 mortality rate of 13 to 32% has been reported among transplant recipients.Strict adherence to the Centers for Disease Control and Prevention guidelines for Covid-19 prevention is mandatory for this patient population, and reduction of immunosuppressive therapy, typically by discontinuing mycophenolate mofetil, is recommended in patients who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).The Pfizer–BioNTech, Moderna, and Johnson & Johnson/Janssen vaccines have been approved for emergency use and are awaiting full approval. A preliminary report shows that administration of two doses of Covid-19 vaccine in immunosuppressed transplant recipients reduces the rate and severity of infection with SARS-CoV-2. However, the antibody response after two doses may be insufficient, especially among transplant recipients who are receiving antimetabolite treatment, and can be augmented by a third dose. Covid-19 infection may still occur after vaccination in immunosuppressed kidney transplant recipients, which underscores the importance of following preventive guidelines recommended by the Centers for Disease Control and Prevention. 

HIV Infection and Hepatitis C 

• Recipients with treated human immunodeficiency virus (HIV) infection can undergo kidney transplantation successfully, though the incidence of acute rejection may be increased.
• Organs from HIV-positive donors are typically discarded. The passage of the HIV Organ Policy Equity (HOPE) Act in 2013 has allowed organs from HIV-positive donors to be successfully allocated to HIV-positive recipients and may provide for expedited transplantation in HIV- positive patients. 
• The availability of highly effective treatments for hepatitis C allows kidneys from donors with hepatitis C infection to be allocated to both hepatitis C–positive and hepatitis C–negative recipients.

4-Post-transplantation lymphoproliferative disease (PTLD) is predominantly a B-cell disorder, is frequently extranodal, and is associated with Epstein–Barr virus infection. The development of PTLD is generally a consequence of effective immunosuppression and may reflect unrecognized overimmunosuppression. CD20+ PTLD can be effectively treated with anti-CD20 agents and cytotoxic chemotherapy when necessary, combined with minimization of immunosuppression. Adoptive T-cell therapy is being explored for the treatment of resistant CMV infection, Epstein–Barr virus–associated PTLD, and BK virus infection.

5-Sensitization 

• Patients with increased levels of antibodies to multiple HLA antigens have difficulty finding an immunologically matched, compatible kidney donor. 
• Sensitised patient may remain on the transplant waiting list for a prolonged period. 
• Patients accrue time on the deceased donor waiting list and are assigned priority points on the basis of their degree of sensitization.
• Desensitization may be an option for transplantation candidates considered to be close to receiving an offer of a kidney from a deceased donor. 
• Desensitization protocols involve the use of intravenous immune globulin, anti-CD20 antibody, and plasmapheresis, with the goal of achieving a negative cross-match. 
• Desensitized patients, however, remain at risk for the development of de novo donor-specific antibodies, antibody-mediated rejection, and graft loss. 
• One study showed that patients who underwent desensitization and received a kidney from an HLA-incompatible donor had improved graft survival, as compared with patients who remained on the waiting list.   

(Orandi BJ, Luo X, Massie AB, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med 2016;374:940-50.)

• Administration of imlifidase, an enzyme that cleaves IgG, reduces the degree of sensitization, permitting a negative cross-match, yet antibody-mediated rejection develops in roughly 40% of patients who have undergone desensitization with imlifidase. 
• Introduction of the national kidney allocation system in 2014, highly sensitized patients have had improved access to the national pool of kidneys from deceased donors. 

Paired Exchange of Transplants from Living Donors 
Living donor paired transplant exchange, pio- neered in South Korea and the Netherlands,87,88 is increasingly used for transplantation candi- dates with living donors who are incompatible on the basis of blood type or HLA matching (Fig. 1). 

• The simplest living donor paired exchange transforms two incompatible donor– recipient pairs into two compatible donor–recipient pairs. 
• An altruistic living donor can trigger a chain of living donor transplant exchanges.Some living donor exchanges are governed by rules that provide equity for all participating candidates, even those with early graft loss.
• Paired exchanges are also being performed with living donors who are biologically compatible but have relative degrees of incompatibility by virtue of age or size differences. 
• Living donor paired exchange remains superior to desensitization for patients with incompatible living donors but is not ideal for highly sensitized patients. 

APOL1, Kidney Disease, and Transplantation 

• Polymorphisms in the genes that encode apolipoprotein L1 (APOL1) are found much more often in persons of African ancestry than in other groups.
• Homozygosity for APOL1 kidney risk variants, which occur in up to a third of Blacks, confers increased risks of nondiabetic chronic kidney disease, hypertensive nephrosclerosis, and focal segmental glomerulosclerosis (a phenomenon that is probably responsible for the increased incidence of end-stage kidney disease among Blacks) and an increased risk of end- stage kidney disease among Black living donors.
• Furthermore, graft survival may be reduced for kidney transplants from deceased donors who were homozygous for APOL1.
• APOL1 homozygosity may also account for the reduced long- term graft survival among Black recipients of kidney transplants. Some transplantation programs routinely test young, Black potential do- nors for APOL1 and advise those who are homozygous not to donate a kidney

Transition of Adolescents from Pediatric to Adult Care 

• Transplant recipients between the ages of 14 and 23 years have an increased risk of graft failure and are particularly likely to have problems with adherence to immunosuppressive regimens.
• Nonadherence has a profoundly negative effect on the lives of young people, including quality of life, ability to return to work and school, sensitization, opportunities for repeat transplantation, and life expectancy. 
• Young patients may get lost in the process of transition from pediatric to adult health care delivery systems and may lose health insurance.
• Improved outcomes may be achieved with structured and personalized care, maintenance of insurance coverage, and a focus on patient education during the transition period.