Physicians at Stanford Medicine have developed a way to provide pediatric kidney transplants without immune-suppressing drugs. Their key innovation is a safe method to transplant the donor’s immune system to the patient before surgeons implant the kidney.
The medical team has named the two-transplant combination a “dual immune/solid organ transplant,” or DISOT. A scientific paper describing the first three DISOT cases, all performed at Lucile Packard Children’s Hospital Stanford, published online June 15 in the New England Journal of Medicine. The journal also ran an editorial about the research.
The Stanford innovation removes the possibility that the recipient will experience immune rejection of their transplanted organ. (Organ rejection is the most common reason for a second organ transplant.) The new procedure also rids recipients of the substantial side effects of a lifetime of immune-suppressing medications, including increased risks for cancer, diabetes, infections and high blood pressure.
“Safely freeing patients from lifelong immunosuppression after a kidney transplant is possible,” said the report’s lead author, Alice Bertaina, MD, Ph.D., associate professor of pediatrics. The senior author of the report is David Lewis, MD, professor of pediatrics at Stanford.
The first three DISOT patients were children with a rare immune disease, but the team is expanding the types of patients who could benefit. The protocol received FDA approval on May 27, 2022, for treating patients with a variety of conditions that affect the kidneys. Bertaina anticipates that the protocol will eventually be available to many people needing kidney transplants, starting with children and young adults, and later expanding to older adults. The researchers also plan to investigate DISOT’s utility for other types of solid-organ transplants.
The scientific innovation from Bertaina’s team has another important benefit: It enables safe transplantation between a donor and recipient whose immune systems are genetically half-matched, meaning children can receive stem cell and kidney donations from a parent.
The advance is especially meaningful for Jessica and Kyle Davenport of Muscle Shoals, Alabama. Their two children, both born with a rare and potentially deadly immune disease, are among the first recipients of DISOT: 8-year-old Kruz received transplants from Jessica, while his 7-year-old sister, Paizlee, received transplants from Kyle.
“They’ve healed and recovered, and are doing things we never thought would be possible,” said Jessica Davenport. After years of helping Kruz and Paizlee cope with severe immune deficiency—and high infection risk—as well as kidney dialysis, she and her husband are thrilled that their children have more normal lives.
The idea of transplanting a patient with their organ donor’s immune system has been around for decades, but it has been difficult to implement. Transplants of stem cells from bone marrow provide the patient with a genetically new immune system, as some of the bone marrow stem cells mature into immune cells in the blood. First developed for people with blood cancers, stem cell transplants carry the risk of the new immune cells attacking the recipient’s body, a complication called graft-versus-host disease. Severe GVHD can be fatal.
Researchers working with adult patients, including a team at Stanford, have performed sequential stem cell and kidney transplants from living donors. When the donor was half-matched they had partial success, but patients were either unable to completely discontinue immune-suppressing drugs after transplant, or—in other trials not conducted at Stanford—they had unacceptably high risks of severe GVHD.
The Stanford pediatric team introduced refinements that greatly improve the success of the two-transplant combination with much lower risk. Their key innovation is a change in how the donor’s stem cells are processed.
After stem cells are removed from the donor’s body, technicians perform alpha-beta T cell depletion, which removes the type of immune cells that cause GVHD. Bertaina’s team had showed that alpha-beta T cell depletion—which she developed while working in Italy prior to coming to Stanford—makes stem cell transplants safer and enables genetically half-matched transplants. The protocol is relatively gentle, making it safe for children with immune disorders who are too medically fragile for a traditional stem cell transplant. The alpha-beta T cells recover in the patient after 60 to 90 days, meaning they regain full immune function.
When physicians at Stanford Children’s Health began caring for a few children with an extremely rare immune disease called Schimke immuno-osseous dysplasia (SIOD), they realized they could meet the patients’ medical needs with a multistep approach.
“SIOD includes chronic kidney disease which ultimately requires kidney transplantation,” Bertaina said. SIOD also causes bone marrow failure, meaning patients need a stem cell transplant to provide a healthy new immune system.
“These were unique patients in which we had to do the stem cell transplant and a kidney transplant,” Bertaina said.
Each of the three children in the new scientific report received a stem cell transplant from one of their parents, incorporating alpha-beta T cell depletion. Five to 10 months later, after recovering from the stem cell transplant, each child received a kidney from the same parent who had donated the stem cells.
One patient had a mild episode of graft-versus-host disease, affecting the skin, which was resolved with medication. After the kidney transplantation, the physicians gave immune-suppressing medications to the first two patients for 30 days, then discontinued the drugs. The third patient experienced short-term side effects from immunosuppression, including high blood sugar; in that case, medication was discontinued even sooner.
All three patients no longer have the immune disorder. They have been living without the immune disease—and with new, fully functioning kidneys that their bodies have accepted—for 22 to 34 months.
“They are doing everything: They go to school, they go on vacation, they are doing sports,” Bertaina said. “They are having completely normal lives.”
This summer, Kruz and Paizlee—who recently completed first grade—are excited about swimming lessons, day camps and trips in their family’s camping trailer. None of these activities were possible before their transplants, Jessica Davenport said.
“They’re walking miracles,” Davenport said. “It’s really cool that they’re paving the way for other families to experience the same things we’ve been able to experience.”
Now, the team is expanding the protocol to more types of patients, including children who have had an initial kidney transplant that their bodies rejected—a group that includes up to half of children who have received kidney transplants. In these cases, the patients’ own immune systems become hypersensitized and are likely to attack a second transplanted kidney, so replacing their immune system before transplant is beneficial.
The new FDA approval covers several diseases causing kidney damage, including SIOD, cystinosis, systemic lupus and loss of a prior kidney transplant due to focal segmental glomerulosclerosis. In these conditions, if the immune problem is not solved before kidney transplant, the immune disease can attack a newly transplanted kidney. DISOT is an alternative that will resolve patients’ immune conditions and allow their new kidneys to stay healthy, Bertaina said.
Adults whose bodies have rejected an initial kidney transplant or have an immune disease that attacks the kidneys could receive DISOT in the future, she said.
The team also plans to investigate how to adapt their approach to other solid organ transplants, including from deceased donors.
“That’s a challenge, but it’s not impossible,” Bertaina said. “We’ll need three to five years of research to get that working well.”
Overview of Kidney Transplant Outcomes in Older Adults
Older adults (often defined as age >=65 years) make up an increasing proportion of patients listed for and receiving kidney transplants worldwide.1–7 In the United States, kidney transplantation for patients >65 years old increased over the past decade, from 2,518 in 2008 to 4,427 in 2018.8 This trend likely reflects the changing demographics of patients developing end-stage kidney disease (ESKD),1,8–11 successful outcomes of kidney transplantation in older recipients, and the development of new strategies for increasing access, such as directed use of expanded criteria donor (ECD) organs.
For appropriate candidates, kidney transplantation is the best treatment for ESKD, as it results in improved survival, lower health care costs, and better quality of life than treatment with dialysis.4,12 Although the absolute survival benefit of kidney transplant is greater in younger ESKD patients, patients of all age groups gain additional years-of-life with a kidney transplant compared with those who remain on dialysis.4,5 The survival benefit of kidney transplantation among the older adults, including those older than 75 years, has been identified in single-center and registry-based studies (Table 1).5–7,13–16
For example, in a retrospective registry study of patients >70 years old (1990–2004), Rao et al. found a 41% reduction in mortality after transplant compared to remaining on the waitlist.17 A survival advantage was also observed in older patients who received ECD kidneys and in those with significant comorbidities including diabetes.17 Recent data confirms the benefit of transplant with higher risk kidneys, as defined by higher kidney donor profile index (KDPI) for recipients older than 60 years.18
Given these benefits, international guidelines recommend against the use of advanced age as an absolute exclusion criterion for kidney transplant.19,20 However, some transplant programs currently offer kidney transplantation only to older candidates with living donors, due to concern for mortality while awaiting a deceased donor transplant offer.21,22
Summary of recent studies reporting outcomes of kidney transplantation in the older adults.
|Reference, Year||Design and participants||Follow-up (years)||Recipient age||Donor characteristics||Outcomes|
|Wolfe et al, 19994||U.S./USRDS (1991–1997)23,275 KTx recipients vs. 22,889 waitlisted ESKD patients||7 (maximum)||<70 years old||Deceased donors||Adjusted mortality risk KTx vs. Waitlist:Age 40–59 years: 0.3 (95%CI: 0.3–0.4)Age 60–74 years: 0.4 (95% CI: 0.3–0.5)|
|Johnson et al, 20005||Australia/Queensland registry (1993–1997)67 KTx recipients vs. 107 waitlisted ESKD patients||2.8 (mean)||>60 years old||Deceased donors||Adjusted mortality risk at 5 years:KTx vs. Waitlist: 0.2 (95% CI: 0.1–0.4)|
|Oniscu et al, 20046||Scotland/National data (1993–1997)128 KTx recipients vs. 197 waitlisted ESKD patients||9 (maximum)||≥60 years old||Deceased donors||Adjusted mortality risk at 5 years:KTx vs. Waitlist: 0.4 (95% CI: 0.2–0.5)|
|Rao et al, 200717||U.S./SRTR between 1990–20042,438 KTx recipients vs. 3,229 waitlisted ESKD patients||15 (maximum)||≥70 years old||Deceased donors||Adjusted mortality risk at 4 years KTx vs. Waitlist:All DDKT: 0.6 (95% CI: 0.5–0.6)ECD: 0.8 (95% CI: 0.6–0.9)|
|Savoye et al, 200713||France/National data (1996–2004)2,099 KTx recipients vs. 746 waitlisted ESKD patients||2.9 (mean)||≥60 years old||Deceased donors||Adjusted mortality risk at 5 years Waitlist vs. KTx:All DDKT: 2.5 (95% CI: 2.0–3.2)SCD: 3.8 (95% CI: 2.7–5.4)ECD: 2.3 (95% CI 1.8–2.9)|
|Lloveras et al, 201415||Spain/Catalonian registry (1990–2010)823 KTx recipients vs. 823 waitlisted ESKD patients||3.2 (median)||Overall: mean 62 yearsSubgroup ≥65 years old: 324 (39%) recipients||Deceased donors ≥65 years old||Adjusted mortality risk at 5 years Waitlist vs. KTx:All ages: 2.7 (95% CI: 2.2–3.2)Age 65–69: 2.2 (95% CI: 1.6–3.1)Age >70: 1.9 (95% CI: 1.1–3.1)|
Abbreviations: CI, confidence interval; DDKT, deceased donor kidney transplantation; ECD, expanded criteria donor; ESKD, end-stage kidney disease; KTx, kidney transplant; SRTR, Scientific Registry of Transplant Recipients; U.S., United States; USRDS, United States Renal Data System.
Despite survival benefits compared to dialysis, older patients experience lower patient and graft survival than younger recipients.5,8,23–25 The primary cause of allograft loss in older recipients is death with a functioning graft. Death with graft function is most commonly a result of cardiovascular disease, infection, or cancer.26–28 Although older recipient age is an important risk factor for allograft failure, this is largely due to this increase mortality, as death-censored survival analyses have revealed comparable allograft survival among older and younger recipients.1,2,29,30 In a series of Scottish transplant recipients, Oniscu et al. found equivalent 8-year death-censored graft survival regardless of recipient age.30 Furthermore, two prospective studies suggest that rates of death-censored graft loss are lower in older adults due to the a reduced incidence of acute rejection.31,32
While the number of kidney transplants among older adults has been increasing, no specific recommendations have been formalized for the management of older kidney transplant recipients.33,34 Prospective multicenter randomized controlled trials assessing immunosuppressive agents in older recipients are currently not available because they are usually excluded from clinical trials.33,35 Therefore, data on outcomes is generally derived from case series and retrospective registry-based analyses. This review considers management of immunosuppression for older kidney transplant recipients, with a focus on minimizing immunosuppression-related morbidity and mortality.
Immune Changes with Aging: Immunosenescence
Immunosenescence encompasses a series of aging-induced modifications in the immune system which are primarily characterized by dysfunctional immune responses and increased systemic inflammation termed as inflamm-aging.36–41 Immunosenescence affects all immune compartments, with the most striking changes seen in the phenotypes and functions of CD4+ and CD8+ T-cell components, and less frequently observed in components of the innate immune system.42–44 Thymic involution plays a crucial role in T-cell immunosenescence.45 Patients >60 years old experience reductions in circulating naïve T-cells, CD4 T-cell receptor (TCR) excision circles, markers of thymic output, and TCR diversity.46 The frequency of memory/effector T-cells increases with age.47 T-cells downregulate the expression of the CD28 molecule with age, and subsets of CD4+/CD28− and CD8+/CD28− T-cells emerge.48 The downregulation of CD28 expression due to chronic immune activation of human T-cells is one of the signatures of replicative senescence and has been associated with impaired vaccine responses in adults.49,50
Immunosenesence leads to alteration in cellular immune function. Recently, Schaenman et al. assessed the T-cell phenotype among 60 kidney transplant recipients by comparing 23 older (≥60 years) and 37 matched younger patients (<60 years) in the first year after transplantation.42 The investigators demonstrated a decrease in the frequency of naïve CD4+ and CD8+ T-cells among older transplant recipients compared with the younger patients. In addition, older recipients demonstrated an increase in the frequency of terminally differentiated and senescent CD8+ T-cells.42 Among older patients with infection after transplantation, there was a significantly increased frequency of T-cell immune senescence.42
Antibody responses are also decreased with age in both mice and humans, leading to increased frequency and severity of infectious diseases and reduced protective effects of vaccination.51 Not only does the production of high-affinity protective antibodies decrease with older age, the duration of protective immunity following immunization is also shortened.51 The decreased ability of older individuals to produce high-affinity protective antibodies against infectious agents likely results from combined defects in T cells, B cells, and other immune cells. These changes in the adaptive immune system in older patients with immunosenescence contribute to impaired ability to respond to infection, vaccination, and tumor cells.42
Immune reconstitution after lymphocyte-depleting treatments also differs with age. Lymphocyte-depleting agents, particularly rabbit anti-thymocyte globulin (rATG), carries the risk of impaired CD4+ T-cell reconstitution after induction.52,53 Previous studies showed that this risk is age-dependent and older age causes a decline in the capacity of the adult immune system to regenerate CD4+ T-cells after rATG.53,54 In a study by Longuet et al., recipient age greater than 40 years and a low CD4+ T-cell count at the time of transplantation were identified as risk factors for impaired CD4+ T-cell reconstitution.52
Older kidney transplant recipients also have a higher risk of post-transplant malignancies.55,56 In a single-center analysis of 1,500 kidney transplant recipients, Danpanich et al. found recipient age to be an independent predictor of post-transplant malignancies.57 The investigators demonstrated a five-fold increase in the risk of malignancy among recipients ≥60 years compared to recipients <45 years.57 Compared to recipients 18–34 years old, an analysis of United States Renal Data System (USRDS) and Medicare billing claims data demonstrated a three-fold increase in the risk of cancers among recipients 50–64 years and a five-fold increase among recipients ≥65 years.58 Thus, there is a concern that age-related immune dysfunction can increase the susceptibility of older adults to cancer.55 While the risk of post-transplant malignancies has been associated with the use of induction therapy with T-cell depleting agents,1,59 a recent study using USRDS and Medicare billing claims data revealed that the use of rATG was associated with increased post-transplant malignancy risk only among younger recipients,60 emphasizing an important perspective that the risk of post-transplant malignancies among older recipients could not be explained only by induction therapy with T-cell depleting agents.
Inflamm-aging also results in chronic, low-grade, systemic inflammation characterized by a shift to the production of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α, and IFN-γ, and reduction of the chemokine receptor expression and expression of several adhesion molecules.61,62 High levels of age-associated pro-inflammatory markers are detected in the majority of older individuals, even in the absence of clinically active diseases.63–65 This inflammatory status contributes to metabolic dysfunction, insulin resistance, and represents a significant risk factor for morbidity and mortality. The pro-inflammatory state has been implicated in the pathogenesis of several debilitating chronic diseases of old age including type 2 diabetes mellitus, osteoporosis, Alzheimer’s disease, rheumatoid arthritis, and coronary heart disease. In older adults, malnutrition is also common and adversely affect T-cell function contributing to a state of relative immunodeficiency.66
Immunosenescence interferes with T-cell function and differentiation, assessed by flow cytometry and T-cell receptors. The resulting alterations in T-cell phenotype modifies both rejection and tolerance.67 Future studies are required to assess the impacts of immunosenescence and inflamm-aging in older kidney transplant recipients on tolerance induction, rejection, infection, and malignancy. In addition, further work is needed to develop methods to optimally measure the levels of immune dysfunction in older transplant recipients to successfully prevent rejection without significantly increasing the risk of infection.68 The ability to assess T-cell maturation, immune senescence and inflamm-aging by peripheral blood mononuclear cell flow cytometry in older kidney transplant recipients may offer the potential for risk stratification and individualization of immunosuppressive therapy to optimally balance risks of rejection and infection.
The reduced risk of acute cellular rejection is consistent with thymic involution and the limited T-cell receptor repertoire observed with aging.69–71 Additionally, humoral immune responses in older patients are altered, with increased memory responses and a skewed B cell repertoire which is more specialized to mount humoral immune responses.72–74 Together with the reduced frequency of naïve T-cells, these changes are associated with impaired host defense against tumors and infections, as well as to defective vaccine responses.72,74–76 In contrast, the heightened subclinical inflammation associated with inflamm-aging and increased reactivity of the innate immune system potentiates cardiovascular risk among older transplant recipients.
Most studies comparing older with younger transplant recipients have focused on T-cell responses and have described reduced frequency of acute T-cell mediated rejections in older patients.70,72,77 However, in the few studies that investigated antibody responses, a gradual decrease in incidence of donor specific antibodies (DSA) has been correlated with increasing chronological age.78,79 Older kidney transplant recipients have a lower risk of developing de novo DSA than pediatric recipients, demonstrating reduced humoral immune reactivity with increasing age.80 Increasing fundamental knowledge of how aging is involved in the immune response to organ transplantation can ultimately inform age-tailored management strategies to improve health outcomes for older transplant recipients.
Age and the Pharmacology of Immunosuppressive Drugs
Aging is associated with altered drug pharmacokinetics, including absorption, distribution across body compartments, metabolism, and excretion.81–85 After intestinal absorption, some drugs are transported back to the intestines via P-glycoprotein (P-gp), a cell transmembrane protein with reduced expression and activity with aging, resulting in alterations of peak medication plasma concentrations and bioavailability.82 Furthermore, bioavailability can be influenced by decreased intestinal or hepatic first-pass metabolism with aging.86 In addition, aging is associated with an increase in relative fat content of the body and a decrease in muscle mass,82 resulting in a larger volume of distribution of lipophilic drugs such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORis).1,55,87
Reduction in protein production is observed with aging and protein binding is decreased by up to 15% to 25% in older compared to younger adults.88 Reduction in protein binding increases free drug concentrations. Furthermore, there is a decrease in albumin, which binds acidic drugs, and an increase in alpha-1-acid glycoprotein (AGP), which binds basic drugs.89,90 Tacrolimus (99%), sirolimus (91%), and mycophenolic acid (MPA) (up to 97%) are highly albumin-bound compounds.82 Protein binding is especially important in the case of MPA, in which the free fraction is the active inhibitor of inosine monophosphate dehydrogenase. Hypoalbuminemia may lead to higher pharmacologic exposure to immunosuppressive medications, especially MPA.91
Aging is also associated with reduced renal and hepatic clearance of pharmaceuticals. The reduced renal clearance of medications has been well described with aging.92–94 Drug clearance via the hepatic Cytochromes P450 (CYP450) enzyme decreases with age, resulting in higher plasma levels of CNIs, mTORis, and corticosteroids.95,96–98 Older kidney transplant recipients also frequently require polypharmacy to treat comorbid conditions, and these additional medications may incur drug–drug interactions with immunosuppressive agents (Table 2).1,99
Age and impact of immunosuppressive medications in older kidney transplant recipients.
|Immunosuppressive agents||Altered drug pharmacokinetics||Impact of aging||Requirement and suggestion|
|Calcineurin inhibitors||Decrease in metabolism from CYP3A4 isozymesReduced P-gp activity||Higher observed maximum concentration and area under the curveDecreased total body clearance||Require lower doses to obtain the same therapeutic levels|
|Mycophenolate||Hypoalbuminemia in older recipients can result in higher clearance of unbound MPA||Lower overall MPA exposure and trough concentrations||Require higher doses to achieve the same trough concentrations|
|mTOR inhibitors||No significant difference of drug clearance across age groups||Stable pharmacokinetic parameter||No significant changes in dose|
|Corticosteroids||Clearance of corticosteroids decreases with aging||Enhanced exposure||Consider minimization of exposure|
Abbreviations: MPA, mycophenolic acid; mTOR, mammalian target of rapamycin inhibitor; P-gp, P-glycoprotein.
In a recent study evaluating the optimal dosing of CNIs in kidney transplant recipients >65 years, Jacobson et al. demonstrated that the normalized CNI trough concentrations were 50% greater among older recipients independent of the choice of CNI.100 The investigators concluded that older recipients may require lower doses of CNIs to obtain the same therapeutic levels due to a decrease in metabolism from CYP3A4 isozymes and reduced P-gp activity, leading to enhanced bioavailability.81,100 David-Neto et al. assessed tacrolimus pharmacokinetics in 44 older kidney transplant recipients compared with 31 younger recipients.101
Despite comparable tacrolimus trough concentrations, the older recipients had vastly different pharmacokinetics including higher observed maximum concentration (Cmax) and area under the curve (AUC), a longer time to achieve the maximum concentration, and a decreased total body clearance. Consequently, a lower total dose of tacrolimus is needed to achieve comparable immunosuppressive effects in older patients. In a study of cyclosporine pharmacokinetics, the required daily dose of cyclosporine to maintain comparable target cyclosporine concentrations was significantly lower among kidney transplant recipients >65 years compared to younger recipients.102 In addition, cyclosporine clearance was decreased, and intracellular concentrations of cyclosporine in T-lymphocytes were higher in older patients.102,103
With regard to side effects, a study of older (age >=55 years) kidney transplant recipient using USRDS data (199–2011) found associations of calcineurin inhibitor-free maintenance immunosuppression regimen with decreased risk of dementia (HR, 0.83; P<0.05), suggesting possible cognitive benefit of avoiding neurotoxic immunosuppression in recipients of this age group.104
Despite receiving similar doses of MPA, Romano et al. demonstrated lower overall MPA exposure and trough concentrations when comparing 44 older (63 ± 1 years) versus 31 younger (41 ± 5 years) kidney transplant recipients.105 Given MPA is strongly bound to serum albumin, data from liver and renal transplant recipients showed that there was a significant higher MPA dose requirement in patients with low serum albumin levels (<3.5 g/dL) compared with recipients who had normal serum albumin.106,107 Hypoalbuminemia can result in higher clearance of unbound MPA. As a result, older recipients commonly require higher doses of MPA compared to younger patients to achieve the same trough concentrations.
Many studies evaluating mTORi pharmacokinetics included subgroup analyses of older patients and found no significant difference of drug clearance across age groups.82,108–111 A recent study assessed the pharmacokinetics of everolimus in 16 older kidney transplant recipients receiving everolimus with low-dose tacrolimus and corticosteroids.112 The investigators demonstrated that older patients had stable everolimus pharmacokinetic parameters without significant changes in dose or exposure during the first 6 months after kidney transplantation.
Corticosteroids are bound to albumin and corticosteroid-binding globulin (CBG). The distribution characteristics of corticosteroids are dose-dependent and nonlinear plasma protein binding. Prednisolone’s protein binding capability is decreased from 95% to 70% when higher doses are given.113 The clearance of corticosteroids decreases with aging, resulting in enhanced exposure; however, the clinical impact of this finding requires further study.114,115
Approach to Immunosuppression in the Older Adults
Older transplant recipients comprise of a heterogeneous group and their response to immunosuppression may vary widely depending on many factors including genetic predisposition. Many biological factors such as sex, race, genetics, and other co-morbidities also contribute to how older adults respond to immunosuppression regimens. Even if we define the “elderly” strictly by chronological age, younger and older individuals are likely to respond to immunosuppression differently. Biological age is likely a better predictor on how older recipients are likely to fare after transplant with certain immunosuppression regimens including immunosuppression efficacy and side effects. One of the tools that we use to determine biological age is frailty testing, such as Fried’s frailty phenotype and Karnofsky Performance Score.116 Some laboratory tests now are able to estimate the biological age and resulting immunosenescence which may assist in profiling older recipients. Unfortunately, large-scale studies that utilize frailty or laboratory tests to determine biological age as a tool to guide immunosuppression have not been performed, but are needed to assess the benefit of these tools.
Similarly, there are no large scale, prospective randomized clinical trials performed specifically in older transplant recipients. In fact, the majority of immunosuppression trials exclude older patients or include only a small proportion of older participants, limiting generalizability. For example, there have been two pivotal, randomized clinical trials that compared rATG to basiliximab which has led to U.S. Food and Drug Administration (FDA) approval for induction indication for rATG.59 In these two studies, less than ten percent of the participants were older than 65 years. Gill et al.10 reported a retrospective study of induction immunosuppression in the 14,820 older adults in the United States. They classified the population into 4 groups based on recipient and donor risk factors: 1) high-immunologic-risk recipients/high-risk donor, 2) high-immunologic-risk recipients/low-risk donor, 3) low-immunologic-risk recipients/high-risk donor, and 4) low-immunologic-risk recipients/low-risk donor. They demonstrated the use of IL2-receptor antibody (IL2rAb) was associated with an increased risk for acute rejection compared with rATG in the first 3 groups (HR 1.78, 95%CI 1.34–2.35; HR 1.45, 95%CI 1.12–1.89 and HR 1.78, 95%CI 1.42–2.23), respectively. However, there was no difference in the risk of functional graft loss between both induction immunosuppression. The same was observed in studies not specific to older adults; there was no significant difference in risk of acute rejection between IL2rAb and ATG in low-risk recipients/low-risk donors.
From current data, the outcomes of induction immunosuppression in older adults are the same as other populations: ATG decreases the risk of rejection, DGF and minimizes maintenance immunosuppression use without increasing complications. An approach for the choice of induction immunosuppression should consider both recipient and donor risk factors as shown in Table 3 & 4. A tailored dose reduction of ATG induction in low-risk non-sensitized recipients showed comparable outcomes of graft survival and rejection rate with typical dose recommendations of 1.5 mg/kg for up to 7 days.117 This provides benefit among older recipients while reducing the complications. Our data do suggest that routine use of alemtuzumab in this population is not recommended.
Recipient and donor high risk definitions
|High-immunological-risk recipients||At risk for side effects||Donor quality|
|Peak PRA>80%Historical or preexisting DSARepeat HLA mismatched transplant||Cancer riskInfection riskMetabolic risk||Lower quality higher KDPIHigh DGF risk score|
Abbreviations: DGF, delay graft function; HLA, human leukocyte antigen; KDPI, kidney donor profile index; PRA, Panel Reactive Antibodies
Immunosuppression strategies in older kidney transplant recipients, considering immunological risk, side effects and donor quality
|Immunologic risk||Side effects risk||Donor quality||Suggested immunosuppression regimen|
|High||Low||Either||rATG with Tac+MPA+steroids|
|High||High||Either||rATG with Tac+MPA+steroidsTailored maintenance regimen per side effects|
|Low||High||Low||IL2rAb or short course rATG with CNI minimization ±steroids withdrawal|
|Low||High||High||Short course of rATG or IL2rAb with both CNI minimization and steroids withdrawal|
|Low||Low||Low||short course rATG or IL2rAb with delayed CNI or CNI minimization|
|low||low||high||IL2rAb with steroids withdrawal and CNI minimization|
Abbreviations: CNI, calcineurin inhibitor; IL2rAb, interleukin-2 receptor antibody; MPA, mycophenolic acid; rATG, rabbit antithymocyte globulin; TAC, tacrolimus
To help address knowledge gaps using observational data, we examined associations of kidney transplant immunosuppression regimens with patient and graft survival in a retrospective cohort of older (>65 years; n=14,887) and younger (18–64 years; n=51,475) adults using U.S. national transplant registry data (2005–2016).118 We found that older transplant recipients were less likely to receive T-cell depleting induction (rATG or alemtuzumab (ALEM)) with triple maintenance immunosuppression, rATG/ALEM + steroid avoidance, and mTORi-based treatment. However, older recipients were more likely to receive IL2-receptor antibody (IL2rAb) + triple maintenance, IL2rAb + steroid-avoidance, and cyclosporine-based regimens. Compared to older recipients treated with rATG/ALEM + triple maintenance, those who received rATG/ALEM + steroid-avoidance and IL2rAb + steroid-avoidance had lower risk of acute rejection, while CsA-based immunosuppression was associated with borderline increased risk of acute rejection (Figure). Compared with those who were treated with rATG/ALEM + triple maintenance, older recipients treated with Tac + antimetabolite avoidance, mTORi-based, and CsA-based carried significant (1.78-fold, 2.14-fold, and 1.78-fold respectively) increased risks of death-censored graft failure. More importantly, our team found that mTORi-based and cyclosporine-based regimens were associated with increased mortality (Figure). Thus, the findings of our study suggest that lower-intensity immunosuppression regimens such as steroid-sparing may be beneficial for older kidney transplant recipients. Conversely, the uses of mTORi and cyclosporine-based maintenance immunosuppression among older recipients should be discouraged or should be used cautiously due to higher risk of adverse outcomes.
To strengthen the evidence for tailored immunosuppression choice, ongoing research needs to define the balance of adequate immunosuppression, determined by the absence of rejection, with the risk of complications. In general, older recipients appear to be a lower risk of cellular rejection than younger patients and may require less intense immunosuppression. However, it is important to note that the consequences of rejection are likely to be more severe in older recipients. Further, older recipients are more likely to receive higher KPDI kidneys which are at risk for delayed graft function which increases the risk of rejection. Acute cellular rejection could lead to more severe and permanent damage in already compromised renal allografts. Older patients are also more likely to have adverse effects from maintenance immunosuppression and rejection treatments, including infection, cancer, post-transplant diabetes and CNI-related nephrotoxicity. As such, recipient comorbidity, immunologic and donor factors should all be taken into account when individualizing immunosuppression regimen. The initial immunosuppression plan should assess the need for and choice of induction agent, what combination of maintenance immunosuppression regimen will be used and whether minimization of certain maintenance immunosuppression can be considered. During the course of transplant, maintenance immunosuppression regimen may need to be further adjusted when efficacy or side effects arise.
Based on these considerations, we can stratify our older recipients according to lower versus higher numbers of comorbidities; grade the donor as optimal versus less than optimal; and immunologic risk as low versus high (Table). Recipients with a higher number of comorbidities, who will be receiving a living donor allograft, have no sensitizing events and have no DSA will be good candidates for a less intense maintenance immunosuppression. In contrast, older recipients with no comorbidities who are receiving a suboptimal deceased donor transplant and have DSA are likely to require more intense immunosuppression, both in the form of induction and maintenance therapy.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244945/
More information: Alice Bertaina et al, Sequential Stem Cell–Kidney Transplantation in Schimke Immuno-osseous Dysplasia, New England Journal of Medicine (2022). DOI: 10.1056/NEJMoa2117028
Thomas R. Spitzer et al, Transplantation Tolerance through Hematopoietic Chimerism, New England Journal of Medicine (2022). DOI: 10.1056/NEJMe2204651