Frailty, while challenging to assess clinically, is associated with poor outcomes post transplant. One study found that frail patients (median age 54 years) were less likely to be listed for kidney transplantation. Assessment of frailty included unintentional weight loss, grip strength, walking speed, exhaustion, and activity level. Though some transplant centers may have an upper age threshold for transplant eligibility, 5-year patient survival was >70% in a cohort of recipients older than 60 years old. In a subgroup of recipients 70 years and older, 5-year survival was 78%. As with all transplant recipients, careful patient selection and shared decision making are paramount. Lower immunosuppression may be advisable in the older population.

There is significant center-to-center variability with respect to transplantation of patients with obesity; some centers have >20% of recipients with body mass index (BMI) >35 while others have <5%. Severe obesity (BMI 35 kg/m ² or greater) has been shown to be associated with more transplant surgery–related complication, delayed graft function (DGF), and poorer allograft survival. ^, A 2021 meta-analysis of UNOS data that compared BMI categories of transplant recipients (median follow-up 4 years) found increased DGF in patients with BMI >30 kg/m ² and no difference in allograft or patient outcomes between BMI >30 to 35 kg/m ² and BMI >35 kg/m ² . There was no difference in patient survival or hospital length of stay following transplant across BMI categories. This study supports the idea of greater flexibility in BMI inclusion criteria for potential kidney transplant recipients. Further, a study of transplant recipients with BMI >30 kg/m ² found that transplantation provides a survival benefit over remaining on the waiting list (receiving dialysis), up to a BMI of 41 kg/m ² . Bariatric surgery before transplantation can be considered for severely obese patients. Body surface area (BSA) mismatch between donors and recipients has been associated with poorer long-term allograft survival. ^, With the advent of the GLP1 receptor agonists, the management of potential recipients with an elevated BMI may change in the future.

Though HIV infection was traditionally considered an absolute contraindication to kidney transplantation due to concerns for infections and short patient survival, improvements in HIV treatments and transplantation of patients with HIV have led to favorable outcomes. ^, On the basis of inclusion criteria from a 2010 study, patients should be maintained on highly active antiretroviral therapy, have a CD4 ⁺ T cell count of at least 200 cells/mm ³ , and undetectable plasma HIV RNA levels. Kidney transplant recipients with HIV infection appear to be at higher risk of acute rejection and thus may benefit from antithymocyte globulin (ATG) induction. The HOPE Act, signed into law in 2013, called for the use of organs from HIV-positive donors for transplantation into HIV-positive candidates under approved research protocols. As of 2020, 170 such kidney transplants have been performed in the United States as a result. More recently, living donors with HIV have successfully donated to recipients with HIV.

Although the survival rate of patients with diabetes after kidney transplantation is lower than that of those without, the benefits of transplantation versus staying on dialysis remain. A subset of potential transplant candidates may be suitable for kidney-pancreas transplantation. The benefits of pancreas transplantation are 1. freedom from insulin therapy and the metabolic derangements of type 1 diabetes mellitus and 2. potential slowing or reversal of the progression of end-organ damage from this condition. Disadvantages include higher risk of surgical complications and the need for higher levels of immunosuppression. Although there is growing evidence to support kidney-pancreas transplantation in those with type 2 diabetes, the vast majority are performed in individuals with type 1 diabetes. Options include simultaneous kidney and pancreas (SPK) transplantation or pancreas-after-kidney transplantation (the latter allows living donor kidney transplantation). The half-life of SPK pancreas grafts is 14 years.

Pancreas transplant alone can be performed in those without kidney failure, though it is unclear if pancreas transplant alone or pancreas after kidney transplantation improves patient survival (worse pancreas allograft outcomes compared with SPK). The major causes of graft failure are technical (40%) and acute rejection (15%) in the early posttransplant period and chronic rejection (25%) in the late posttransplant period. Rates of pancreas transplantation have decreased somewhat over the past decade from a peak of ∼1200 procedures in 2010 to ∼1000 in 2021 as the management of type 1 diabetes has improved with closed loop systems, etc.

Complications of pancreatic transplantation include thrombosis, infection, rejection, and problems related to drainage of the exocrine secretions. Drainage of exocrine secretions into the bladder (compared with enteric drainage) affords the advantages of sterility and of serial measurement of urinary amylase concentrations that can aid in early detection of pancreatic allograft dysfunction. Important disadvantages include severe cystitis, hypovolemia, and acidosis (the last two due to large losses of bicarbonate-rich fluid).

The presence of preformed recipient antibody against either the donor ABO blood group or donor HLA may result in hyperacute rejection. Solid-phase technologies such as the Luminex single-antigen bead (SAB) anti-HLA antibody assay permit detection and quantification of a wide array of anti-HLA donor-specific antibodies (DSAs) (discussed further in Chapter 68 ). Multiple color-coded beads coated with a broad range of HLA antigens are incubated with recipient serum. Binding of recipient antibody to a bead coated with a specific HLA antigen results in a distinct fluorometric signal, which is then detected by flow cytometry. Molecular (polymerase chain reaction) HLA typing techniques have now superseded serologic identification of HLA type for both donors and recipients. Accurate molecular donor HLA typing and SAB-based recipient anti-HLA antibody screening can be combined to perform a virtual crossmatch. For high-immunologic-risk donors, virtual crossmatching has assisted in the identification of potentially compatible donors and has improved transplant rates for sensitized donors. Computerized virtual crossmatch algorithms have also been central to the success of kidney paired donor exchange. ^, In the United States, wait-listed kidney transplant candidates usually have SAB-based HLA-antibody screening performed every 3 months. HLA antigens against which a candidate has antibodies are listed as unacceptable HLA antigens.

In 2009, the calculated panel reactive antibody (cPRA) replaced the measured PRA as the main measure of immune sensitization. Sensitizing events include transfusions, pregnancy, and prior transplants. The cPRA is calculated using an algorithm that correlates donor anti-HLA antibody (as measured by SAB assay) with the population frequency of HLA antigens to generate a percent score. A score of 0% suggests no anti-HLA antibodies, while a sensitized candidate with a cPRA of 85% will be immunologically incompatible with 85% of the donor population.

DSA may be present pretransplant or develop de novo post transplant. De novo DSA development frequently follows T cell–mediated rejection (TCMR) and is also associated with patient nonadherence. Both preformed and de novo DSA are associated with an increased risk of antibody-mediated rejection (ABMR) and poor graft outcomes. ^, DSAs may also be measured using a variation on the SAB technique, the Luminex C1q assay, which detects DSA that bind and activate complement. The development of de novo C1q-binding DSA is strongly associated with poor graft outcome. DSA IgG subtyping also yields similarly helpful prognostic information, with DSAs of the IgG3 subclass being associated with the worst clinical prognosis.

Though not widespread in clinical use, HLA epitope matching is performed by separating HLA antigens into a series of epitopes—regions that are capable of binding antibody (discussed further in Chapter 68 ). HLA epitopes may be shared across different HLA molecules. The regions of the epitope that are targets for antibody binding are short, polymorphic, often nonlinear amino acid sequences on the HLA molecule that are clustered together in the three-dimensional structure of the HLA molecule and known as “eplets.” Donor-recipient compatibility is then expressed as the number of eplet mismatches. Minimizing donor-recipient epitope mismatch reduces the number of viable foreign targets to which the recipient may make antibodies and represents a more relevant way to quantify tissue mismatch.

The complement-dependent cytotoxicity (CDC) assay, which incubates donor lymphocytes with recipient serum, was developed in the 1960s. Preformed recipient antibody to donor lymphocytes (subsequently identified as anti-HLA antibody) resulted in lymphocyte death in vitro and predicted rapid (hyperacute) graft failure in vivo. The test is now performed as two separate donor T cell (express HLA class I antigen) and B cell assays (express HLA class II antigen). A positive CDC T cell crossmatch is an absolute contraindication to transplantation. An isolated positive CDC B cell crossmatch may indicate the presence of preformed antibody to class II HLA antigen, low-level antibodies against class I antigen, or non-HLA antibodies.

The flow crossmatch (FCXM) is a more sensitive assay for detection of donor anti-HLA antibody. Donor T cells or B cells are mixed with recipient serum and a fluorescent anti-IgG antibody. Any recipient antibody that binds to donor HLA will be tagged by the fluorescent IgG and subsequently detected using flow cytometry. FCXM can detect low-titer and non–complement-binding anti-HLA antibodies and may be positive when a CDC crossmatch is negative. A negative CDC crossmatch but positive T cell FCXM is associated with poor short-term transplant outcomes and is a relative contraindication to transplantation.

Basiliximab is a chimeric monoclonal antibody against the α chain of the T cell IL-2 receptor (CD25), which provides prophylaxis for 30 days post transplant. Compared with placebo, it reduces rejection rates approximately 30% to 40%. As it is not a lymphocyte-depleting agent and acts on downstream T cell activation pathways, infection risk is lower compared with the lymphocyte-depleting agents rabbit ATG and alemtuzumab. Compared with polyclonal lymphocyte-depleting therapies, injection-related side effects and risk of infection and cancer are minimal. ^, Basiliximab is administered as two 20 mg doses, on the day of transplantation and postoperative day 3 or 4.

Polyclonal antibodies against lymphocytes are prepared by inoculation of animals with human lymphoid cells. The first clinical use in the 1970s of a polyclonal lymphocyte-depleting agent was that of ATG derived from horse inoculation (hATG, Atgam). Rabbit ATG (rATG, Thymoglobulin) is derived from rabbit inoculation with human lymphoid cells, which results in production of antibodies that target more than 20 different T cell epitopes. ^, T cell depletion is thought to involve complement-dependent lysis, apoptosis, and phagocytosis in the peripheral lymphoid tissue. Antibodies against adhesion molecules that are present in ATG preparations may also play a role by modulating leukocyte function. Horse ATG is now rarely used as initial induction therapy, though it may be considered in individuals with a hypersensitivity reaction to rATG or significant pretransplantation rabbit exposure. A 2008 randomized trial that compared hATG with rATG induction therapies demonstrated rATG superiority in terms of reduction of the composite of death, graft loss, or rejection.

Several RCTs have compared ATG induction with other strategies such as IL-RA, alemtuzumab, and OKT3 (a murine monoclonal anti-CD3 antibody no longer used to due to adverse effects). Induction with rATG resulted in equivalent 1-year graft survival but a lower rate of acute rejection, as well as both infection and non–infection-related complications compared with OKT3 in patients treated with cyclosporine, azathioprine, and steroid maintenance immunosuppression. In sensitized patients, defined as current or peak panel reactive antibodies (PRA) >30% or >50%, respectively, rATG induction was associated with significantly lower rates of biopsy proven acute rejection and steroid-resistant rejection in the first year post transplant, without any difference in 1-year survival compared with daclizumab (IL-2 receptor agonist [RA] no longer used) induction. Multiple clinical studies have compared rATG with other agents.

A 1981 study that compared hATG induction with no induction in patients treated with azathioprine and steroid-based maintenance immunosuppression regimen found a significantly improved 2-year graft survival in the hATG-treated group. In another study of kidney transplant recipients with risk factors for delayed graft function (DGF) or acute rejection, rATG resulted in a lower acute rejection rate than basiliximab induction, but no difference in DGF or 1-year graft survival. Five-year follow-up of this study showed sustained superiority of rATG in terms of acute rejection. ^, Notably, infectious complications were more common in the recipients of rATG (vs. IL-2 RA) in both trials. In immunologically high-risk kidney transplant recipients randomly assigned to either rATG or alemtuzumab (see later) induction, no differences were seen in acute rejection rates between the groups followed out to 3 years post transplant, although infectious complications were more common in rATG-treated subjects. A 2017 retrospective analysis of U.S. kidney transplant recipients that compared outcomes in matched patients receiving induction with rATG versus alemtuzumab or basiliximab found that rATG use was associated with improved outcomes: death or allograft failure versus alemtuzumab, death versus basiliximab.

ATG also has an important role in the treatment of severe or steroid-resistant acute cellular rejection. A randomized study showed rATG superior to hATG in the treatment of acute rejection in terms of rejection reversal and 90-day recurrence rates.

ATG increases the risk of malignancy when compared with IL-2 RA induction therapy, and greater exposure may lead to greater incidence of malignancy. Infusion-related side effects, such as fever, chills, hypotension and, less frequently, cardiovascular events, are usually mild, particularly with adequate steroid and antihistamine premedication and a slow infusion rate. These reactions are more likely to occur during the first few infusions and become rare with subsequent infusions. Cytokine release syndrome, a systemic inflammatory response with high interleukin-6 (IL-6) levels, has been reported after ATG administration and can present with mild, flulike symptoms or severe life-threatening manifestations. Serum sickness, characterized by fever, rash, and arthralgia occurring 10 to 15 days after treatment, has also been reported, possibly more frequently in patients not receiving steroid prophylaxis.

Alemtuzumab, a humanized monoclonal antibody against CD52, which was originally developed to treat refractory B cell chronic lymphocytic leukemia, depletes both T and B cells. In an RCT that compared alemtuzumab with induction with basiliximab (immunologically low risk) and rATG (high risk), alemtuzumab was superior to basiliximab and equivalent to rATG for acute rejection up to 3 years. Development of autoimmune disease has been reported in solid organ transplant recipients treated with alemtuzumab induction. ^, One limitation to its use is the lack of wide commercial availability. It is typically dosed as a one-time 30-mg injection.

Rituximab is a chimeric anti-CD20 cytolytic monoclonal antibody used as induction therapy for immunologically high-risk patients based on evidence that it has a favorable safety profile and is associated with a reduction in rejection and antibody-mediated graft dysfunction. In patients at high risk for ABMR, rituximab may be used in conjunction with intravenous immunoglobulin (IVIG, see later). ^, Hepatitis B prophylaxis should be initiated in patients with prior hepatitis B infection. Rituximab may also be used for desensitization (see later) ^, or treatment of recurrent or de novo posttransplant glomerular diseases (e.g., membranous nephropathy, focal segmental glomerulosclerosis [FSGS]). ^, Premedication with steroid, acetaminophen, and an antihistamine is given to avoid an infusion reaction. Obinutuzumab, a newer anti-CD20 monoclonal antibody directed at a different CD20 epitope, has been shown to effectively deplete B cells in kidney transplant recipients.

Various pooled human IVIG formulations are available to use before transplantation as part of both HLA- or ABO-incompatible desensitization protocols, as part of induction therapy in patients with preformed DSAs or for treatment of ABMR. ^, While its mechanism of action is not fully understood, it is thought to involve: 1. neutralization of circulating antibody, 2. complement inhibition, 3. modulation of B cell and APC function, and 4. cytokine inhibition. Adverse effects include infusion reaction, headache, aseptic meningitis, hemolysis (especially in patients who are blood group A) and, rarely, thrombosis. IVIG can also be used to treat posttransplant viral infections such as BK virus (discussed later) and parvovirus, a viral infection associated with severe anemia and proteinuria.

Desensitization protocols attempt to lower anti-HLA antibody titers to create an immunologic window for successful transplantation in highly sensitized patients and are associated with good medium-term graft survival rates, as well as a survival advantage compared with remaining on dialysis. ^{, ,} Unfortunately, ABMR rates are high ^, and few data are available about long-term graft survival in these patients.

Desensitization protocols fall into two broad categories: 1. high-dose IVIG/anti-CD20-based and 2. low-dose IVIG/plasmapheresis-based regimens. A number of studies have suggested that IVIG without rituximab or plasmapheresis is associated with a posttransplant rebound in DSA titers and increased incidence of ABMR. More recent reports have described successful desensitization using newer agents such as the anti-IL-6 receptor antibody (tocilizumab) and the IgG-degrading enzyme (IdeS). ^,

For living donor candidates, a donor exchange program can avoid the need for desensitization. The new U.S. Kidney Allocation System (KAS), which offers significant allocation score bonuses and high priority access to kidney transplants across the country for the most sensitized patients on the list (calculated PRA >98%), was implemented in December 2014. KAS has resulted in a significant increase in transplantation rates for highly sensitized patients. ^,

An important immunologic barrier in kidney transplantation is ABO blood group status, as blood group antigens are expressed on endothelial cells. With certain exceptions, ABO-incompatible transplantation without desensitization will result in ABMR. In patients with low baseline anti-A/B titers, ABO-incompatible transplant has been shown to be safe with minimal pretreatment. Blood group A donors are composed of individuals with different A subtypes. The most common are type A1 and A2; A2 antigens are less highly expressed than A1 antigens. The transplantation of blood group A2 donors into B recipients with low anti-A titers is considered safe without desensitization. KAS has permitted that A2 or A2B deceased donor kidneys be allocated to selected blood group B candidates to reduce the long wait times faced by this group.

Much of the pioneering work on desensitization for ABO-incompatible transplant has been done in Japan, where deceased donor transplants are not performed. ABO-incompatible desensitization protocols mimic those described earlier, with a goal to lower anti-A/B titers to under 1:8 or 1:16. Some protocols also include posttransplant plasmapheresis or IVIG. The long-term outcome of desensitized recipients of blood group incompatible organs is favorable, although perhaps slightly inferior to that of ABO-compatible kidney transplant recipients. ^,

Calcineurin is a calcium-dependent serine/threonine phosphatase that is involved in a diverse range of cellular functions including T cell signal transduction. Signal 2 (described earlier) activates the calcium-calcineurin pathway, triggering cytosolic influx of calcium and the downstream activation of calcineurin. Activated calcineurin dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT), which then allows its translocation to the nucleus. In the nucleus, NFAT activates a host of target genes including the cytokine IL-2. IL-2 then binds to its receptor and initiates T cell expansion. The excellent posttransplant outcomes seen with the advent of the CNIs in the 1980s made the widespread expansion of solid organ transplantation possible. CNIs, first in the form of cyclosporine (CsA, binds the immunophilin cyclophilin) and then later tacrolimus (FK, binds the immunophilin FK binding protein 12), have remained a backbone of maintenance immunosuppression regimens. Pharmacokinetic monitoring is most often done by measuring a 12-hour trough level (C ₀ ) of CsA and FK, a reasonable proxy for area under the curve for clinical use.

As the cytochrome P450 enzyme system (CYP3A) is responsible for CNI metabolism, inducers (e.g., rifampin, phenobarbital, phenytoin) or inhibitors (e.g., ketoconazole, erythromycin, ritonavir, diltiazem, cannabidiol) of this enzyme can decrease or increase CNI levels, respectively ( Table 69.3 ). Polymorphisms in CYP3A5 and ABCB1 (encodes efflux transporter P-glycoprotein present in enterocytes) can also impact CNI levels.

Unfortunately, CNIs are not without side effects including CNI-associated nephrotoxicity, which may contribute to a reduction in long-term graft survival in a proportion of kidney transplant recipients ( eTable 69.2 ). CNI nephrotoxicity may present as diverse kidney pathology including thrombotic microangiopathy, striped interstitial fibrosis, and arteriolar hyalinosis. Other side effects include hypertension (more with CsA), post-transplant diabetes (more with FK), neurotoxicity (more with FK), hyperkalemia (more with FK), hypomagnesemia, metabolic acidosis, hypercalciuria, and dyslipidemia (more with CsA). FK and CsA can have opposing effects on hair growth, with FK associated with alopecia and CsA with hypertrichosis. CsA may cause gingival hyperplasia, particularly when used in combination with dihydropyridine calcium channel blockers. The overall contribution of CNI-specific chronic injury, however, remains controversial in the landscape of current therapy. Concern regarding CNI nephrotoxicity has led to a greater focus on strategies to minimize CNI exposure. Data from two RCTs from the late 2000s supported the efficacy and safety of lower-dose cyclosporine and tacrolimus-based regimens in immunologically low-risk patients. ^, However, antibody-mediated allograft injury has been increasingly recognized as an important cause of late graft loss. CNI underexposure may allow for increased allo-recognition, chronic ABMR, and higher risk of new DSA formation. To date, belatacept (see later) probably represents the best available option for calcineurin avoidance.

Sirolimus (Rapamune), a macrocyclic antibiotic with immunosuppressive properties, and Everolimus (Zortress), derived from sirolimus and with a shorter half-life, are examples of mammalian target-of-rapamycin (mTOR) inhibitors. Even though it shares its cytoplasmic binding protein with FK, the resulting complex does not interfere with calcineurin and instead binds mTOR. mTOR inhibition prevents the propagation of IL-2-mediated cell proliferation signaling through the PI3K/AKT/mTOR pathway. Sirolimus inhibits cellular proliferation of T and B lymphocytes and reduces antibody production. Its immunosuppressive effects have been demonstrated in preclinical studies to be synergistic with CsA and FK. ^, Side effects of sirolimus include hyperlipidemia, thrombocytopenia, anemia, poor wound healing, diarrhea, pneumonitis, mouth ulcers, proteinuria, and peripheral edema.

mTOR inhibitors are not routinely used as part of maintenance immunosuppression regimen, as clinical studies have shown inferior outcomes (increased acute rejection, lower GFR) when compared with CNI. Sirolimus-related adverse events and drug discontinuation have also been a challenge in clinical studies. In addition, a trend toward worse GFR in CNI and sirolimus treatment combinations (especially cyclosporine) is consistent with animal studies that show that sirolimus cotreatment potentiates CNI nephrotoxicity.

Late conversion from CNI to sirolimus has shown some promise in improving/stabilizing kidney function in patients with chronic allograft dysfunction, with the caveat that the development of nephrotic or subnephrotic range proteinuria following conversion to sirolimus is relatively common and requires cessation of the treatment. The presence of proteinuria before conversion is predictive of a poor response and should be screened for before considering a switch to sirolimus. Finally, conversion from CNI to sirolimus is associated with regression of Kaposi sarcoma and reduction in the development of squamous cell skin cancers. ^, Everolimus is approved for the treatment of advanced renal cell carcinoma.

Belatacept, given as an intravenous infusion, is composed of human IgG1 Fc fragment linked to the modified extracellular domain of cytotoxic T lymphocyte–associated antigen 4 (CTLA4). It selectively binds B7 (CD80 and CD86) on APCs and prevents their interaction with CD28 on T cells (Signal 2 of T-cell activation). Two studies of living or standard deceased donor recipients (BENEFIT ) and those of expanded criteria deceased donor kidneys (BENEFIT-EXT ) randomized subjects to higher-dose belatacept, lower-dose belatacept, or CsA, with all receiving IL-2 RA induction, and MMF and steroid maintenance concurrently. Of note, these studies did not compare belatacept to FK, which has been shown to have superior outcomes when compared with CsA. One-year results showed similar graft and patient survival across the groups but significantly higher GFR in belatacept-treated subjects. ^, Acute rejection was significantly higher in those treated with belatacept in BENEFIT, but not BENEFIT-EXT. ^, However, graft and patient survival were significantly higher at 7 years post transplant in the belatacept- versus CsA-treated group in the BENEFIT Study. An analysis of a subset of patients from these two trials showed a lower rate of development of de novo DSA in belatacept versus CsA at 3 years post transplant.

More recently, several studies have evaluated the safety and efficacy of either de novo belatacept or belatacept conversion, as well its impact on vaccine, infection-related, and malignancy outcomes. ^, As in the BENEFIT study, rates of acute rejection were again higher in belatacept-treated groups without an impact on allograft survival or eGFR. ^, A 2023 study found that early conversion to belatacept (<6 months post transplant) may improve eGFR compared with later conversion. Patients receiving belatacept may have a blunted response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and high-CMV risk patients may be higher risk for late CMV infection. The incidence of (mostly central nervous system) posttransplant lymphoproliferative disorder (PTLD) was higher in patients treated with belatacept in both trials and was associated with pretransplant EBV seronegativity. While the current package insert recommends use of belatacept only in those who are EBV seropositive (IgG+), a 2014 analysis of 5 studies and 1535 kidney transplant recipients found no difference in the incidence of PTLD in belatacept versus CNI groups or among those who were EBV seronegative versus seropositive. Data are limited on use in pregnant transplant recipients, though a 2023 case series of 12 recipients with 16 pregnancies reported no birth defects or fetal deaths in 13 live births.

Corticosteroids have both antiinflammatory and immunosuppressive properties and have played an important role in the immunosuppressive management of transplant recipients for not only induction and maintenance therapy but also treatment of acute rejection. The antiinflammatory effects of steroids are mediated by reduction of proinflammatory molecules including the platelet activated factor (PAF), prostaglandins, leukotrienes, and reduction of the release of tumor necrosis factor-α (TNF-α). Immunosuppressive properties of steroids include prevention of T cell proliferation, inhibition of cytokine production including IL-2, and interference with antigen presentation. Some of these effects are mediated through inhibition of the transcription factor nuclear factor kappa B (NF-κB). Chronic use of steroids potentiates lymphocyte apoptosis, resulting in lymphopenia, and interferes with the leukocyte trafficking.

The combination of these mechanisms make steroids a potent and versatile immunosuppressive drug, though adverse effects related to chronic use are also extensive (e.g., diabetes, hypertension, hyperlipidemia, osteoporosis, avascular necrosis, truncal obesity, hypertrichosis, acne, cataracts) and have led to increasing interest in steroid-sparing regimens. The emergence of new, more potent immunosuppressive drugs has allowed the successful implementation of such protocols (steroid avoidance, minimization, or withdrawal). ^, This is reflected by a significant trend toward decreased steroid utilization, with 67% compared with 90% of U.S. kidney transplant recipients maintained on the drug in the years 2021 and 1995, respectively. In 2021, 26% were maintained on tacrolimus/MMF alone. Reported benefits of steroid-sparing strategies are manifold and include improvements in blood pressure, glycemic and lipid control, reduced posttransplant weight gain, better bone mineral density, growth, and physical appearance. A Cochrane review of 30 RCTs of steroid avoidance (<2 weeks of exposure) and steroid withdrawal (>2 weeks exposure) demonstrated that such steroid-sparing strategies were not associated with an increase in mortality or all-cause graft loss but were associated with an increase in death-censored graft loss and acute rejection. However, the increased risk of acute rejection was seen in those treated with CsA but not FK-based immunosuppression regimens. Of note, a 2020 randomized study that was halted early found that corticosteroid avoidance in patients initiated on belatacept therapy after rATG induction therapy had increased rates of acute cellular rejection, with or without the addition of FK. Steroid-sparing strategies are a reasonable option for low-immunologic-risk patients who are treated with CNI/MPA-based immunosuppression regimens. Most steroid withdrawal protocols wean steroids within 3 to 6 months of transplant. Late withdrawal from steroids (>1 year post transplant) has been associated with increased acute rejection rates and deterioration in graft function in studies from the CsA/azathioprine era. ^, While late withdrawal may be safer today, caution is recommended with this approach.

Hypovolemia may develop after intravascular volume depletion from any cause including gastrointestinal losses. Diarrhea is a common adverse effect of MMF, especially when used with tacrolimus. Similarly, immunosuppression increases the risk of gastrointestinal infections including CMV disease, which can result in diarrhea and volume contraction; more than 50% of kidney transplant patients report experiencing diarrhea. The transplanted kidney is denervated with impaired autoregulation and therefore responds less to changes in circulating blood volume than native kidneys, which can exaggerate prerenal insults.

Transplant renal artery stenosis is the most common transplant vascular complication and is associated with reduced long-term allograft survival, ^, occurring most commonly between 3 months and 2 years post transplant. ^, The reported incidence varies widely on account of heterogenous diagnostic criteria. Transplant renal artery stenosis may be a consequence of inadequate arterial anastomosis, arterial kinking, or preexisting vascular disease of the donor or recipient. Immune-mediated or infection-related damage to the transplant renal artery also plays an important role in some patients; new posttransplant DSAs and CMV infection are both associated with the development of transplant renal artery stenosis. ^, Stenosis may occur in the donor or recipient artery or at the anastomotic site. Resultant renal hypoperfusion activates the renin-angiotensin-aldosterone system and may manifest as worsening or refractory hypertension, fluid retention, flash pulmonary edema, erythrocytosis, or allograft dysfunction. ^{, , ,} Clinical examination may reveal a new vascular bruit over the graft. Ultrasound with Doppler, magnetic resonance, and computed tomography angiography can support a diagnosis; however, direct angiography is usually required for confirmation, acknowledging the associated risk of contrast-mediated acute kidney injury given the large iodinated contrast load with invasive angiography. CO ₂ or minimal contrast angiography can be used to reduce the risk of radiocontrast injury. In the absence of hemodynamically significant stenosis on imaging or progressive kidney dysfunction, transplant renal artery stenosis can be managed conservatively with antihypertensive therapy and consideration of aspirin and/or statin adjuncts as appropriate. For patients with progressive stenosis, worsening kidney function, or uncontrolled hypertension, percutaneous transluminal angioplasty with or without stent placement may be indicated, with early success rates >70% but relatively high risk of recurrence in the following 6 to 8 months. ^{, ,} An open surgical approach can be considered for unsuccessful angioplasty or severe stenosis inaccessible to percutaneous transluminal angioplasty; however, due to potential serious complications, surgery is generally reserved for rescue therapy.

Acute CNI toxicity is discussed earlier. Chronic CNI exposure has been shown to irreversibly impact all three renal compartments including the vessels, tubulointerstitium, and glomeruli. Histologically, this may present as arteriolar hyalinosis, tubular atrophy, and striped interstitial fibrosis or thickening of the Bowman capsule with or without corresponding focal or global glomerulosclerosis. ^, In a study of 120 diabetic kidney transplant recipients (119 of whom underwent SPK) with sequential kidney transplant biopsies, histologic evidence of CNI toxicity defined as “striped cortical fibrosis or new-onset arteriolar hyalinosis and tubular microcalcification” was demonstrated in >50% of biopsies at 5 years and 100% of biopsies at 10 years post transplant. This study did not include a control arm however, and newer studies have suggested a much lower prevalence of interstitial fibrosis at 5 years post transplant, questioning the specificity of arteriolar hyalinosis for the diagnosis of CNI toxicity. ^, This, combined with increased evidence for immune-mediated injury in many cases of late allograft failure, has led many to deemphasize the importance of chronic CNI toxicity. Currently, evidence to support CNI withdrawal, conversion, or minimization is lacking in light of the competing risk of allograft rejection. Calcium channel antagonists may be protective against chronic CNI toxicity due to their vasodilatory mechanism preventing the corresponding fall in renal plasma flow and GFR observed with CNI therapy.

BK virus (BKV) is a nearly ubiquitous nonenveloped polyoma virus that typically presents as a mild self-limited respiratory event in healthy individuals (usually in childhood), with BKV seropositivity >80% to 90% in people older than 10 years of age. ^, Following primary infection, the virus remains latent in renal tubular and uroepithelial cells, with viral reactivation associated with later immunosuppression. This may manifest as isolated viruria or viremia, tubulointerstitial nephritis with slowly progressive graft dysfunction (BK nephropathy), sterile pyuria, hemorrhagic or nonhemorrhagic cystitis, ureteritis, or ureteric stenosis with resultant obstruction. While controversial, emerging data also suggest potential oncogenic properties of BKV. Risk factors for BKV include greater immunosuppression exposure (e.g., thymoglobulin), rejection or ischemia episodes, DGF, decreased cellular immunity, male sex, African American race, ureteral stent placement, and older age.

BK nephropathy is most common in the first 2 years post transplant or following treatment for rejection. Approximately 30% to 40% of renal transplant recipients develop BK viruria, 10% to 20% develop BK viremia, and 1% to 10% progress to BK nephropathy. ^, BK viruria and viremia almost always precede BK nephropathy, so urine or plasma BK viral screening offer an opportunity to identify early preclinical viral replication and institute preemptive management strategies to help mitigate progression to BK nephropathy. Given the higher positive predictive value with plasma BK levels, this is the preferred BK screening method utilized by most centers ; however, approaches to screening vary and are influenced by local prevalence and economic factors.

The risk of BK nephropathy increases with higher BK viral titers; a plasma BK viral load ≥10,000 copies/mL is generally considered a “presumptive” diagnosis of BK nephropathy. However, given the potential for concurrent histologic diagnoses (including rejection), transplant biopsy is still warranted in most cases. The presence of intranuclear tubule cell inclusions by light microscopy should raise suspicion; diagnosis is confirmed by immunohistochemistry using antibodies against BK viral proteins (SV-40). However, BKV is associated with focal disease primarily effecting the renal medulla, with histologic evidence of BK nephropathy missed in ∼30% of cases. A negative biopsy therefore does not rule out BK nephropathy, and with high clinical suspicion, a nonconfirmatory biopsy may need to be repeated.

The mainstay of BKV treatment is reduction in immunosuppression. A number of strategies have been proposed, but most commonly, significant viremia or biopsy evidence of nephropathy will prompt dose reduction or discontinuation of the antiproliferative agent (usually MMF). If this intervention fails to result in a favorable viral response, the dose of CNI is reduced by 30% to 50% with continued monitoring of viral titers and for the precipitation of concurrent rejection in light of reduced immunosuppression. Switching tacrolimus to cyclosporine may be considered; some, but not all RCTs, have shown less BKV in patients treated with cyclosporine than tacrolimus, whereas most studies show benefit with mTORi versus mycophenolate. Tacrolimus is believed to increase in vitro BKV replication independent of its immunosuppressive properties, whereas cyclosporine and mTOR inhibitors appear to directly inhibit BKV replication (although this may simply represent a de facto reduction in immunosuppression).

A number of adjunct strategies may be considered in subjects who either fail to respond to immunosuppression reduction or in whom very aggressive immunosuppression reduction is unattractive because of their high-risk immune status; however, evidence of benefit is conflicting. IVIG preparations (which contain high titers of neutralizing antibodies against all BKV genotypes) have also shown promise in treating BKV that has not responded to immunosuppression reduction in isolation. IVIG antiviral benefit has been demonstrated fairly consistently and is seemingly well tolerated in small case series, yet large trial data are lacking and cost has limited enthusiasm at many centers, pending more comprehensive and robust data demonstrating efficacy. A number of small series have suggested that treatment with leflunomide (usually as a substitute for an antimetabolite) may result in enhanced BK viral clearance, although in the absence of clinical trials its efficacy remains contentious with no clear benefit demonstrated in meta-analyses. Similarly, the antiviral cidofovir has been associated with a reduction in BK viral load in some, but not all, case series with significant potential for nephrotoxicity and no antiviral benefit demonstrated in larger meta-analyses. ^, Neither leflunomide nor cidofovir is currently recommended for the treatment of BK viremia or nephropathy. Finally, hopes for fluoroquinolones as a therapy for BKV were dashed by two randomized controlled trials that showed levofloxacin to be no better than placebo at 1. treating or 2. preventing BK viremia/viruria in kidney transplant recipients. ^,

Urinary tract infections (UTIs) are relatively common in kidney transplant recipients, with an estimated 10% to 20% of patients experiencing acute graft pyelonephritis (AGPN) posttransplant. UTIs and AGPN may occur at any period but are most frequent in the first 3 to 6 months after transplantation because of catheterization, stenting, and aggressive immunosuppression. In addition to standard risk factors including anatomic abnormalities and neurogenic bladder, other risk factors for UTIs in transplant recipients include shorter ureters and increased urinary reflux due to impaired antireflux mechanisms at the vesicourethral anastomosis. Fever, allograft pain, and leukocytosis are usually more pronounced in acute pyelonephritis than in rejection. Diagnosis requires urine culture, but empiric antibiotic treatment should be started immediately if there is clinical suspicion. Delay in treatment can lead to rapid clinical decline in the immunosuppressed patient. The most commonly implicated microorganisms are gram-negative bacilli, coagulase-negative staphylococci, and enterococci. Kidney function usually returns to baseline quickly with antimicrobial therapy and volume expansion. Recurrent pyelonephritis requires investigation to exclude underlying predisposing urologic abnormalities.

TMA after kidney transplantation is a rare but serious complication that can present as either a de novo process (often in the setting of preexisting genetic susceptibility) or a recurrence of a primary disease, typically related to dysregulated overactivation of the alternative complement pathway (e.g., in atypical hemolytic uremic syndrome [aHUS]). In the setting of an acquired or genetic predisposition, triggers of new TMA after transplant include CNIs, ABMR, viral infections (including CMV and BKV), ischemia-reperfusion injury, and the recurrence of a previously undiagnosed primary disease. Patients with complement-mediated TMA as a cause for ESKD have a high risk of recurrence in the transplant allograft, which, without prophylactic therapy, ranges from 50% to 100% depending on the underlying complement abnormality; complement factor (CF) I, CFH, CFB, and C3 mutations portend the highest risk of posttransplant recurrence.

Posttransplant TMA occurs most commonly in the first 3 months after transplant but can occur at any time. It is often accompanied by increasing plasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis, and low haptoglobin concentrations, but it may also present in a localized fashion with isolated renal insufficiency, proteinuria, or arterial hypertension. A TMA diagnosis can be overlooked because thrombocytopenia and anemia occur commonly after transplantation in the setting of ATG induction therapy and occasionally with MMF maintenance immunosuppression. The diagnosis is confirmed by allograft biopsy, which shows endothelial damage and, in severe cases, thrombosis of glomerular capillaries and arterioles.

Early diagnosis of TMA is essential to salvage kidney function. There are no controlled trials of therapy for de novo TMA after transplant; however, withdrawal of potential offending agents and neutralization of any potential inciting triggers should be a priority. If immunosuppression-related TMA is suspected, an initial measure is to switch CNIs (either from tacrolimus to cyclosporine or cyclosporine to tacrolimus) or discontinue the CNI drug class altogether in favor of a belatacept or mTORi-based immunosuppression regimen. Other potential underlying etiologies should also be sought including ABMR; in ABMR-associated TMA, the mainstay of treatment is plasmapheresis, optimization of immunosuppression, and often IVIG. In patients with de novo TMA that fails to improve with the above measures, plasma exchange has been recommended, yet while plasma exchange has been shown to improve hematologic parameters, its effect on renal outcomes has been inconsistent at best. Eculizumab is an anti-C5 monoclonal antibody that inhibits the alternative complement pathway and has been employed successfully for the treatment of posttransplant TMA relating to aHUS recurrence or as a prophylactic therapy in the setting of known high-risk complement mutations. ^, However, even in the absence of a known complement mutation or prior diagnosis of aHUS, in many cases, de novo posttransplant TMA relates to complement overactivation, suggesting a role for eculizumab in this population as well, particularly amongst nonresponders to initial strategies. ^,

GN is the cause of ESKD in 30% to 50% of patients who undergo subsequent kidney transplant, with an overall recurrence rate of 7% to 55%. The true incidence of recurrence is difficult to estimate given most relevant studies are small and retrospective with variable follow-up periods. Given the heterogenous pathology and acuity of the various GN subtypes, the presentation and consequences of recurrence differ by GN diagnosis. An Australian study of patients with biopsy-proven GN found a 10-year incidence of graft loss from recurrence of 8.4%, rendering recurrent GN the third most common cause of graft loss. Most GN recurrence results in allograft failure 3 to 5 years post transplant; however, certain etiologies may present early and aggressively post transplant (e.g., MPGN, FSGS). Recurrent GN typically presents similarly as for native kidney disease, with decreasing eGFR, proteinuria, or hematuria. Treatment is typically supportive and includes RAAS inhibition and strict blood pressure control. Immunosuppressive therapy for the prevention or treatment of posttransplant GN has shown limited benefit. There is a paucity of data to support specific preventative or treatment strategies for most recurrent GN presentations, with treatment recommendations extrapolated from native kidney disease and outcomes in the transplant setting poorly described. However, targeted therapies have been more widely accepted for some posttransplant GN recurrences including plasmapheresis in patients with recurrent primary FSGS. A summary of recurrent GN presentations and recommendations posttransplant is shown in Table 69.5 , acknowledging the inconsistencies in reporting and lack of consensus regarding therapeutics for most conditions.

Although urinary tract obstruction can occur at any time after transplantation, it is most common within the first 6 months. It can occur at any location but most frequently involves the site of implantation of the ureter into the bladder. Intrinsic causes include ureteric kinking, intraluminal blood clots or slough material, poor implantation of the ureter into the bladder, and fibrosis of the ureter due to ischemia or rejection. As described earlier, BKV can lead to ureteric stenosis, and rarely renal calculi may also cause obstruction. Extrinsic causes include an enlarged prostate in elderly men (causing bladder outlet obstruction) and compression by a lymphocele, urinoma, or other fluid collection. The transplanted allograft is denervated: Urinary tract obstruction is often asymptomatic and should always be considered in the differential diagnosis of allograft dysfunction. This is of particular importance given that both upper and lower obstruction of the solitary graft can precipitate acute and substantial graft dysfunction. Ultrasound often demonstrates hydronephrosis, but some dilation of the transplant urinary collecting system may be normal and is often seen in the early postoperative period due to anastamotic edema and increased urine output. Serial scans showing worsening hydronephrosis may be needed to confirm the diagnosis. Renal scintiscan with diuretic washout is useful in equivocal cases. Percutaneous antegrade pyelography is the best radiologic technique for determining the site of obstruction and can be combined with interventional endourologic techniques. In expert hands, endourologic techniques (e.g., balloon dilation, stenting) may be effective in treating ureteric stenosis and stricture. More complicated cases require open surgical repair. Extrinsic compression requires specific intervention such as draining or fenestration of a culprit fluid collection. Obstruction in the early postoperative period due to an enlarged prostate should be managed with bladder catheter drainage and standard urologic therapies including tamsulosin.

Routine intraoperative ureteric stenting at the time of kidney transplantation has significantly reduced the risk of major urologic complications post transplant (urine leak and/or stenosis decreased from a median of 7.0% in unstented patients to 1.0% in stented patients). When UTI prophylaxis is employed, there is no increased infectious risk in stented versus unstented transplant recipients. Intraoperative ureteric stenting is now considered standard practice in most transplant centers, although there remains some disagreement regarding the optimal timing for stent removal.

The KDPI is a measure of donor kidney function calculated from the kidney donor risk index (KDRI), which is based on 10 donor characteristics and is a modified version of the predictive tool first described by Rao and colleagues. The KDPI is determined relative to all deceased donor kidneys recovered in the United States in the preceding year and is expressed as a percentile score with 0% and 100% signifying excellent quality and marginal organs, respectively. For example, a KDPI of 70% would indicate a graft failure risk that is higher than 70% of kidneys recovered in the United States the prior calendar year.

There has been a significant increase in the use of DCD kidneys. DCD donors can be sub-classified as “uncontrolled” or “controlled.” Uncontrolled donors are either unsuccessfully resuscitated or present dead on arrival to hospital, while controlled donors suffer a cardiac arrest following the withdrawal of life support in the intensive care unit or operating room immediately before donation. The duration of warm ischemia time is likely to be significantly greater in the setting of uncontrolled donation. Protocols for managing DCD kidneys vary from center to center. In uncontrolled donation, isolated perfusion of the kidneys with cold preservation solution can be achieved using double-balloon aortic catheterization (with balloons inflated in the aorta above and below the renal arteries) to minimize warm ischemia time.

Short-term outcomes (such as rates of DGF and primary nonfunction) are inferior to those seen for neurologic determination of death (NDD) donors; the adjusted risk of DGF is nearly three times higher in DCD than NDD donors. However, long-term outcomes of DCD organs are similar to those from NDD donors, including for more marginal donor kidneys. ^,

Maximizing the life span of donated organs is a key goal in kidney transplantation. The criteria used for allocation of deceased donor allografts can have an important effect on overall allograft survival. A purely utilitarian approach (to maximize allograft survival) would direct organs only to the youngest and healthiest, maximizing the “life years from transplant” gained from transplantation. In practice, a balance must be struck between utility and equity (ensuring that anyone medically fit for a transplant has a reasonable chance of obtaining one).

The number of potential transplant kidneys discarded has been increasing over time. Currently about 25% of deceased donor kidneys recovered for transplant are discarded; this is consistent across all age groups and most KDPI categories. This is despite a growing mismatch between the number of people waiting for a deceased donor kidney and the number of available kidney donors. Significant variability in deceased donor acceptance criteria has been demonstrated between transplant centers ; however, factors commonly associated with organ decline include a higher KDPI, older age, female sex, Black race, obesity, diabetes, hypertension, hepatitis C positivity, and “donor quality concerns.” Despite donors with AKI resulting in acceptable posttransplant graft outcomes, a terminal creatinine >2 mg/dL is associated with a 7-fold increase in the risk of organ discard. Notably, even patients who receive “marginal” deceased donor kidneys achieve a survival benefit versus remaining on dialysis; the 1-year graft survival rate for recipients of marginal kidneys where the other kidney was discarded exceeds 90%. Likewise, a deceased donor kidney with a KDPI >85% confers a better survival at 5 years than declining that offer in favor of waiting for a lower KDPI option, particularly for older patients with long anticipated wait times.

The mortality rate among kidney transplant recipients is lower than that for patients with ESKD on dialysis; however, despite advances in immunosuppression and antiviral therapies over time, kidney transplant recipients continue to experience increased mortality compared with the age-, sex-, and race-matched general population. Beyond the first year post transplant, death with graft function is the leading cause of allograft loss. Causes of death with graft function vary geographically and with time since transplant; however, in the United States and Australia/New Zealand, they include cardiovascular events, infection, and malignancy. ^,