# 07 - 325 Kidney Transplantation

## 325 Kidney Transplantation

Jamil R. Azzi, Naoka Murakami, 

Anil K. Chandraker

Kidney Transplantation
Kidney transplantation is the treatment of choice for patients with 
end-stage kidney disease (ESKD). Worldwide, tens of thousands of 
kidney transplants have been performed, and >220,000 patients are 
living with a functioning kidney transplant in the United States today. 
The first successful kidney transplant was performed in Boston in 
1954 between identical twins. The introduction of immunosuppressive 
therapies such as azathioprine and prednisone in the 1960s established 
kidney transplantation across nonidentical individuals (allografts). 
During the 1970s and 1980s, the success rate at the 1-year mark for 
deceased-donor allografts markedly improved after the introduction of 
calcineurin inhibitors. Currently, 1-year survival rates for living-donor 
and deceased-donor allografts are 98 and 93%, respectively, in the 
United States. However, long-term survival has not improved as much 
over time, and the average allograft survival time is 19 and 12 years for 
living-donor and deceased-donor grafts, respectively.
Age-related mortality rates after transplantation are highest in the 
first year due to the surgical risks: 2% for ages 18–34 years, 3% for 
ages 35–49 years, and 6.8% for ages ≥50–60 years. Despite this, the 
actual survival benefit of transplantation compared to chronic dialysis 
becomes apparent within days to months following transplantation, 
even after risk adjustments for age, diabetes, and cardiovascular status. 
While the loss of kidney transplant due to acute rejection is now a rare 
event, most allografts eventually succumb at varying rates to a chronic 
process consisting of interstitial fibrosis, tubular atrophy, vasculopathy, 
and glomerulopathy, the pathogenesis of which in varying degrees is 
likely a combination of an alloimmune response, drug toxicity, and the 
result of a variety of other insults. Overall, transplantation results in 
an improved life expectancy with a higher quality of life compared to 
patients who remain on dialysis.
RECENT ACTIVITY AND RESULTS
In 2022, >19,000 deceased-donor kidney transplants and approxi­
mately 6000 living-donor transplants were performed in the United 
States, with the ratio of deceased-donor to living-donor transplants 
remaining stable over the past few years. As the number of patients 
with ESKD increases, the number of patients on the transplant waitlist 
also increases. The donor shortage remains a critical challenge; as of 
2022, there were nearly 139,000 adult kidney transplant candidates on 
the waiting list, with 25,000 patients being transplanted yearly. This 
imbalance is set to worsen over the coming years with the predicted 
increased rates of kidney failure associated with obesity and diabetes 
worldwide. In an attempt to increase utilization of marginal kidneys 
and allocate organs equitably, a new allocation system within the 
United States was implemented in 2014. The guiding principles of the 
changes were to offer an opportunity for transplantation to patients 
who were highly sensitized and, thus, less likely to find a suitable 
donor, while at the same time allowing patients expected to survive the 
longest to receive the best-quality deceased donor organs. The Kidney 
Donor Profile Index (KDPI) score, which ranges from 0 to 100%, was 
introduced to estimate the potential risk of graft failure after kidney 
transplant based on 10 donor factors. The lower KDPI values are 
associated with higher expected posttransplant survival. Hence, the 
kidneys with a KDPI <20% are allocated to the 20% of the potential 
recipients with the highest expected posttransplant survival. Kidneys 
with a KDPI >85% (previously called expanded criteria donor [ECD] 
kidneys) are directed toward patients who are expected to fare less well 
on dialysis and would benefit from being transplanted earlier even if it 
means accepting a lower-quality organ.
In 2021, a new distance-based kidney allocation policy was intro­
duced. Under this policy, deceased-donor kidneys are to be offered first 
to candidates listed at transplant hospitals within 250 nautical miles of 

the donor hospitals. While intended to reduce geographic disparities 
in access to kidney transplantation, this program has resulted in more 
complex organ sharing, unintended higher kidney discard rates, and 
increased cold ischemia time. A variety of other means to increase 
the donor pool and equity have also become more popular. Kidneys 
from donors after cardiac death (DCD) are now commonly used to 
overcome the demand for organs, consisting of 30% of total deceased 
kidney transplants (Table 325-1). Furthermore, with the advance­
ment of the direct-acting antiviral therapies for hepatitis C virus 
(HCV), transplantation from HCV-positive donors to HCV-positive 
or -negative recipients has been performed since 2017 in order to 
increase the donor pool. Now this practice is becoming more common, 
consisting of 9% of deceased kidney transplants. Recently, the HOPE 
(Human Immunodeficiency Virus [HIV] Organ Policy Equity) Act 
authorized organ donation from HIV-positive candidates, and >100 
transplants have been performed. As patients with blood group B wait 
longer for deceased donor offers, eligible B blood type candidates who 
have low anti-A titer are eligible for an allograft from A blood type 
donors. This helps improve access and reduce disparities in wait time 
for minorities, especially for the African-American ESKD population, 
in whom blood type B is more common than in other ethnicities. 
Finally, with recent advances in gene editing technology, xenotrans­
plantation is becoming a more realistic endeavor. Using kidneys from 
genetically engineered pigs, three experimental kidney transplanta­
tions into brain-dead recipients were performed in 2022. There are still 
multiple issues to overcome, including xenoimmunity, transmission 
of zoonosis, and ethical challenges, but xenotransplantation has the 
potential to provide an unlimited source of organs.

CHAPTER 325
Kidney Transplantation
The overall results of transplantation are presented in Table 325-2. 
At the 1-year mark, allograft survival is higher for living-donor recipi­
ents. This is most likely related to less ischemic injury of the transplant 
organ. The introduction of more effective immunosuppression and 
more accurate matching between recipients and donors has almost 
equalized the risk of graft rejection in the majority of patients within 
the first year. At 5- and 10-year follow-up, however, there remains a 
steeper decline in survival of those with deceased-donor kidneys.
RECIPIENT EVALUATION
Virtually all patients with ESKD benefit from transplantation with a 
longer life expectancy and a better quality of life. While the mortality 
rate after transplantation is highest in the first year due to perioperative 
complications, recipient evaluation is critical in identifying patients at 
risk. It involves a multidisciplinary approach that requires thorough 
medical, surgical, social, and psychosocial evaluations to identify the 
risk factors that prohibit transplantation or mandate treatment before 
proceeding, as well as ensuring the appropriate use of limited organs.
There are a few absolute contraindications to kidney transplanta­
tion: chronic illness that limits predicted survival for <2 years, active 
malignancy, active infection, psychosocial issues affecting adherence 
to the medical care, and active substance abuse. Cardiovascular risk 
assessment is crucial during both the perioperative and postoperative 
periods. Patients with ESKD are at higher cardiovascular mortality risk, 
TABLE 325-1  Definition of a Non-Heart-Beating Donor (Donation 
After Cardiac Deatha [DCD])
  I: Brought in dead
 II: Unsuccessful resuscitation
III: Awaiting cardiac arrest
IV: Cardiac arrest after brainstem death
 V: Cardiac arrest in a hospital patient
aKidneys can be used for transplantation from categories II–V but are commonly 
only used from categories III and IV. The survival of these kidneys has not been 
shown to be inferior to that of deceased-donor kidneys.
Note: Kidneys can both have a Kidney Donor Profile Index (KDPI) score >85% and 
be DCD. High KDPI kidneys have been shown to have a poorer survival, and there 
is a separate shorter waiting list for those kidneys. They are generally utilized 
for patients for whom the benefits of being transplanted earlier outweigh the 
associated risks of using a lower-quality kidney.

TABLE 325-2  Mean Rates of Graft and Patient Survival for Kidneys Transplanted in the United States from 1999 to 2018a
1-YEAR FOLLOW-UP
5-YEAR FOLLOW-UP
10-YEAR FOLLOW-UP
 
GRAFTS, %
PATIENTS, %
GRAFTS, %
PATIENTS, %
GRAFTS, %
PATIENTS, %
Deceased donor

Living donor

aAll patients transplanted are included, and the follow-up unadjusted survival data from the 1-, 5-, and 10-year periods are presented to show the attrition rates over time 
within the two types of organ donors.
Source: Data from Summary Tables, 2021 Annual Reports, Scientific Registry of Transplant Recipients.
and thorough cardiovascular evaluation for coronary artery diseases, 
valvular diseases, and heart failure is critical.
At most centers, there is no official age limit for transplantation, 
with >20% of waitlisted candidates currently being older than 65. 
However, overall physical and cognitive function of the candidates 
needs to be fully assessed. While history of malignancy itself is not a 
contraindication for kidney transplantation, potential recipients should 
be treated to ensure cancer-free wait time of 2–5 years depending on 
the type and stages of malignancy to decrease the risk of cancer recur­
rence. Latent or indolent infection (HIV, hepatitis B or C, tuberculosis) 
should be a routine part of the candidate workup. While historically 
transplant centers considered overt AIDS and active hepatitis absolute 
contraindications to transplantation because of the high risk of oppor­
tunistic infection, with the introduction of potent antiviral regimens, 
many centers are now transplanting individuals with hepatitis and HIV 
infection under strict protocols.
PART 9
Disorders of the Kidney and Urinary Tract
One of the few “immunologic” contraindications to transplantation 
is the presence of preformed antibodies against the donor kidney at the 
time of the anticipated transplant that can cause hyperacute rejection. 
Those harmful antibodies include natural antibodies against the ABO 
blood group antigens and antibodies against human leukocyte antigen 
(HLA) class I (A, B, C) or class II (DR, DQ, DP) antigens. These 
antibodies are routinely excluded by proper screening of the candidate’s 
ABO compatibility and direct cytotoxic cross-matching of candidate 
serum with lymphocytes of the donor. Removal of these antibodies 
directed at donor tissue through a variety of strategies (desensitization) 
is now routinely performed with varying levels of success.
TISSUE TYPING AND CLINICAL 
IMMUNOGENETICS
Matching of HLA major histocompatibility complex antigens 
(Chap. 361) is an important criterion for the selection of donors. 
Each mammalian species has a single chromosomal region that 
encodes the major histocompatibility antigens, and this region on 
the human chromosome 6 codes the HLA genes. HLA is highly 
polymorphic; therefore, it can be an immunologic target of organ 
rejection when mismatched between the donor and the recipient. 
Historically, HLA antigens have been defined by serologic techniques 
by adding sera of a recipient (potentially containing anti-HLA anti­
bodies) with a “library” of leukocytes with known serotypes. How­
ever, currently, molecular typing of HLA by genomic sequencing is 
almost universally used. Other “minor,” non-HLA antigens may also 
elicit an alloimmune response in addition to the ABH(O) antigens 
and endothelial antigens that are not expressed on lymphocytes. The 
number of HLA antigen mismatches in A, B, and DR loci correlates 
with allograft survival; the more mismatches, the higher is the risk of 
allograft rejection. Nevertheless, some HLA-identical renal allografts 
are rejected, often within the first few weeks after transplantation. 
These observations may represent prior sensitization to non-HLA 
antigens. Non-HLA minor antigens are relatively weak when initially 
encountered and are, therefore, suppressible by conventional immu­
nosuppressive therapy. If prior exposure to the antigen and priming 
of the recipient immune system have occurred, secondary exposure at 
the time of transplantation may lead to an immune response refrac­
tory to treatment. More recently, a genetics study of donor-recipient 
pairs revealed that non-HLA antigen polymorphisms in the LIMS-1 
locus can contribute to the risk of acute rejection; more of these nonHLA antigens are likely to be discovered.

DONOR EVALUATION
■
■LIVING-DONOR EVALUATION
Living kidney donors experience the immediate risk of surgery and 
the long-term potential risk of developing kidney dysfunction pre­
maturely; thus, the basic principle of “first, do no harm” (Chap. 12) 
is important. Therefore, donor evaluation must take every effort to 
exclude any medical conditions that may cause morbidity and mor­
tality after kidney donation, such as hypertension, diabetes, and/or 
proteinuria. Although studies have shown that the risk of ESKD after 
kidney donation is not greater than that of the general population, 
donation is associated with a small but significant potential lifetime 
risk of ESKD (0.3–0.4%; absolute risk increased by 0.2–0.3% compared 
to that of healthy nondonors). The mechanism of premature renal 
failure is thought to be due to increased blood flow and hyperfiltration 
injury in the remaining kidney. There are a few reports of the develop­
ment of hypertension, proteinuria, and even lesions of focal segmental 
sclerosis in donors over long-term follow-up. In family members of 
type 1 diabetics, anti-insulin and anti-islet cell antibodies should be 
measured, and a glucose tolerance test should be performed. AfricanAmerican donors have a higher risk of ESKD after donation (in line 
with their higher risk of kidney failure in general), and the genetic 
screening for APOL1 risk alleles may be appropriate (Chap. 326). 
Additionally, as more robust genetic testing becomes available, predo­
nation genetic testing per protocol is being introduced to stratify the 
risks of kidney donors. From the surgical perspective, selective renal 
arteriography is essential to reveal any anatomic anomaly and to assess 
the size imbalance and laterality of donor kidneys. In most cases, donor 
nephrectomy is performed laparoscopically to minimize the surgical 
scar and to enhance a faster postsurgical recovery. Lastly, although 
financial and nonfinancial conflicts of interest between kidney donors 
and recipients are strictly prohibited, removing financial disincentives 
is increasingly accepted to reduce barriers toward living donation, and 
legislative efforts to protect kidney donors are ongoing (Chap. 12).
■
■DECEASED-DONOR EVALUATION
Deceased donors should be free of malignant neoplastic disease, hepa­
titis, and HIV owing to possible transmission to the recipient, although 
under certain circumstances, HCV- and HIV-positive organs may be 
used. Increased risk of graft failure exists when the donor is elderly or 
has acute kidney injury or when the kidney experiences a prolonged 
period of ischemia.
In the United States, there is a national system of regulations, alloca­
tion support, and outcomes analysis for kidney transplantation called 
the Organ Procurement Transplant Network. Studies have shown that 
deceased-donor kidneys can be maintained for up to 48 h on cold 
pulsatile perfusion or on ice before being used for transplantation. 
Normothermic perfusion of donated organs has been studied, but it 
has not been part of clinical care as of yet. Generally, an ischemic time 
of <24 h is preferred; this approach permits adequate time for typing, 
cross-matching, transportation, and selection issues to be resolved.
■
■PRESENSITIZATION
The presence of antibodies against donor antigens, either HLA or nonHLA, can be a potential cause of allograft injury after transplantation, 
and, hence, it is important to perform crossmatching prior to trans­
plantation. For the purposes of crossmatching, donor T lymphocytes, 
which express class I but not class II HLA, are used as a surrogate 
target for detection of circulating anti–class I (HLA-A and -B) antibodies

in the recipient. Note that T cells are used as surrogate cells to detect class I 
HLA as a matter of convenience and this is unrelated to the risk of “T 
cell–mediated” rejection. A positive cytotoxic crossmatch of recipient 
serum with donor T lymphocytes indicates the presence of preformed 
donor-specific anti-HLA class I antibodies and is usually predictive 
of an acute vasculitic event termed hyperacute rejection. This finding 
represents the only widely accepted absolute immunologic contrain­
dication for kidney transplantation. Recently, an increasing number of 
tissue-typing laboratories have shifted to a more sensitive flow cyto­
metric crossmatch assay, which detects the presence of anti-HLA IgG 
antibodies that are not necessarily detected on a cytotoxic crossmatch 
assay and may not be an absolute contraindication to transplantation. 
The known sources of sensitization are blood transfusion, a prior 
transplant, pregnancy, and less commonly, vaccination or infection.
Preformed anti–class II (HLA-DR and -DQ) antibodies against the 
donor also carry a higher risk of graft loss, particularly in recipients 
who have suffered early loss of a prior kidney transplant. B lympho­
cytes (again, used for convenience), which express both class I and 
class II HLA, are used as a surrogate target in these assays. Some nonHLA antigens restricted in expression to endothelium and monocytes 
have been described, but their clinical relevance is not well established. 
A series of minor histocompatibility antigens do not elicit antibodies, 
and sensitization to these antigens is detectable only by cytotoxic T cells, 
an assay too cumbersome for routine use. Recent studies revealed the 
importance of “eplet” matching in antigen recognition. Eplets are short 
sequences of polymorphic amino acids on the surface of HLA antigens, 
recognized by HLA antibodies, and can be shared among different 
HLA antigens. Especially in class II HLA DQ loci, eplet mismatches are 
shown to be important risk factors for acute rejection.
Desensitization prior to transplantation by reducing the level of anti­
donor antibodies utilizing plasmapheresis and/or the administration of 
pooled immunoglobulin (IV immunoglobulin [IVIG]) has been useful 
in reducing the risk of hyperacute rejection following transplantation. In 
addition, kidney paired donation programs where living donor kidneys 
are swapped so each recipient receives a compatible transplant organ are 
increasingly popular to transplant presensitized candidates safely.
IMMUNOLOGY OF REJECTION
Both T cell–mediated and antibody-mediated effector mechanisms can 
play roles in kidney transplant rejection.
T cell–mediated rejection is caused by recipient T lymphocytes that 
respond to donor HLA antigens expressed within the transplanted 
TCR
Indirect Pathway
Direct Pathway
MHC II
Tfh
CD4 T Cell
Allogeneic peptide
Th1
Plasma Cell 
Self APC
Th2
CD4 T Cell
Th17
CD4 
MHC I 
CD8 T Cell
Allogeneic APC 
CD8
FIGURE 325-1  Recognition pathways for major histocompatibility complex (MHC) antigens. Graft rejection is initiated by CD4 helper T lymphocytes (TH) having antigen 
receptors that bind to specific complexes of peptides and MHC class II molecules on antigen-presenting cells (APC). In transplantation, in contrast to other immunologic 
responses, there are two sets of T-cell clones involved in rejection. In the direct pathway, the class II MHC of donor allogeneic APCs is recognized by CD4 TH cells that bind 
to the intact MHC molecule, and class I MHC allogeneic cells are recognized by CD8 T cells. The latter generally proliferate into cytotoxic cells (TC). In the indirect pathway, 
the incompatible MHC molecules are processed into peptides that are presented by the self-APCs of the recipient. The indirect, but not the direct, pathway is the normal 
physiologic process in T-cell recognition of foreign antigens. Once TH cells are activated, they proliferate and, by secretion of cytokines and direct contact, exert strong 
helper effects on macrophages, TC, and B cells. (Courtesy of Andrew Badoui and Nadim Al Rahy.)

organ. CD4+ lymphocytes respond to class II (HLA-DR) incompatibility 
by proliferating and releasing proinflammatory cytokines that augment 
the proliferative response of the immune system. CD8+ cytotoxic lym­
phocytes respond primarily to class I (HLA-A, -B) antigens and mature 
into cytotoxic effector cells that cause organ damage through direct con­
tact and lysis of donor target cells. Full T-cell activation requires not only 
T-cell receptor binding to the alloantigens presented by self or donor 
HLA molecules (known as indirect and direct presentation, respectively) 
but also engagement of costimulatory molecules such as CD28 
on T cells and CD80 and CD86 ligands on antigen-presenting 
cells (Fig. 325-1). Signaling through both of these pathways induces 
activation of the kinase activity of calcineurin, which, in turn, activates 
transcription factors leading to upregulation of multiple genes, includ­
ing interleukin (IL) 2 and interferon γ. IL-2 signals through the target 
of rapamycin (TOR) to induce cell proliferation in an autocrine fashion.

Antibody-mediated rejection is caused by circulating antibodies 
against donor antigens. After transplantation, donor-derived antigens 
are delivered to the recipient’s draining lymph nodes and activate an 
alloimmune response. A subset of CD4+ T cells called follicular helper 
T cells (Tfh) are activated and promote differentiation of B cells into 
antibody-secreting plasma cells. Plasma cells produce donor-targeting 
antibodies against HLA and non-HLA antigens, which can deposit 
in allograft kidney and cause injury via complement-dependent and 
independent mechanisms. C4d deposition in peritubular capillaries 
and glomerular basement membrane is a footprint of complement acti­
vation and is one of the diagnostic criteria of antibody-mediated rejec­
tion, together with the presence of circulating donor-specific antibody.
CHAPTER 325
Kidney Transplantation
IMMUNOSUPPRESSIVE TREATMENT
Kidney transplant recipients need to take immunosuppressive drugs 
for life, except identical twins or simultaneous bone marrow–kidney 
transplant recipients. Currently clinically available immunosuppres­
sive therapies suppress all immune responses nonspecifically, includ­
ing those to exogenous pathogens (bacteria, viruses, and fungi) and 
even malignant tumors, and tend to spare memory immune responses. 
Immunosuppressive agents are divided into induction and mainte­
nance agents. Those currently in clinical use are listed in Table 325-3.
■
■INDUCTION THERAPY
Induction therapy is given to most kidney transplant recipients in the 
United States at the time of transplant to reduce the risk of early acute 
rejection and to minimize or eliminate the use of either steroids or 
B Cell Activation 
Naïve B Cell 
Cytokine
Production
Antibody Mediated
Rejection
GzmB 
Cellular Rejection
and Organ Damage
CD8 Activation 
Cytotoxic CD8 T Cell 
Perforin 
Attack on Target Cells

TABLE 325-3  Maintenance Immunosuppressive Drugs
AGENT
PHARMACOLOGY
MECHANISMS
SIDE EFFECTS
Glucocorticoids
Increased bioavailability with 
hypoalbuminemia and liver disease; 
prednisone/prednisolone generally used
Binds cytosolic receptors and heat shock proteins. 
Blocks transcription of IL-1, -2, -3, -6, TNF-α, and 
IFN-γ
Cyclosporine (CsA)
Lipid-soluble polypeptide, variable 
absorption, microemulsion more 
predictable
Trimolecular complex with cyclophilin and 

calcineurin → block in cytokine (e.g., IL-2) production; 
however, stimulates TGF-β production
Tacrolimus
Macrolide, well absorbed
Trimolecular complex with FKBP-12 and 

calcineurin → block in cytokine (e.g., IL-2) production; 
may stimulate TGF-β production
Azathioprine
Mercaptopurine prodrug
Hepatic metabolites inhibit purine synthesis
Marrow suppression (WBC > RBC > 
platelets)
Mycophenolate 
mofetil/sodium
Metabolized to mycophenolic acid
Inhibits purine synthesis via inosine monophosphate 
dehydrogenase
Sirolimus/everolimus
Macrolide, poor oral bioavailability
Complexes with FKBP-12 and then blocks p70 S6 
kinase in the IL-2 receptor pathway for proliferation
Belatacept
Fusion protein, intravenous injections
Binds CD80 and CD86, prevents CD28 binding and 
T-cell activation
Abbreviations: FKBP-12, FK506 binding protein 12; IFN, interferon; IL, interleukin; RBC, red blood cells; TGF, transforming growth factor; TNF, tumor necrosis factor; WBC, 
white blood cells.
PART 9
Disorders of the Kidney and Urinary Tract
calcineurin inhibitors and their associated toxicities. Induction therapy 
consists of antibodies that could be depleting or nondepleting.
Depleting Agents 
Antithymocyte globulin (ATG) is a lympho­
cyte-depleting agent. Peripheral human lymphocytes, thymocytes, or 
lymphocytes from spleens or thoracic duct fistulas are injected into 
horses or rabbits to produce antilymphocyte serum, from which the 
immunoglobulin fraction is then separated. Those polyclonal antibod­
ies induce lymphocyte depletion, and the immune system may take 
several months, if not years, to fully recover.
Monoclonal antibodies against defined lymphocyte subsets offer 
a more precise and standardized form of therapy. Alemtuzumab is 
directed against CD52, widely expressed on immune cells such as B 
and T cells, natural killer cells, macrophages, and some granulocytes.
Nondepleting Agents 
Another more selective approach is to target 
the 55-kDa alpha chain of the IL-2 receptor, which is expressed only on 
activated T cells. This approach is used as prophylaxis for (but not treat­
ment of) acute rejection in the immediate posttransplant period and is 
effective at decreasing the early acute rejection rate with few adverse side 
effects.
■
■MAINTENANCE THERAPY
The most frequently used combination is a calcineurin inhibitor (CNI), 
usually tacrolimus, and an antimetabolite, usually mycophenolic acid, 
with or without early steroid withdrawal. Belatacept is a co-stimulatory 
bocking antibody, used as an alternative to long-term toxic CNI therapy. 
The mammalian TOR (mTOR) inhibitors sirolimus and everolimus are 
infrequently used as first-line maintenance immunosuppression.
Antimetabolites 
Azathioprine is a prodrug that must first be acti­
vated to form thioguanine nucleotides. Thiopurine S-methyltransferase 
(TPMT) inactivates azathioprine. Patients with two nonfunctional 
TPMT alleles experience life-threatening myelosuppression when treated 
with azathioprine, and those who carry one nonfunctional TPMT allele 
may also have significant side effects; therefore, the U.S. Food and Drug 
Administration (FDA) recommends TPMT genotyping or phenotyping 
before starting treatment with azathioprine. Azathioprine, which inhibits 
synthesis of DNA and RNA and thereby inhibits T-cell proliferation, 
was the keystone of immunosuppressive therapy in kidney transplant 
recipients until the 1990s but has been replaced by more effective agents. 
Concomitant use of allopurinol is best avoided and, if used, very care­
fully monitored, owing to inhibition of xanthine oxidase.
Mycophenolate mofetil and mycophenolate sodium, both of which 
are metabolized to mycophenolic acid, are now used in place of 
azathioprine based on superior efficacy. Mycophenolic acid has a 
similar mode of action as azathioprine and is associated with a mild 
degree of gastrointestinal toxicity but less bone marrow suppression.

Hypertension, glucose intolerance, 
dyslipidemia, osteoporosis
Nephrotoxicity, hypertension, dyslipidemia, 
glucose intolerance, hirsutism/hyperplasia 
of gums
Similar to CsA, but hirsutism/hyperplasia of 
gums unusual, and diabetes more likely
Diarrhea/cramps; dose-related liver and 
marrow suppression is uncommon
Hyperlipidemia, thrombocytopenia
Posttransplant lymphoproliferative disease 
(PTLD)
Steroids 
Glucocorticoids are important adjuncts to immunosup­
pressive therapy and used as both induction and maintenance ther­
apy. In general, methylprednisolone 250–500 mg is given immediately 
before or at the time of transplantation, and the dose is tapered to 20 mg 

within a week. The side effects of the glucocorticoids, particularly 
impairment of wound healing and predisposition to infection, make 
it desirable to taper the dose as rapidly as possible in the immediate 
postoperative period. Early discontinuation or avoidance of steroids 
is common to avoid long-term adverse effects on bone, skin, and glu­
cose metabolism. Most patients whose renal function is stable after 
6 months or a year do not require large doses of prednisone; mainte­
nance doses of 5–10 mg per day are the rule. A major effect of steroids 
is preventing the release of IL-6 and IL-1 by monocytes-macrophages.
Calcineurin Inhibitors 
Cyclosporine is a fungal peptide with potent 
immunosuppressive activity. It acts on the calcineurin pathway to inhibit 
transcription of IL-2 and other proinflammatory cytokines, thereby inhib­
iting T-cell proliferation. It works synergistically with glucocorticoids and 
mycophenolate. Among its toxic effects (nephrotoxicity, hepatotoxicity, 
hirsutism, tremor, gingival hyperplasia, and diabetes), nephrotoxicity 
presents a serious management problem and is further discussed below.
Tacrolimus (FK506) is a fungal macrolide that has the same mode of 
action as cyclosporine as well as a similar side effect profile; it does not, 
however, produce hirsutism or gingival hyperplasia; in contrast, it can 
be associated with hair loss. Posttransplant diabetes mellitus more com­
monly occurs with tacrolimus. An extended-release formulation of tacro­
limus is now available and is given once daily. Owing to its nephrotoxicity 
and narrow therapeutic window, the drug level of CNIs should be moni­
tored, and drug–drug interactions should be carefully examined. Antibi­
otics and antifungals (e.g., erythromycin, ketoconazole, fluconazole) and 
nondihydropyridine calcium channel blockers (e.g., diltiazem, verapamil) 
inhibit the activity of cytochrome P450 C3A enzyme and cause elevated 
levels of CNIs. On the other hand, antiepileptics, such as phenytoin and 
carbamazepine, increase metabolism, resulting in lower levels.
mTOR Inhibitors 
Sirolimus (previously called rapamycin) is 
another fungal macrolide but has a different mode of action from 
tacrolimus; i.e., it inhibits T-cell growth factor signaling pathways, pre­
venting the response to IL-2 and other cytokines. Sirolimus can be used 
in conjunction with cyclosporine or tacrolimus, or with mycophenolic 
acid, to avoid the use of CNIs.
Everolimus is another mTOR inhibitor with similar mechanism of 
action as sirolimus but with better bioavailability. mTOR inhibitors are 
modestly tolerated and are associated with gastrointestinal disturbance, 
stomatitis, mucositis, and pneumonitis. Poor wound healing associ­
ated with mTOR inhibitors makes them less preferable agents during 
the perisurgical period. While the PI3K-mTOR is the most commonly

mutated cellular pathway in malignant cells, mTOR inhibitors have 
been used more frequently in transplant patients who develop cancers, 
in particular recurrent skin cancers.
Belatacept 
Belatacept is a fusion protein composed of the Fc frag­
ment of human IgG1 immunoglobulin and the extracellular domain of 
cytotoxic T-lymphocyte associated protein 4 (CTLA-4). It binds to its 
costimulatory ligands (CD80 and CD86) on antigen-presenting cells, 
interrupting their binding to CD28 on T cells. This inhibition leads 
to T-cell anergy and apoptosis. Belatacept is FDA approved for kidney 
transplant recipients and is given monthly as an intravenous infusion. 
The 7-year follow-up of the Belatacept Evaluation of Nephroprotec­
tion and Efficacy as First-Line Immunosuppression Trial (BENEFIT) 
showed improved patient and graft survival for the belatacept-treated 
group compared to patients treated with cyclosporine, despite shortterm risks of higher rates of acute rejection.
CLINICAL COURSE AND MANAGEMENT 
OF THE RECIPIENT
Adequate hemodialysis should be performed within 48 h prior to 
the surgery as needed to control serum potassium to prevent cardiac 
arrhythmias. During the transplantation surgery, the kidney allograft 
is usually placed in the recipient’s iliac fossa using a retroperitoneal 
approach. An anastomosis is made between donor renal artery and 
recipient external iliac artery and donor renal vein to recipient external 
Recipient high %PRA (sensitized)
Recipient with prior transplant
Recipient with autoimmune GN 
Donor cold ischemia time >24 h or
Donor age >60 years or
Donor with high KDPI
High risk
Low risk
Antithymocyte globulin induction
Steroids, mycophenolic acid
Calcineurin inhibitor (a few days after)
Persistent allograft dysfunction
Delayed graft function/HD support
Good urine output
Improvement in Cr 
Allograft biopsy
Acute rejection
No rejection
Adjust CNI dose.
Supportive care (BP control, fluid) 
Outpatient follow-up
FIGURE 325-2  A typical algorithm for early posttransplant care of a kidney recipient. If any of the recipient or donor “high-risk” factors exist, more aggressive management 
is called for. Low-risk patients can be treated with a standard immunosuppressive regimen with no or less-potent induction therapy (e.g., basiliximab). Patients at higher 
risk of rejection or early ischemic transplant dysfunction are often induced with an antithymocyte globulin to provide more potent early immunosuppression or to spare 
calcineurin use in the immediate posttransplant period. When there is early transplant dysfunction, prerenal, obstructive, and vascular causes must be ruled out by 
ultrasonographic examination. The panel reactive antibody (PRA) is a quantitation of how much antibody is present in a candidate against a panel of cells representing the 
distribution of antigens in the donor pool. BP, blood pressure; CNI, calcineurin inhibitor; Cr, creatinine; DM2, type 2 diabetes; GN, glomerulonephritis; HD, hemodialysis; HTN, 
hypertension; KDPI, Kidney Donor Profile Index.

iliac vein. The donor ureter is anastomosed to the recipient bladder 
mucosa. Native kidney nephrectomy is rarely performed except in the 
case of an extremely enlarged polycystic kidney or chronic pyelone­
phritis. In many cases, especially after living kidney transplantation, 
the allograft starts to produce urine immediately after anastomosis. The 
allograft often has some degree of acute tubular injury due to ischemia, 
which accounts for postoperative diuresis. Large amounts of sodium, 
potassium, and water may be lost postoperatively, which requires close 
monitoring and replacement. The recipient’s serum creatinine should 
start to fall as the allograft starts to function, and recovery usually 
occurs within 2 weeks, although periods as long as 6 weeks have 
been reported. Slow recovery or oliguria should prompt an allograft 
biopsy because superimposition of rejection on acute tubular injury 
is common and difficult to distinguish without an allograft biopsy. 
Induction immunosuppression therapy and maintenance steroids and 
antimetabolites start on the day of surgery, and it is usually safe to delay 
introduction of a CNI for a few days if a lymphocyte-depleting induc­
tion agent is used. Figure 325-2 illustrates a typical algorithm followed 
by transplant centers for early posttransplant management of recipients 
at high or low risk of early renal dysfunction.

■
■MANAGEMENT OF REJECTION
Early diagnosis of rejection allows prompt institution of therapy to 
preserve allograft function and prevent irreversible damage. Clinical 
CHAPTER 325
Recipient PRA <10% (unsensitized)
Recipient first transplant, or >65 years old
Original disease non-immune related (DM2, HTN)
Kidney Transplantation
Living donor
Donor cold ischemia time <12 h or
Donor age 15–35 years old 
Basiliximab induction
Steroids, mycophenolic acid
Calcineurin inhibitor (day 1–2)
Good urine output
Improvement in Cr
--> Outpatient follow-up 
Adjust CNI dose.
If kidney function remains inadequate or low. 
IV steroid (methylprednisolone, 0.5–1 g/d × 3 days), or
antithymocyte globulin

evidence of rejection is rarely characterized by fever, swelling, and 
tenderness over the allograft. Rejection may present only with a rise 
in serum creatinine, with or without a reduction in urine volume. The 
focus should be on ruling out other causes of functional deterioration, 
such as acute tubular injury, calcineurin toxicity, BK nephropathy, and 
recurrent glomerular diseases.

Doppler ultrasonography is useful in ascertaining changes in the 
allograft vasculature and in blood flow. Thrombosis of the renal vein 
occurs rarely; it may be reversible if it is caused by technical factors 
and intervention is prompt. Diagnostic ultrasound is also helpful in 
identifying urinary obstruction or the presence of perirenal collections 
of urine (urinoma), blood (hematoma), or lymph (lymphocele).
Allograft biopsy is the gold standard for diagnosis of acute T cell–
mediated and antibody-mediated rejection. Acute T cell–mediated 
rejection is diagnosed by the presence of immune cell infiltration in 
the interstitial, tubular, or vascular compartments, according to the 
Banff classification. Treatment of T cell–mediated rejection involves 
a high-dose steroid, e.g., IV administration of methylprednisolone, 
500–1000 mg daily for 3 days. Failure to respond is an indication for 
antibody therapy, usually with ATG.
Evidence of antibody-mediated rejection is present when endothe­
lial injury and deposition of complement component C4d is detected in 
peritubular capillaries. This is usually accompanied by detection of the 
circulating donor-specific antibody in the recipient’s blood. Treatment 
of antibody-mediated rejection remains a challenge, and aggressive use 
of plasmapheresis, IVIG, anti-CD20 monoclonal antibody (rituximab) 
to target B lymphocytes, and bortezomib to target antibody-producing 
plasma cells is indicated. Recently, noninvasive biomarkers such as cir­
culating donor-derived cell-free DNA, urine chemokine markers (e.g., 
CXCL9), and characterization of the urine exosome have been used 
as adjunct diagnostic markers for rejection. Future studies to identify 
prognostic, noninvasive biomarkers that predict response to therapy, 
that risk stratify, and that provide personalized immunosuppression 
strategies will be needed.
PART 9
Disorders of the Kidney and Urinary Tract
■
■MANAGEMENT OF CHRONIC COMPLICATIONS
Cardiovascular events (29%), infection (18%), and malignancy (17%) 
are the major causes of death in kidney transplant recipients. Typi­
cal time courses of opportunistic infections after transplantation are 
shown in Table 325-4.
The signs and symptoms of infection may be atypical due to immu­
nosuppression, which makes diagnosis challenging. In addition to 
commensal infections, opportunistic infections should be considered 
based on the clinical presentation. Diagnostic measures such as culture 
(blood, urine, drain fluids), viral load in plasma, and imaging (allograft 
ultrasound and computed tomography [CT]) should be obtained. 
Overall therapy involves adequate source control, anti-microorganism 
therapy, and reduction of immunosuppression.
Pneumocystis jirovecii is a rare but critical opportunistic infec­
tion (Chap. 227). Aggressive diagnostic procedures, includ­
ing transbronchial and open-lung biopsy, are frequently indicated. 
TABLE 325-4  The Most Common Opportunistic Infections in Renal 
Transplant Recipients
Peritransplant (<1 month)
Late (>6 months)
  Wound infections
  Aspergillus
  Herpesvirus
  Nocardia
  Oral candidiasis
  BK virus (polyoma)
  Urinary tract infection
  Herpes zoster
Early (1–6 months)
  Hepatitis B
  Pneumocystis carinii
  Hepatitis C
  Cytomegalovirus
 
  Legionella
 
  Listeria
 
  Hepatitis B
 
  Hepatitis C
 

Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of 
choice; amphotericin B has been used effectively in systemic fungal 
infections. Prophylaxis against P. jirovecii with daily low-dose TMPSMX for 6 months is effective. Involvement of the oropharynx with 
Candida (Chap. 222) may be treated with local nystatin. Tissueinvasive fungal infections require treatment with systemic agents such 
as fluconazole or one of the newer antifungal agents. Aspergillus 
(Chap. 223), Nocardia (Chap. 179), and especially cytomegalovirus 
(CMV) (Chap. 200) infections also occur.
CMV infection is a serious complication after kidney transplanta­
tion associated with increased morbidity and mortality. While the 
seronegative recipients of seropositive donors are at the highest risk, 
presentation varies from asymptomatic CMV viremia to a systemic 
syndrome (fever, leukopenia) and tissue-specific manifestation (hepa­
titis, gastroenteritis, and retinopathy). Plasma viral load and a rise 
in IgM antibodies to CMV are diagnostic. Valganciclovir has proved 
effective in both prophylaxis and treatment of CMV disease. Acyclovir 
is an effective therapy for herpes simplex virus infections.
BK virus is a latent polyomavirus that lies dormant in the kidney 
and urothelial tract and can be activated in the setting of immunosup­
pression. Reactivation of BK, if left untreated, will lead to progressive 
fibrosis and loss of the graft within 1 year in most cases. However, as 
risk of reactivation of BK infection is associated with the overall degree 
of immunosuppression, in most cases, BK infection can be managed 
by regular testing of BK viral load and judicious reduction of mainte­
nance immunosuppression. Renal biopsy can be useful in examining 
for the presence of interstitial nephritis, tubular cytopathic changes of 
BK nephropathy, and viral antigens in the allograft. In difficult to treat 
cases beyond reduction in immunosuppression, a variety of therapies 
including leflunomide, cidofovir, and quinolone antibiotics (which are 
effective against polyoma helicase) and IVIG have been tried but with 
inconsistent results.
■
■CHRONIC LESIONS OF THE 
TRANSPLANTED KIDNEY
Although current 1-year transplant survival is excellent, most recipi­
ents experience a progressive decline in kidney function over time 
thereafter. Chronic renal transplant dysfunction can be caused by 
chronic active antibody-mediated rejection, recurrent glomerular 
disease, hypertension, CNI nephrotoxicity, secondary focal glomeru­
losclerosis, or a combination of these pathophysiologies. Chronic 
vascular changes with intimal proliferation and medial hypertrophy 
are commonly found. Control of systemic and intrarenal hypertension 
with calcium channel blockers is thought to have a beneficial influence 
on the rate of progression of chronic allograft dysfunction. Kidney 
allograft biopsy can distinguish subacute cellular rejection from recur­
rent disease or secondary focal sclerosis.
MALIGNANCY
The incidence of tumors in patients on immunosuppressive therapy is 
5–6%, or ~100 times greater than that in the general population in the 
same age range. The most common lesions are cancer of the skin and 
lips. Hence, surveillance for skin cancers and protection from ultra­
violet radiation are necessary. Solid organ transplant recipients are at 
higher risk to develop posttransplant lymphoproliferative disease, most 
frequently seen early (<1 year) or late (7–10 years) after transplanta­
tion. Most cases are associated with Epstein-Barr virus infection, and 
the prognosis is poor. The overall malignancy risks are increased in 
proportion to the total immunosuppressive load administered and the 
time elapsed since transplantation. Treatment of cancer after transplant 
involves the reduction of immunosuppression, surgery, conventional 
cytotoxic chemotherapy, and radiotherapy. Cancer immunotherapy 
is associated with a high risk of allograft rejection (30–40%), and the 
multidisciplinary risk-benefit discussion should be made before the 
initiation of therapy.
■
■OTHER COMPLICATIONS
Both chronic dialysis and renal transplant patients have a higher 
incidence of death from myocardial infarction and stroke than the