Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5258_Библиотеки_им_академика_М_И_Перельмана.pdf
56
Medicaid Services included referral for transplantation as Percent of Prevalent
Patients Waitlisted (PPPW) as a quality metric for dialysis facilities [5–7].
The rst successful transplantation of a kidney from one human to another was
performed in 1954 by Joseph E. Murray at the Peter Bent Brigham Hospital in
Boston, MA. The left kidney was surgically removed from 23-year-old Ronald
Herrick and implanted in his identical twin brother, Richard Herrick, who was suf-
fering from kidney failure. Upon completion of the surgical anastomosis the surgi-
cal team “removed the clamps on the vessels and Richard’s blood began to ow into
his new organ…urine began owing briskly” [8]. Richard’s condition improved
dramatically within the rst week after surgery and he went on to live for another 9
years with his brother’s kidney before dying of a heart attack in 1963.
Since then, almost 600,000 kidney transplants have been performed in the
USA.Kidney transplants account for nearly 60% of all solid organ transplantations
performed in the last 30years, and in 2023 alone 27,332 kidney transplants were
performed in the USA [9]. In a typical year more than two-thirds of the transplanted
kidneys come from deceased donors, with the remainder coming from living donors
either related or unrelated to the recipient.
The increasing number of kidney transplantations performed, combined with
improvements in post-transplant allograft and patient survival, have stretched the
available infrastructure at kidney transplant centers, such that the long-term care of
kidney transplant recipients has largely shifted to a multidisciplinary team.
Accordingly, it is common practice for patients to be followed exclusively by the
transplant center for the rst 3–6months after surgery, after which the majority of
care is transitioned to the general nephrologist and primary care provider, both of
whom will play a critical role in maintaining the function of the kidney allograft and
the well-being of the patient in the years that follow. It is therefore essential that
primary care providers be familiar with the unique issues and specialized care needs
of kidney transplant recipients.
4.1.2 Pre-transplant Course
While this book focuses on the care of solid organ transplant recipients after trans-
plantation, the pre-transplant clinical history is important to review.
4.1.2.1 Indication forKidney Transplantation
The optimal timing for kidney transplantation remains uncertain. To be eligible for
a transplant, a person must experience a progressive and irreversible decline in kid-
ney function. In the USA, candidates typically qualify for kidney transplantation
when their estimated glomerular ltration rate (eGFR) drops to 20mL/min/1.73m
2
or lower, or if they are undergoing chronic dialysis. Nephrologists often refer
patients for pre-transplant evaluation when the eGFR falls below 30mL/min/1.73m
2
,
B. Boonpheng and I. C. De Castro
57
particularly in cases of evident kidney function decline. This proactive approach
allows for thorough evaluation and the management of any relative contraindica-
tions. Additionally, early referral increases the likelihood that patients can receive a
transplant before they require dialysis, ultimately improving their outcomes and
quality of life.
The most common causes of ESKD in the USA are diabetes and hypertension,
followed by glomerulonephritis, obstructive nephropathy, cystic kidney disease,
and other less common etiologies [1]. While it is always preferable to make a spe-
cic diagnosis, in some cases, the underlying cause of disease is unknown, as a
patient may present to medical care with late-stage disease, a diagnostic workup
fails to elucidate a cause, or a kidney biopsy cannot be obtained. Unlike most other
solid organ transplants, the native kidneys are typically not explanted to yield a
pathologic diagnosis. Nevertheless, the original etiology of kidney failure is usually
known prior to transplantation and has prognostic signicance for the kidney trans-
plant recipient. The underlying diagnosis may cause other organ system involve-
ment (for example, cystic disease can involve the liver), and it may recur in the
kidney allograft (for example, C3 Glomerulonephritis, FSGS, IgA Nephropathy,
and so on) [10, 11].
4.1.2.2 Pre-Transplant Treatment
Most patients who undergo kidney transplant are receiving treatment with dialysis
at the time of transplant, although a small percentage may receive pre-emptive
transplantation prior to dialysis initiation. The following information is helpful
to obtain:
• Pre-transplant dialysis: Both the number of years spent on dialysis prior to trans-
plant, as well as the dialysis modality—hemodialysis or peritoneal dialysis—
have prognostic implications as it relates to post-transplant cardiovascular risk
and overall mortality [12]. Increased time on dialysis before transplantation is
associated with decreased patient and graft survival.
• Dialysis access: Patients who were previously on hemodialysis may still have
vascular access, such as an arteriovenous graft or stula, which can develop com-
plications over time even when not being used routinely for hemodialysis.
4.1.2.3 Waiting List
After placement on the waiting list, the average wait time for a deceased donor kid-
ney transplant in the USA is 3.6years. However, there is considerable variability
between different regions of the country [9]. Factors other than geography can also
inuence wait time, including recipient blood type and immune system sensitiza-
tion [13]. Wait time for living donor kidney transplantation is typically much less,
as it relies solely on the availability of a suitable donor.
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
58
4.1.2.4 Allocation
For other solid organ transplants, there exists no mechanical support system equiva-
lent to dialysis. Therefore, organ allocation is prioritized based on need (severity of
disease). For kidney transplants, however, deceased donors are allocated based pri-
marily on time, such that the more time a potential recipient accrues on the waiting
list the more likely those potential recipients are to be transplanted [14].
• Reducing inequality: In the USA, changes were made to the national kidney
allocation system in 2014, in an attempt to address several systemic inequalities
in the prior system [15]. Priority is now given to patients with sensitized immune
systems for whom it can be difcult to nd a suitable donor match. This has led
to substantial improvements in rates of transplantations for highly sensitized
individuals [16]. As late referral to a nephrologist is associated with reduced
access to kidney transplantation [17], the new system now retroactively gives
waitlist credit for time spent on dialysis prior to transplant referral, which has
helped to improve transplant rates for ethnic and racial groups that have histori-
cally had decreased access to care and decreased rates of timely transplant refer-
ral [18].
• Longevity matching: Not every donated kidney has the same projected longevity.
In order to allocate kidneys deemed to be of higher quality to recipients with the
longest post-transplant life expectancy, every donor is assigned a kidney donor
prole index (KDPI) score which attempts to quantify how long an organ from
that donor is expected to function, and, similarly, each recipient is assigned an
estimated post-transplant survival (EPTS) score.
4.1.3 Anatomy
• Location: Kidney transplantation is a heterotopic procedure in which the native
kidneys are left in place. Recipient nephrectomy is rarely performed and is typi-
cally considered in cases of severe uncontrolled hypertension, large symptomatic
polycystic kidneys, or recurrent kidney infections. The kidney allograft is placed
in the extraperitoneal iliac fossa. Occasionally, as in instances in which the
allograft is too large to be easily placed in the pelvis, the kidney may be implanted
intraperitoneally.
• Anastomoses (Fig.4.1): In the conventional approach, a curvilinear incision is
made in the right or left lower quadrant of the recipient and the iliac vessels are
exposed. The right side is often preferred because the right iliac vessels are more
supercial and thus more easily accessed. End-to-side anastomoses are per-
formed between the donor renal vein and the recipient’s external iliac vein, fol-
lowed by the donor renal artery and the recipient’s external iliac artery. Less
commonly, the surgeon may perform an end-to-side anastomosis between the
B. Boonpheng and I. C. De Castro
59
Fig. 4.1 Kidney transplant
anastomoses
donor renal artery and the recipient’s common iliac artery, or an end-to-end anas-
tomosis with to the recipient’s internal iliac artery. The ureter is then implanted
to the bladder. Although practice varies, many centers place a double-J ureteral
stent to reduce pressure on the ureteral anastomosis in the early post-operative
period, and then retrieve it 2–8weeks after surgery. A transplant from a deceased
donor may include an aortic patch along with the renal artery—this longer length
of donor vasculature can facilitate an easier anastomosis shown is the end-to-side
anastomosis of the donor renal vein to the recipient iliac vein or its branch (blue),
the donor renal artery to the recipient iliac artery or its branch (red). (The exter-
nal iliac vein and artery is commonly used; anastomoses may vary depending on
a patient’s anatomy.) The donor ureter is implanted into the bladder (brown).
From Forsyth JLR, reprinted with permission [19].
• En-bloc Pediatric Kidneys: To address the ongoing organ shortage, kidneys from
small pediatric donors—typically dened as weighing less than 20kg or around
2years of age—are increasingly being transplanted into carefully selected adult
recipients in transplant centers with technical expertise. Due to the very small
size of the renal vasculature and concerns about the number and maturity of
functioning nephrons in these donors, a surgical technique known as en-bloc
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
60
Fig. 4.2 En-bloc pediatric kidney—surgical anatomy. Shown here are the end-to-side arterial
anastomosis between the distal aorta of the graft and the external iliac artery, the end-to-side
venous anastomosis between the distal inferior vena cava of the graft and the external iliac
vein of the recipients as well as two uretero-neocystostomy anastomoses. Note that the proxi-
mal stump of the inferior vena cava and the aorta are oversewn. From Spaggiari etal. reprinted
with permission [20]
transplantation has been utilized. This involves transplanting both kidneys from
the same donor, with vascular anastomoses performed using the aortic and infe-
rior vena caval conduits (see Fig.4.2).
En-bloc transplantation requires surgical expertise from both the organ
procurement team and during back-table reconstruction. It is most commonly
performed with pediatric donors weighing less than 10–12kg and recipients
weighing no more than 65–80kg, depending on donor–recipient size match-
ing [21]. Early surgical complications, such as vascular thrombosis and uri-
nary tract complications, are more common; therefore, most recipients are
started on daily aspirin to prevent vascular thrombosis. Despite these chal-
lenges, long-term outcomes have proven excellent, with en-bloc pediatric
kidneys showing rapid growth in the rst few months to nearly adult size and
continuing to grow over the next 3–5years, corresponding with signicant
improvements in kidney function as indicated by eGFR [22, 23].
B. Boonpheng and I. C. De Castro
61
Fig. 4.3 One-year rst cadaveric renal allograft survival and rejection episodes over time. From
Zand [24]. Reprinted with permission. “The time that various immunosuppression medications
were introduced is indicated by their position on the graph.” 6-MP 6 mercaptopurine, ATGAM
horse anti thymocyte globulin, AZA azathioprine, CY-A cyclosporine, FTY720 Fingolimod, MMF
mycophenolate mofetil, OKT3 muromonab-CD
4.1.4 Immunosuppression Regimen
Advances in immunosuppression have been associated with improved graft survival
and reduced rejection. Figure4.3 shows 1-year graft survival, rejection within the
rst year, and introduction of immunosuppression medications over a 45-year period.
Immunosuppression typically occurs in two phases: an induction phase, admin-
istered during the peri-transplant period to avert early rejection, and a maintenance
phase, which continues indenitely to sustain long-term graft function. By attenuat-
ing anti-donor immune response, contemporary immunosuppressive therapies have
signicantly reduced the incidence of acute rejection and altered its natural progres-
sion, thereby enhancing short-term outcomes. However, these improvements in
short-term outcomes have not translated into a substantial increase in long-term
graft survival, which continues to be an Achilles’ heel for transplant nephrology
practice.
4.1.4.1 Induction Immunosuppression inKidney Transplantation
Nearly all kidney transplant recipients require induction immunosuppression to
mitigate the risk of acute rejection in the rst few months after transplant. The
choice of induction regimen considers the recipient’s risk for rejection, infection,
malignancy, predilection to adverse effects from the induction medication and the
transplant center’s preferences. A recipient receiving a two-haplotype match from a
living related donor, which confers substantially less risk of rejection, may require
less initial immunosuppression.
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
62
In general, patients at higher risk for acute rejection tend to be younger, African
American, or have an immunologic prole that confers higher than average rejec-
tion risk such as higher calculated panel reactive antibody (cPRA) or the presence
of preformed donor-specic antibodies (DSA) at the time of transplantation
(Table4.1) [25]. The cPRA is based upon unacceptable HLA antigens to which the
recipient has been sensitized and which, if present in a donor, would represent an
unacceptable risk for the candidate or the transplant program. The cPRA is com-
puted from HLA antigen frequencies among donors in the United and thus repre-
sents the percentage of actual organ donors that express one or more of those
unacceptable HLA antigens [26]. Although useful as an initial immunologic risk
stratication, the main goal of cPRA is to estimate the probability of nding a donor
whom the recipient has no preformed DSA, based on each center’s criteria.
For patients at risk for acute rejection, a common practice is to administer lym-
phocyte depleting antibody therapy. The most common agent used for induction in
the USA is rabbit antithymocyte globulin (rATG). rATG is created by immunizing
rabbits with human thymocytes and then purifying the resultant polyclonal immu-
noglobulins which, when administered to a human recipient, will target T-cells and
cause complement-mediated apoptosis. Protocols differ between centers with
respect to total dosing; the most conventional approach is to administer three doses:
intraoperatively in conjunction with intravenous corticosteroids, followed by subse-
quent doses on post-operative days. Doses may be reduced or held if there is signi-
cant leukopenia, thrombocytopenia or adverse effect, such as transfusion reaction
causing hemodynamic instability, temporarily related to drug administration.
Recipients at lower risk for rejection as well as whose allografts are expected to
function quickly (e.g., living donor kidney transplantation or recipients of excellent
quality kidneys with short ischemia time) or those who cannot receive lymphocyte-
depleting therapy due to clinical contraindications such as prohibitive leukopenia,
thrombocytopenia, hypotension, or having a higher risk for infection or malignancy
are typically administered induction therapy with non-depleting antibodies. The
most common non-lymphocyte depleting drug is basiliximab (Simulect
®
), an anti-
body directed against the IL-2 receptor (CD25). Basiliximab is dosed intraopera-
tively and on post-operative day four.
There is a large and growing body of literature comparing the efcacy of various
induction immunosuppression regimens; a full appraisal of these studies is beyond
Table 4.1 Possible risk factors for acute rejection [25]
Number of human leukocyte antigen (HLA) mismatches
Younger recipient age
Older donor age
African American ethnicity (in the United States)
Panel-reactive antibody (PRA) >30%
Presence of a donor-specic antibody
Blood group incompatibility
Delayed onset of graft function
Cold ischemia time >24h
B. Boonpheng and I. C. De Castro
63
the scope of this chapter. It has been clearly demonstrated that induction with rATG
reduces the rate of acute rejection when compared with no induction, but is also
associated with higher rates of leukopenia, thrombocytopenia and CMV infection
[27, 28]. IL-2 receptor antagonists have also been shown to be superior to placebo
with respect to reducing the risk of acute rejection and allograft failure, but have
been associated with a higher incidence of biopsy-proven, subclinical acute rejec-
tion when compared to other induction agents [29]. rATG appears to be superior to
other forms of induction therapy, including horse-derived antithymocyte globulin
(Atgam
®
), the anti-CD52 humanized, monocolonal antibody alemtuzumab
(Campath
®
), and basiliximab with respect to the risk of acute rejection, particularly
in high-risk individuals [30–32]. Results are less clear with respect to risk for
delayed graft function, long term allograft survival and mortality.
Familiarity with what type and dosage of induction immunosuppression is perti-
nent to primary care practice. While under the primary provider’s care, the patient
may be treated again with rATG if they develop moderate to severe cellular rejec-
tion. The recipients would become intensively immunosuppressed for at least
3months. If they develop moderate to severe antibody-mediated rejection, a various
combination of plasmapheresis, rituximab, IVIg or rATG or other agents such as
anti-IL6 (tocilizumab), anti-complement blockade, or a proteasome inhibitor may
be used—again increasing the net state of immunosuppression for the next
3–6months. Also, it is important to note that the cumulative dose of rATG has been
associated with higher incidence of post-transplant lymphoproliferative disorder
(PTLD) (see Chap. 10) [33]. Repeated exposure to other agents also increase the net
state of immunosuppression leading to higher risk of infection, PTLD or malignancy.
4.1.4.2 Maintenance Immunosuppression inKidney Transplantation
Nearly all kidney transplant recipients need immunosuppressive therapy post-
induction to prevent rejection and allograft loss. Maintenance therapy involves a
combination of immunosuppressive drugs with varying mechanisms of action,
which helps reduce the side effects associated with each class while enhancing
overall effectiveness.
Key Components ofMaintenance Therapy
• The Standard Three-Drug Regimen: Most kidney transplant recipients are treated
with a three-drug regimen consisting of a calcineurin inhibitor (CNI), an anti-
metabolite—most commonly mycophenolate mofetil (MMF, CellCept
®
) or
enteric-coated mycophenolate sodium (MPA, Myfortic
®
)—and a corticosteroid.
In 2022, nearly 70% of patients were maintained on a combination of tacrolimus,
mycophenolate, and a corticosteroid [9] (Fig.4.4).
• Anti-metabolites: Mycophenolate is the most frequently used anti-metabolite,
with gastrointestinal and bone marrow suppression as its main side effects. If
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…
64
Fig. 4.4 Maintenance immunosuppressive regimens in kidney transplant recipients. “From the
OPTN/SRTR 2022 Annual Data Report; Reprinted with permission [9]
gastrointestinal issues are severe, an enteric-coated formulation can be consid-
ered. Azathioprine is occasionally used for patients who cannot tolerate myco-
phenolate and for female recipients contemplating pregnancy due to the
teratogenic risks associated with mycophenolate.
• Calcineurin Inhibitors (CNIs): Calcineurin inhibitors have formed the backbone
of nearly all maintenance immunosuppression regimens for kidney transplant
recipients since the 1980s. Currently, over 90% of kidney transplant recipients
are maintained on tacrolimus-based regimens. Remarkably, the risk of acute
rejection within the rst year is less than 10%, even among patients with higher
baseline immunologic risk [9].
– Tacrolimus versus Cyclosporine
Tacrolimus has almost completely replaced cyclosporine, with 92% of kidney
recipients receiving tacrolimus compared to only 2% on cyclosporine [9].
Although tacrolimus is associated with slightly higher rates of certain side
effects, most prominently neurotoxicity, pancreatic islet beta cell toxicity
leading to new onset diabetes after transplant and certain infections such as
BK virus. These risks are generally thought to be offset by the superiority of
tacrolimus with respect to preservation of allograft function and less intrinsic
nephrotoxicity [34]. Occasionally, a patient who experiences intolerable side
effects from tacrolimus, such as severe neurotoxicity or difcult to control
diabetes, may be switched to cyclosporine as a last resort option after the fail-
ure of switching to extended-release formulation of tacrolimus (Envarsus
®
),
although there is relatively little data to support this practice [35].
– Calcineurin inhibitor dosing
Dosing of tacrolimus or cyclosporine can vary signicantly between patients
due to genetic differences and the presence of other medications, both of
which may affect drug metabolism. In general, the standard immediate- release
tacrolimus is dosed twice daily with serial monitoring of 12-h trough levels.
It is important to note that the oral capsule formulations of immediate- release
tacrolimus in the United States are available in 0.5mg, 1 mg, and 5 mg.
B. Boonpheng and I. C. De Castro
65
Patients may need to take different combinations of these strengths to achieve
their target dosages [36]. For example, a patient might need to take 2.5mg at
8AM and 3mg at 8PM, necessitating the dispensing of both 0.5mg and 1mg
capsules in sufcient quantities. For primary care providers, regular reviews
of the dosages taken, as well as meticulous medication reconciliation, should
be consistently veried and recorded. There are extended-release, once a day
preparations available as capsules (Astagraf XL
®
) and tablets (Envarsus XR
®
).
Specic trough targets may vary depending on factors such as the type of
induction immunosuppression, the risk of rejection related to the patient’s
immunophenotype and the transplant center protocol. A common approach is
to target a trough level of 8—10ng/mL for the rst 3months and then a level
of 5–7ng/mL after 1-year post-transplant. Cyclosporine is available in several
formulations, including non-modied capsules and solutions (Sandimmune
®
and generics), as well as modied capsules and solutions (Neoral
®
, Gengraf
®
,
and generics). It is essential to recognize that these formulations are not bio-
equivalent and therefore cannot be used interchangeably, even within the
same strength. In the USA, 25mg, 50mg, and 100mg strengths are available.
It is also dosed twice daily with serial monitoring of 12-h trough levels [37].
– Calcineurin inhibitor nephrotoxicity
The most common side effect of calcineurin inhibitors that can limit their
long-term use is the development of nephrotoxicity in the kidney allograft
with both acute toxicity by renal vasoconstriction and chronically by promot-
ing brosis [38].
Alternative Immunosuppressive Strategies
• CNI-free and steroid-free protocols
There has been increasing interest in CNI-free and steroid-free protocols to miti-
gate the long-term nephrotoxicity associated with calcineurin inhibitors and the
adverse effects of steroid exposure. Different transplant centers have developed
protocols based on local experience, allowing for personalization according to
each recipient’s risks and preferences. While enthusiasm for steroid-free regi-
mens has waned due to slightly higher rejection risks, they may be suitable for
recipients at lower immunologic risk with conditions such as congenital anoma-
lies or polycystic kidney disease.
The two most common calcineurin-free approaches involve the use of either
mammalian target of rapamycin (mTOR) inhibitors such as sirolimus or everoli-
mus, or belatacept, a selective blocker of T-cell co-stimulation.
• Co-stimulation blockage
Belatacept, a co-stimulation blocker, has emerged as an alternative maintenance
agent due to its favorable side effect prole and its ability to conrm recipient adher-
ence without nephrotoxicity. However, infection risk remains a concern, particularly
in EBV-naïve recipients who are at higher risk for post-transplant lymphoprolifera-
tive disorder (PTLD) [39, 40]. Early trials indicate that while belatacept can lead to
4 Primary Care of the Adult Kidney Transplant and Kidney-Pancreas Transplant…