2. • Diabetes mellitus, hypertension, and
glomerulonephritis are the three leading causes
of end-stage renal disease and account for more
than 70% of patients .
• Patients with medical conditions such as
unstable cardiac disease or recently diagnosed
malignancy, for whom the risk of surgery or
chronic immunosuppression would be greater
than the risks associated with chronic dialysis,
are generally excluded from consideration for
transplantation.
3. • The glomerular filtration rate of a successfully
transplanted kidney may be near normal almost
immediately after transplantation. In some patients,
however, the concentration of standard biochemical
indicators of renal function, such as serum
creatinine and blood urea nitrogen, may remain
elevated for several days.
• take several weeks for other physiologic
complications of ESRD, such as anemia, calcium
and phosphate imbalance, and altered lipid profiles,
to resolve. The renal production of erythropoietin
and 1-hydroxylation of vitamin D may return toward
normal early in the postoperative period
4. • the onset of physiologic effects may be delayed,
continuation of the patient’s pretransplantation
vitamin D, calcium supplementation, and/or
phosphate binders may be warranted. Patients
should be monitored for hypophosphatemia and
hypercalcemia for the first few days to weeks
after kidney transplantation.
5. Pathophysiology of rejection
• Rejection is primarily mediated by activation of
alloreactive T cells and antigen-presenting cells such
as B lymphocytes, macrophages, and dendritic cells.
Acute allograft rejection is caused primarily by the
infiltration of T cells into the allograft, which
triggers inflammatory and cytotoxic effects on the
graft. Complex interactions between the allograft
and cellular cytokines, cell-to-cell interactions,
CD4+ and CD8+ T cells, and B cells ultimately lead
to chronic rejection and graft loss if adequate
immunosuppression is not maintained.
6.
7. Hyperacute rejection
• Hyperacute rejection may be evident within minutes
of the transplantation procedure when preformed
donor-specific antibodies are present in the
recipient at the time of the transplant. It can also be
induced by immunoglobulin G antibodies that bind
to antigens on the vascular endothelium, such as
class I MHC, ABO, and vascular endothelial cell
antigens. Tissue damage can be mediated through
antibody-dependent, cell-mediated cytotoxicity or
through activation of the complement cascade. If
present the ischemic damage to the
microvasculature rapidly results in tissue necrosis.
8. Acute cellular rejection
• can occur at any time during the life of the
allograft. It is mediated by alloreactive T-
lymphocytes that appear in the circulation and
infiltrate the allograft through the vascular
endothelium. After the graft is infiltrated by
lymphocytes, the cytotoxic cells specifically
target and kill the functioning cells in the
allograft. At the same time, local release of
lymphokines attracts and stimulates
macrophages to produce tissue damage through
a delayed hypersensitivity-like mechanism.
9. • is evidenced by an abrupt rise in serum
creatinine concentration of greater than or equal
to 30% over baseline, Hypertension often
worsens during an episode of rejection, and
edema and weight gain are common as a result
of sodium and fluid retention. Symptomatic
azotemia may also develop in severe cases.
• A specific histologic diagnosis can be obtained
via biopsy of the allograft and is often used to
guide rejection therapy. A biopsy specimen with
a diffuse lymphocytic infiltrate is consistent with
acute cellular rejection (ACR).
10. Antibody mediated rejection
• Antibody-mediated rejection (AMR), sometimes referred
to as vascular or humoral rejection, is characterized by
the presence of antibodies directed against HLA antigens
present on the donor vascular endothelium. The
antibodies activate complement, which creates a
membrane attack complex that directly damages the
organ and further attracts inflammatory cells to the
allograft.
• Definitive diagnosis of AMR is based on the presence of
three criteria: presence of donor-specific antibodies,
immunofluorescence staining of C4d deposits in the
peritubular capillaries, and evidence of allograft
dysfunction.
11. • This form of rejection is less common than
cellular rejection and generally occurs in the first
3 months after transplantation. It is associated
with an increased fatality rate .
• An increased risk of humoral rejection is
associated with female gender, elevated PRA,
cytomegalovirus seropositivity, a positive
crossmatch, and prior sensitization to OKT3
(muromonab CD3).
12. Treatment
• to reverse humoral rejection include
plasmapheresis, often in combination with
intravenous immunoglobulin, high-dose
intravenous corticosteroids, antithymocyte
globulin (ATG), bortezomib , rituximab, and
mycophenolate mofetil.
13. Chronic rejection
• the involvement of the humoral immune system
and antibodies in addition of T cells against the
vascular endothelium appear to play a role.
• As a result of the complex interaction of multiple
drugs and diseases over time, it is difficult to
delineate the true nature of chronic rejection.
Unlike acute rejection, chronic rejection is not
reversible with any immunosuppressive agents
currently available.
14. • chronic allograft nephropathy remains the most
common cause of graft loss in the late post-
transplantation period (greater than 1 year).
• The syndrome is characterized in histological terms
as interstitial fibrosis and tubular atrophy (IFTA) of
unknown etiology.
• Factors that contribute to the development of
chronic allograft nephropathy include calcineurin
inhibitor nephrotoxicity, polyomavirus infection,
hypertension, donor-related factors including
ischemia time and undetected kidney disease in the
donor kidney, and recurrence of the primary kidney
disease in the recipient.
15. Acute rejection
• Cytolytic agents are often reserved for those with
corticosteroid-resistant rejection, signs of hemodynamic
compromise (heart), or more severe rejections.
• Other innovative forms of therapy for persistent or intractable
rejection have been investigated, including mycophenolate
mofetil, tacrolimus, low-dose methotrexate, sirolimus, total
lymphoid irradiation, and plasmapheresis and intravenous
immunoglobulin.
• Prophylactic agents such as valganciclovir, nystatin,
trimethoprim-sulfamethoxazole, H2-receptor antagonists or
proton-pump inhibitors, and/or antacids may be added to
minimize adverse effects associated with these intensive
immunosuppression regimens.
16. Induction therapy
• Induction therapy provides a high level of
immunosuppression, at the time of
transplantation, with or without the immediate
introduction of cyclosporine or tacrolimus .
• The rationale for delayed calcineurin inhibitor
administration varies slightly depending on the
type of transplant. In renal transplantation, it is
not being delayed as kidney is susceptible to
nephrotoxic injury .
17. Rejection empiric therapy
• biopsy can be done to ascertain the definitive
diagnosis or the patient may be empirically treated
for rejection. Empiric treatment generally involves
administration of high-dose corticosteroids, usually
500 to 1,000 mg of methylprednisolone
intravenously for one to three doses.
• If rejection is confirmed by biopsy, treatment may
be based on the severity of rejection with polyclonal
and monoclonal antibodies being reserved for
moderate to severe rejections for those patients that
have not responded to a course of corticosteroids.
18.
19. • RATG (Thymoglobulin, Genzyme, Cambridge,
MA).
• Interleukin-2 receptor alpha chain , It is a
type I transmembrane protein present on
activated T cells activated B cells,
some thymocytes
20. Calcineurin Inhibitors
• Cyclosporine and tacrolimus,
• MOA, Calcineurin inhibitors block T-cell proliferation by
inhibiting the production of IL-2 and other cytokines by
T cells .
• Adverse effects :
• The nephrotoxic potential of both drugs is equal and is
often related to the dose and duration of exposure.
Neurotoxicity typically manifests as tremors, headache,
and peripheral neuropathy; occasionally, however,
seizures have been observed. Tacrolimus may be
associated with an increased occurrence of neurologic
complications compared with cyclosporine.
21. • Cyclosporine cause mainly hyperlipidemia and
gingival hyperplasia , hirsutism.
• Tacrolimus manily cause hyperglycemia .
22. Dose
• Initial oral cyclosporine doses range from 8 to 18
mg/kg per day administered every 12 hours.
Higher doses of cyclosporine are used more
commonly in two-drug regimens, whereas lower
doses are part of triple-drug regimens.
• Oral tacrolimus doses usually are in the range of
0.1 to 0.3 mg/kg per day given every 12 hours.
23. • If oral administration is not possible, both CSA
and TAC can be administered intravenously at
approximately one third the oral dosage.
• The usual intravenous dose of cyclosporine is 2
to 5 mg/kg per day, given as a continuous
infusion or as single or twice-daily injection.
• Intravenous tacrolimus doses range from 0.05 to
0.1 mg/kg per day and must be administered by
continuous infusion.
24. Therapeutic drug monitoring
• tacrolimus should be 15 to 20 ng/mL (mcg/L; 18.6
to 24.8 nmol/L) 0 to 1 month after transplantation,
10 to 15 ng/mL (mcg/L; 12.4 to 18.6 nmol/L) 1 to 3
months after transplantation, and 5 to 12 ng/mL
(mcg/L; 6.2 to 14.9 nmol/L) greater than 3 months
after transplantation.36 Blood drug concentrations
should be measured frequently (daily or three times
per week) following initiation of the drug and during
the stabilization period after transplantation. With
time, blood concentrations can be measured less
frequently.
25. Corticosteroids
• MOA : Corticosteroids block cytokine activation
by binding to corticosteroid response elements,
thereby inhibiting IL-1, IL-2, IL-3, IL-6, γ-
interferon, and tumor necrosis factor-
α synthesis . Additionally, corticosteroids
interfere with cell migration, recognition, and
cytotoxic effector mechanisms.
26. Dosing
• An intravenous corticosteroid, commonly high-dose
methylprednisolone (250-1,000 mg), is given at the
time of transplantation. The dose of
methylprednisolone is tapered rapidly and usually
discontinued within 3 to 5 days when oral
prednisone is initiated.
• Prednisone doses are tapered progressively over
several weeks to months, depending on the type of
additional immunosuppression and organ function.
It is preferable to administer corticosteroids
between 7 AM and 8 AM to mimic the body’s diurnal
release of cortisol.
27. • The first-line therapy for the treatment of acute
graft rejection is high-dose intravenous
methylprednisolone (250-1,000 mg) daily for 3
days or oral prednisone (200 mg) daily for 3
days. Doses of oral prednisone are then tapered
over 5 days to 20 mg/day.
28. Antimetabolite
• they prevent proliferation of lymphocytes.
Azathioprine, mycophenolic acid .
• Because MPA is unstable in an acidic environment,
mycophenolate mofetil acts as a prodrug that is
readily absorbed from the GI tract, after which it is
rapidly and completely converted to MPA in the
liver.
• side effects are related to the GI tract, including
nausea, vomiting, diarrhea, and abdominal pain,
leukopenia and anemia, particularly with higher
doses.
29. • MPA is administered in two divided doses given
every 12 hours. The total daily dose for kidney
and liver transplants is typically 2 g/day for
mycophenolate mofetil and 1.44 g/day for
mycophenolate sodium.
• Mycophenolate mofetil is currently available in
both oral and intravenous formulations.
Although intravenous administration of equal
doses closely mimics oral administration, the
two cannot be considered bioequivalent.
• Mycophenolate sodium is only available as an
oral formulation.
30. • Patients with trough MPA levels between 1.0 and 3.5
mcg/mL (mg/L; 3.1-10.9 μmol/L) experienced fewer
significant complications.
• Unbound concentrations as opposed to total MPA
concentrations have been suggested in patients with liver
disease, hypoalbuminemia, and severe infection.
• Trough concentrations may not be accurate in
predicting total drug exposure during a 12-hour interval
and thus AUC monitoring has been proposed as the most
appropriate measure of MPA drug exposure to guide
therapy.
• Better outcomes are associated with MPA AUC
concentrations of greater than 42.8 mcg/mL (mg/L; 134
μmol/L) per hour (by HPLC),52 although a reference
range of 30 to 60 mcg/mL (mg/L; 94 to 188 μmol/L) has
been proposed.
31. • Azathioprine and biological agents , such as
rituximab , Alemtuzumab , Basiliximab .
Notes de l'éditeur
Standard formulas used to predict drug dosing rely on a stable serum creatinine and may be inaccurate immediately following transplantation
A multidrug approach is rational from an immunomechanistic viewpoint because the many agents have overlapping and potentially synergistic mechanisms of action. Furthermore, the use of a multidrug immunosuppression regimen may allow the use of lower doses of individual agents, thus reducing the severity of dose-related adverse effects
monitoring calcineurin inhibitor trough blood concentrations, reducing the calcineurin inhibitor dosage if the vasoconstrictive effects are problematic, and avoiding other nephrotoxins (eg, aminoglycosides, amphotericin B, and nonsteroidal antiinflammatory agents) when possible