Kidney Transplant Part 1 Flashcards
The allograft expresses class I and Class II MHC molecules that differ from the recipient’s MHC molecules and can directly stimulate recipient T cells
direct allorecognition
donor antigens can be processed and peptide fragments presented by the host MHC molecules on self-APCs, indirectly stimulating recipient T cells
Indirect allorecognition
Ultimate goal of immunosuppression
Induce specific tolerance to the graft
State of unresponsiveness to specific antigens derived from either self or non-self proteins
immune tolerance
plays central role in presenting foreign antigenic peptide molecules to T cells in a way that they can be recognized by the antigen-specific T cell receptors (TCRs)
MHC/HLA
provides the strongest Mixed Lymphocyte Reaction (MLR) stimulues
HLA-DR
target for anti-HLA antibodies involved in antibody mediated rejection
HLA-DQ
recognized only by primed or previously immunized cells
HLA-DP
HLA-A, B, C
Class I HLA
HLA D
Class II HLA
antibodies react with both B and T lymphocytes
Anti-Class I
react with B, but not T , lymphocytes
Anti-Class II
most important in the first 6 months after transplant
HLA-DR matching
effect is during the first 2 years
HLA-B
does not have effect before 3 years
HLA-A
primary and central event that initiates allograft rejection.
T cell recognition of alloantigens on the APCs
recognize processed antigen on MHC class I molecules
CD8 Cytotoxic T cells
on MHC Class II molecules
CD4 Helper T cells
important regulators of rejection, targets of immuntherapy
adhesion molecules
best-characterized costimulatory molecule, expressed on the surface of essentially all CD4+ and 50% of CD8+ peripheral T lymphocytes
CD28
proteins that function for growth, activation and diffferentiation
Cytokines
chemoattractants of inflammatory cells to a site of immune response
chemokines
alloimmune response against the graft, cellular or humoral
Acute rejection
normally in the first 3 months, but can occur anytime
Acute Cellular Rejection
mononuclear cellular interstitial infiltrate, edema and tubulitis
acute cellular rejection
requires CD4+ T cells and preformed anti-HLA; peritubular C4d staining within the allograft; detection of circulating anti-HLA antibodies
Acute humoral rejection
histologic changes of neutrophilic infiltration of the peritubular capillaries;
acute humoral rejection
slow progressive deterioration in kidney function; increasing creatinine, proteinuria, progressive hypertension; tubular atrophy, interstitial fibrosis, fibrous non-intimal thickening of arterial walls
chronic rejection; chronic allograft nephropathy, interstitial fibrosis and tubular atrophy
swollen glomeruli, infiltration by mononuclear cells, mesangial matrix expansion mesangiolysis, splitting of the GBM with subendothelial deposition of electron lucent material
transplant glomerulopathy
C4d staining
antibody mediated injury
modulates immune response by regulating transcription of genes for IL-1, IL-2, IFN alpha, TNF alpha and IL-6
corticosteroids
purine analog, enzymatically converted to 6-mercaptopurine; antimetabolite; incorporated into the DNA, inhibits purine nucleotide synthesis and alteration of RNA synthesis
azathioprine
blocks DNA replication and prevents lymphocyte proliferation after antigenic stimulation
azathioprine
Adverse effects: severe leukopenia, thrombocytopenia, GI disturbances, hepatotoxicity, increased risk for neoplasia
azathioprine
reversible inhibitor of inosine monophosphate dehydrogenase, the rate-limiting enzyme in the de novo synthesis of guanosine nucloetide and nucleosides
mycophenolic acid
main active metabolite of MMF; decreased by CyA, but not by tacrolimus or FK 506
mycophenolic acid glucuronide (MPAG); lower dose if given with tacrolimus
small cyclic peptide of fungal origin; blocks the expression of cytokine genes produced by T cells
cyclosporine
blocks the calcium-dependent component of the TCR signal transduction pathway; inhibits calcineiruin, prevents transcription of gene for IL-2
cyclosporine
macrolide antibiotic produced by fungi, inhibit the phosphatase activity of calcineurin
tacrolimus
adverse effect of cyclosprine
hirsutism, gingival hyperplasia
adverse effect of tacrolimus
alopecia and neurotoxicity
macrolide antibiotic, also binds to same family of FKBP isomerase proteins
-binds to mTOR and prevents phosphorylation of p70- S6 kinase in the CD28 costimulatory and IL-2R signal transduction pathways
sirolimus; mammaliana target of rapamycin inhibitors
blocks T cell proliferation during the late G1 phase of the cell cycle, before S phase; potent inhibitors of vascular endothelial growth factor
mTOR
phagocytic cells, natural killer (NK ) cells,
complement
natural or innate immunity
immune reactants that
specifically recognize foreign molecules or antigens
from the microbial world
adaptive immunity/specific (T and B cells
development of antigen specific clones of T and B
cells but the full force of rejection involves components
of BOTH innate and adaptive immunity
acute rejection
Polyclonal antibody against human T cells, prepared by
immunization of animals (rabbit or horse) with human
lymphoid cells
thymoglobulin
complement dependent lysis in
blood and apoptosis and phagocytosis in peripheral
lymphoid tissue, antibodies against adhesion molecules
thymoglobulin
dose of thymoglobulin
1.5 mkd for 7-14 days for 3 days
Side effects of thymoglobulin
fever, chills, hypotension, cardiovascular; serum sickness after 10-15 days
anti-CD52 for CLL; long lasting depletion of T and B cell lymphocytes
alemtuzumab
chimeric monoclonal antibody;
immunoglobulin G1 antibody directed against the alpha
chain of the IL2 receptor (CD25 antigen) on activated T lymphocytes; inhibits key T lymphocyte proliferation
signaling
basiliximab
dose of basiliximab
30 mg IV on day of KT and day 4 post KT
chimeric , anti CD20, cytolytic
monoclonal antibody; used for PTLD, non Hodgkins lymphoma, CLL, and
rheumatoid arthritis; targets normal B lymphocytes; used in desensitization and treatment of acute humoral rejection
rituxumab
dose of rituximzb
375 mg/m2
more sensitive tissue crossmatching
flow cytometric crossmatch
options for desensitization
high dose IVIG/anti-CD20 vs low dose IVIG/plasmapharesis based
high viscosity, difficult to flush, multi organ transplant, high K
University of Wisconsin
Low K, low viscosity, buffer of histidine
histidine, tryptophan-ketoglutarate (HTK) solution
for living donor KTs with short ischemia time
heparinized lactated ringers with procaine
most common cause of delayed graft function
ischemic ATN
defines a group of recipients with moderate
early graft dysfunction. Serum creatinine level higher than 3 mg/ dL at 1
week posttransplantation
slow graft function
rejection, cyanosis and mottling of the kidney
and anuria occur minutes after the vascular anastomosis is
established
classic hyperacute rejection
Histology: widespread, small vessel endothelial damage and
thrombosis, usually with neutrophils incorporated into the thrombus.
hyperacute rejection
Rejection occurring roughly 2 to 5 days after
transplantation; Occurs in recipients with pre transplantation
sensitization to donor alloantigens; (+) low titer pretransplantation antidonor antibodies; rapid post transplantation antibody production by memory B cells
accelerated rejection
Sudden anuria ; absent arterial and venous blood flow to graft,
no pain; absent arterial and venous blood flow; no graft perfusion on renography
arterial thrombosis
treatment of arterial thrombosis
graft nephrectomy
local swelling, pain and hematuria; doppler ultrasound presence of arterial flow, no diastolic flow
venous thrombosis
Transplant renal artery or renal vein thrombosis usually occurs in
first 72 hours to 10 weeks
most common cause of allograft
loss in the first week
acute vascular thrombosis
Tx for pseudoaneurysm
transplantation nephrectomy , vascular reconstruction, excision
with extraanatomic bypass
lymphatic fluid collection from the severed lymphatics , or
lymphatic drainage of the graft
lymphocoele
drainage : fluid has high lymphocyte
count and creatinine concentration similar to serum
lymphocoele
Usually asymptomatic except for increasing creatinine; low grade fever, oliguria , and graft pain or tenderness may
occur; most common in the first 6 months post transplant
acute cellular rejection
treatment of acute cellular rejection
Uncomplicated ACR is generally treated with a short course of high dose steroids. –. Methylprednisolone , 250 to 500 mg IV , 3 to 5 days,
failure of improvement in urine; output or plasma creatinine level within 5 days of starting pulse treatment
Steroid resistant ACR (Banf II-III)
Tx of steroid resistant aCR
depleting antibodies
resistant to treatment with anti-lymphocyte antibody
refractory ACR
allograft dysfunction and at least two of the following:
(1) histologic features, including peritubular capillaritis, glomerulitis, thrombi in glomerular capillaries, arterioles
or small arteries, and arterial fibrinoid necrosis; (2) diffusely positive staining of peritubular capillaries for C4d; (3) serologic evidence of antibody against donor HLA or ABO antigens
Acute antibody mediated rejection
Management of ABMR
: Plasma exchange to remove DSA and/or intrave
nous immunoglobulins and anti CD20 monoclonal antibody to
suppress DSA
Graft dysfunction associated with severe tremor (neurotoxicity), moderate increase in plasma creatinine
(>25% over baseline), high trough blood CNI concentrations (e.g.,
cyclosporine levels >350 ng / mL or tacrolimus levels >20
ng/mL
Acute CNI toxicity
Management of Acute CNI toxicity
Reduce dose, repeat crea and drug levels within 48-96 hours
Desired level of cyclosporine in early post transplant vs late post transplant
C0: 150-300 vs 100-200
C2: 1400-1800 vs 800-1200
Tacrolimus desired level early post transplant
standard: 5-15; low 3-7
CNIs are metabolized by
cytochrome P450
isoenzyme CYP3A5,
the dosage of CNI should be reduced when taken with
diltiazem, verpamil, ketoconazole, macrolide antibiotics
these meds lower CNI level hence dose should be increased
rifampin, phenobarbital, phenytoin
foor that can increase cni level
grapefruit juice
herb that can decrease cni level
st john’s wort
Increasing plasma creatinine and lactate dehydrogenase levels,
thrombocytopenia, falling hemoglobin level, schistocytosis , and low
haptoglobin concentrations
acute thrombotic microangiopathy
Management of acute TMA
cessation of CNI, control of htn, plasma exchange, eculizumab
biomarker associated with acute rejection by up to 10 days
urinary mRNA levels of perforin and granzyme B
predict the reversibility of acute rejection and identify patients at high risk for graft loss
FoxP3 mRNA in urinary cells
biomarker of acute allograft injury
donor derived, cell free DNA
common causes of acute pyelonephritis in KT
gram negative bacilli, cons, enterococci
diagnostic of choice if with recurrent pyelonephritis
VCIG
mononuclear cell and eosinophil infiltration of the transplanted kidney
acute allergic interstitial nephritis
duration of dialysis and negative anti-GBM serology before transplant in patients with ant-gbm disease
6 months
HUS-TTP should be quiescent for how long before transplant
6 months
fluid collection with higher creatinine than plasma, renal scintigraphy with extravasation of tracer
urine leaks (infarction of the ureter, breakdown of anastomosis, severe obstruction, rupture)
management of urine leaks
surgical exploration and repair
most common vascular complication
renal artery stenosis
clinically significant ras
> 70%
CINICAL MANIFESTATIONS: Worsening or difficult to control
hypertension, an unexplained deterioration in kidney function, or
azotemia associated with the introduction of an ACE or ARB
transplant renal artery stenosis
management of ras
angioplasty and stent placement
quantitative plasma PCR testing for polyoma virus
monthly (3-6 months), q3 months (1st year), unexplained rise in crea and after treatment of acute rejection
threshold of plasma viral titers when biopsy is advocated for polyoma virus
> 104 copies
biopsy findings in polyoma virus
intranuclear tubule cell inclusions, (+) SV40 staining
treatment of bk nephropathy
reduction in immunosuppression (discontinue MMF, reduce CNI by 30-50%)
positive C4d staining
presence of circulating antidonor antibodies
morphologic evidence of chronic tissue injury, such as
glomerular double contours and/or peritubular capillary basement membrane
multilayering and/or IF/TA and/or fibrous intimal thickening in arteries.
positive peritubular capillary immunostaining for the complement split product, C4d
chronic active antibody mediated rejection
slow decline in hypertension and often heavy proteinuria
chronic active antibody mediated rejection
Striped cortical fibrosis or new onset arteriolar hyalinosis; tubular microcalcification
CNI toxicity
Cold ischemia time associated with poorer graft survival
> 24 hours
Extended criteria donors
> 60 years old, 50-59 with 2 of the following criteria: CVA as cause of death; history of htn, terminal crea > 1.5 mg/dL
principal cause of hyperkalemia in post KT
Principal cause: CNI induced impairment of tubular
potassium secretion.
indication for post transplantation parathyroidectomy
severe symptomatic hypercalcemia in early post transplantation, persistent moderately severe hypercalcemia for more than 1 year after transplantation or if with calciphylaxis
procedure of choice for hyperparathyroidism
subtotal parathyroidectomy
dose of azathioprine if used with allopurinol
75% of the original dose or change to MMF
Dexa scanning indicated post transplant for patients on steroids with risk factors (HPT, vitamin D deficiency, phosphate depletion, DM)
3 months post transplant
Tx within 1 year transplant GFR > 30, low BMD
vitamin D, calcitriol. alfacalcidol, bisphosphonate
target Hba1c level for post transplant DM
7-7.5
CNI that may increase statin blood levels
cyclosporine
CNI risk factor for post transplant DM
tacrolimus
drug of choice for post transplant DM if with normal GFR
metformin
Tx for post transplant lymphoproliferative disorder
immunosuppression reduction, rituximab, CHOP (cyclophospamide, doxorubicin, vincristine and prednisone)
treatment for cmv infection
immunosuppression and oral valganciclovir (if severe start with IV ganciclovir)
prophylaxis for P. jiroveci
SMX-TMP
immunization should be completed before transplantation
at least 4 weeks
immunization should be avoided in the
first 6 months post transplantation
vaccines contraindicated after transplantation
live vaccines
CD$ count for hiv to proceed with transplant
200/m3
pregnancy post kt can be allowed
good general health more than 18 months before conception, stable allograft Crea < 1.5, minimal hypertension, proteinuria, immunosuppresion maintenance doses, no dilation
indications for graft nephrectomy
allograft failure with symptomatic rejection (graft pain), infarction due to thrombosis, severe infection (emphysematous pyelonephritis), allograft rupture
Adequate glomeruli in post transplant biopsy donor
> 25 glomeruli, > 2 arteries
Banff classiciation: normal biopsy or nonspecific changes
Cat 1
Banff: antibody mediated changes
Cat 2
Banff borderline changes
Cat 3
TCMR Banff
Cat 4
Tx for acute abmr
Pulse steroids + plasmapharesis + IVIG + Rituximab
Mild/moderate tcmr
Steroid pulse
Severe tcmr tx
steroid pulse/thymoglobulin
occurs when an individual is exposed to nonself HLA epitopes via pregnancy prior transplant or blood transfusion
sensitization
describe the perfentage of donors in a candidate donor population to whom recipient may have dsa
Panel reactive antibody
predictor of adverse graft outcomes
Moderate to severe ifta
hallmark of chronic active tcmr and abmr
Allograft vascular involvement
Arterial intimal fibrosis with mononuclear cell infiltration and neointima formation, key feature of chrinic active abmr
chronic allograft arteriopathy
first line of tx for acute tcmr
Steroid pulses
2: ATG and alemtuzumab
Banff grade 2 tcmr or higher
Antibodies + corticosteroids
anti-IL 2R class
Basiliximab
serine threonine phosphatase that dephosphorylates the cytosolic component if the nuclear factpr of activated t cells (nfat)
calcineurin
first iv immunosuppressive agent that was marketed
belatacept
chimeric murine/human monoclonal ab directed against CD20
Rituximab
reversible inhibitor of the 26S proteasome
bortezomib
humanized monoclonal antibody that targets the complement C5a component
eculizumab
humanized monoclonal antibody directed at the soluble and membrane forms of IL6R
tociluzimab
Implantation of the ureter to the bladder to minimize urinary reflux into thenureter
Lich Gregoir
where is a kidney allograft placed?
extra peritoneal iliac fossa
procedure of choice for live donor nephrectomy
laparoscopic approach
high K cold storage preservation solution
wisconsin
most impt side effect of azathioprine
Myelosuppression
cpra that needs to be sensitized
more than or equal to 20
period during donor sx between aortic cross clamping or asystole and establishment of cold preservation
donor warm ischemia time
period between removal of kidney from coldstorafe to reperfusion of graft
graft warm ischemia time
time that the kidney spends in cold preservarion
cold ischemia time
