CHAPTER 70 - CLINICAL MANAGEMENT OF THE ADULT KIDNEY TRANSPLANT RECIPIENT Flashcards
1
Q
If acute CNI nephrotoxicity is suspected, our practice is to reduce the CNI dose and repeat a serum creatinine and drug level when?
A
within 48 to 96 hours
2
Q
Indicators of diagnosis of acute CNI nephrotoxicity and acute rejection
A
Indicators of a diagnosis of acute CNI nephrotoxicity
- Severe tremor (neurotoxicity)
- A moderate increase in plasma creatinine (>25% over baseline)
- High trough blood CNI concentrations (e.g., cyclosporine >350 ng/mL or tacrolimus levels >15 ng/mL)
Indicators of a diagnosis of acute rejection
- low-grade fever
- allograft pain and tenderness
- Rapid, non-plateauing increases in plasma creatinine
- low drug concentrations
3
Q
The treatment of acute CNI nephrotoxicity is
A
dose reduction
4
Q
Histologic findings of acute CNI nephrotoxicity
A
Because acute CNI nephrotoxicity is mainly hemodynamic in origin, histology is frequently normal. However, with prolonged CNI toxicity tubular cell vacuolization and hyaline arteriolar thickening may be seen
5
Q
The best studied non-HLA antibody implicated in graft injury
A
The best studied non-HLA antibody implicated in graft injury is probably the angiotensin II type 1-receptor activating antibody, the effects of which may be mitigated by angiotensin receptor blockade blocker therapy
6
Q
Management of ABMR
A
Optimal treatment is yet to be established but.
The most commonly employed regimens for active ABMR include some combination of pulsed steroids, plasmapheresis, intravenous immunoglobulins, and anti-CD20 monoclonal antibody to suppress/remove DSA
Other therapies that have been used for active ABMR include C1 inhibition, eculizumab, bortezomib, and bortezomib plus conversion to belatacept
7
Q
Which has poorer prognosis? ABMR or TCMR?
A
Active ABMR
8
Q
Diagnosis of active ABMR requires the presence of (3)
A
- characteristic histological features which include microvascular inflammation (peritubular capillaritis and/or glomerulitis), intimal or transmural arteritis, thrombotic microangiopathy (TMA), and acute tubular necrosis
- evidence of recent antibody-endothelial interaction, usually identified using C4d staining of peritubular capillaries
- serologic evidence of antibody against donor HLA or other antigens
9
Q
Therapeutic options for refractory T-cell mediated rejection (3)
A
- continuing maintenance immunosuppression in the hope that
kidney function will slowly improve - repeating a course of antilymphocyte antibody therapy
- switching from cyclosporine to tacrolimus if not already done
10
Q
Refractory TCMR is generally defined as
A
Refractory TCMRis generally defined as TCMR resistant to treatment withanti-lymphocyte antibody. By definition, the patient hasalready received aggressive immunosuppression; the risksand benefits of further amplifying immunosuppressionshould be very carefully considered
11
Q
This is the most commonly used depleting agent for steroid-resistant TCMR
A
ATG
12
Q
Steroid-resistant TCMR is defined somewhat arbitrarily asfailure of improvement in urine output or plasma creatininewithin _____ of starting pulse treatment
A
5 days
Treated with depleting antibodies (but allograft biopsy must be done first prior to treatment)
13
Q
Treatment of uncomplicated TCMR
A
- Short course of high dose steroids - methylprednisolone 250-500mg IV for 3-5 days; then tapering of oral steroids to maintenance dose
- review compliance to immunosuppresion (increased or changed)
Lymphocyte-depletingantibodies are highly effective in treating first rejectionepisodes but because of toxicity and cost, these agents areusually reserved for steroid-resistant cases or when there issevere rejection on the initial biopsy.
14
Q
The presence of this cells in theinfiltrate suggests severe rejection
A
Eosinophils
but allergic interstitial nephritis should also be considered
15
Q
Histologic findings fall belowthe threshold for Banff 1A TCMR
A
Borderline TCMR
A fairly frequent finding.
We usually treat borderline rejection
16
Q
Histologic findings characteristic of TCMR (3)
A
Histologic findings characteristic of TCMR
1. mononuclear cell infiltration of the interstitium, mainly with T cells but also with some macrophages and plasma cells
2. tubulitis (infiltration of tubule epithelium by lymphocytes)
3. arteritis which manifests as infiltration of mononuclearcells beneath the endothelium
Vascular involvement reflectsmore severe rejection
17
Q
This is a widely used schema for classifying rejection
A
Banff classification
18
Q
Definitive diagnosis of acute rejection
A
In the era of modern immunosuppression, symptoms andsigns of acute rejection are rarely pronounced, but low-gradefever, oliguria, and graft pain or tenderness may occur. Mostcases of acute rejection are identified through surveillance monitoring of graft function. However, creatinine is a ratherlate and insensitive marker of renal injury. There is, therefore,a growing interest in development of early biomarkers ofimmune system activation. However, for now, the definitivediagnosis of acute rejection requires transplant biopsy
19
Q
Acute rejection can occur anytime but mostly occurs when
A
1st 6 months posttransplant
20
Q
Difference between renal artery thrombosis and renal vein thrombosis
A
Both present with abrupt onset of anuria and rapidly increasing plasma creatinine BUT
Renal artery thrombosis
- negligible graft pain
- Duplex studies: absent arterial and venous blood flow
- Renography or MR angiography: absent perfusion of the transplanted kidney
- Management: removal of infarcted kidney
Renal vein thrombosis
- Pain, tenderness, swelling inthe graft, and hematuria are more pronounced
- Severe complications such as embolizationor graft rupture and hemorrhage may occur.
- Duplex studies: absentrenal venous blood flow and characteristic highlyabnormal renal arterial waveforms
- MR venography: thrombus in the vein
- Management:Transplant nephrectomy and anticoagulation if extends beyond renal vein
21
Q
The most common cause ofallograft loss in the first week.
A
Acute vascular thrombosis
22
Q
Transplant renal artery or renal vein thrombosis usually occurs when?
A
in the first 72 hours but may be delayed for up to 10 weeks
23
Q
These drugs will cayse functional preranal failure in the early posttransplant period
A
ACEi
ARBs
NSAIDs
24
Q
Diarrhea is a common adverse effect of this immunosuppresant
A
Diarrhea is a common adverse effect of the MMF, especially when used with tacrolimus.
25
Primary measure of early and late transplant function
Primary measure of early and late transplant function remains the **plasma creatinine concentration**, despite its known limitation
26
This class of drug have been shown in experimental models to prevent ischemic injury and attenuate CNI-mediated renal vasoconstriction
Calcium channel blockers
These properties suggested that their administration to recipients or to the donor before organ retrieval might reduce the incidence and duration of ischemic ATN
27
Intraoperative mean arterial pressure should be maintained ________ in the recipient.
greater than 70 mm Hg
28
Treating the donor with this medication prior to organ retrieval has been shown to reduce the rate of DGF
dopamine
29
Graft injury can occur at this times (5)
Graft injury may occur
1. prior to donation
2. at retrieval
3. during transport
4. during transplant surgery
5. postoperatively
30
How will CNI cause acute decrease in GFR?
Cyclosporine and tacrolimus, especially in high doses or by intravenous route of administration, may result in an acute decrease in GFR through **renal vasoconstriction, particularly of the afferent glomerular arteriole**. Potentially, such vasomotor effects could exacerbate ischemic ATN. Acute CNI toxicity is now rare with the targeting of lower CNI levels. Caution should, however, be taken in the context of drug interactions that raise CNI levels.
31
How to diagnose accelerated acute rejection superimposed on ischemic ATN?
Accelerated acute rejection may be superimposed on ischemic ATN, in which case there may be no signs of rejection, or it may occur in an initially functioning allograft. Diagnosis is made by **kidney biopsy in conjunction with crossmatch findings and DSA titers**. Histology usually shows evidence of predominantly antibody rather than cell-mediated immune damage.
32
Refers to rejection occurring roughly 2 to 5 days after transplant
Accelerated acute rejection
Accelerated rejection occurs in recipients with pretransplant sensitization to donor alloantigen and is frequently associated with the presence of historic or low-titer pretransplant anti-donor antibody. Rapid post-transplant antibody production by memory B cells may represent an important mechanism for this phenomenon.
33
Management of hyperacute rejection
Transplant nephrectomy
34
Clinical manifestation of classic hyperacute rejection
In classic hyperacute rejection, **cyanosis and mottling of the kidney** and **anuria occur minutes after the vascular anastomosis** is established. Disseminated intravascular coagulopathy may occur.
Histology shows widespread small vessel endothelial damage and thrombosis, usually with neutrophils incorporated into the thrombus
35
Anti-HLA class I antibodies are formed in response to (3):
previous transplantation
blood transfusion
pregnancy
36
Caused by preformed recipient antibodies reacting with antigens on the endothelium of the allograft, resulting in activation of the complement and coagulation cascades
Hyperacute rejection
These antibodies are usually directed against antigens of the ABO blood group system or against HLA class I antigens.
Less commonly, hyperacute rejection is caused by antibodies directed against donor HLA class II antigens or endothelial or monocyte antigens (the last two are not detected in the standard crossmatch)
37
Why does acute rejection occurs more frequently in allografts with delayed versus immediate function?
The postulated mechanism is that **ischemia-reperfusion injury increases the immunogenicity of the allograft**, thereby predisposing to acute rejection
38
Management of uncomplicated ATN posttransplant
Management of the patient during this period is **supportive**. When early hemodialysis is required, minimal anticoagulation should be used to reduce the risk of postsurgical bleeding. Intradialytic hypotension should also be avoided in order to prevent further renal ischemic injury. Peritoneal dialysis may be successfully continued posttransplant, although should be avoided if the peritoneum was opened at the time of surgery. Early postoperative treatments should be performed with low volume exchanges.
39
The natural history of uncomplicated ATN
Spontaneous resolution.
Usually, improvements in urine output begin from 5 to 10 days after transplant, but ATN may persist for weeks.
40
On reanal imaging,there is intact allograft perfusion and absence of obstruction. On histology, there is tubular cell damage and necrosis. Patchy interstitial mononuclear cell infiltrates with no tubulitis may be present.
ATN
41
Describe the resistive index in transplant kidney ultrasound in the setting of intrarenal graft dysfunction
Standard ultrasonography is commonly used to assess potential surgical complications in the immediate postoperative period. Ultrasonography can be performed quickly, is inexpensive and noninvasive, and is usually effective in identifying postrenal causes of kidney failure. Duplex sonography is also useful in assessing the graft’s arterial and venous blood flow. The resistive index (RI) is often reported in transplant kidney ultrasounds and is **elevated** in the setting of intrarenal graft dysfunction. However, a raised RI does not discriminate between ATN and rejection and is therefore of limited diagnostic utility.
42
The most common cause of DGF
Although the causes of DGF include prerenal, intrarenal, and postrenal insults, **ischemic acute tubular necrosis (ATN)** is by far the most common cause of DGF
43
Define slow graft function
SGF defines a group of recipients with moderate early graft dysfunction. One commonly employed definition of SGF is a **plasma creatinine level greater than 3 mg/dL at 1 week posttransplant**
44
Delayed graft function is defined as
DGF is usually defined by the **need for one or more dialysis treatments within the first posttransplant week**
45
Excellent allograft function is manifested by (2):
Excellent allograft function is manifest by:
1. ample urine output
2. rapidly falling plasma creatinine concentration
46
A surrogate measure for both donor nephron mass, as well as recipient metabolic demand
**Body surface area** has been used as a surrogate measure for both donor nephron mass, as well as recipient metabolic demand.
47
The principal reasons for sensitization (3)
Previous transplants
pregnancy
blood transfusion
48
This is responsible for more than 50% of graft failures in elderly
Death with a functioning allograft
49
Common causes of graft loss in the very young and in elderly
In the very young:
1. technical causes of graft loss such as **vessel thrombosis**
2. **Acute rejection**
In the elderly:
1. **Death with a functioning allograft** - responsible for more than 50% of graft failures
50
In general, allograft survival rates are poorer in what ages?
In general, allograft survival rates are poorer in those at the extremes of age, that is, **younger than 18 or older than 65 years of age**
In the very young, technical causes of graft loss such as vessel thrombosis are relatively more common. Acute rejection is also a more common cause of allograft loss; conversely, death with a functioning graft is relatively rare. Death with a functioning allograft is a much more common cause of graft loss in the elderly (responsible for more than 50% of graft failures). Conversely, acute rejection may be less common. Thus, although randomized controlled trials are not available to definitively inform practice, it seems reasonable, in general, to use less aggressive immunosup-pression in the elderly.
51
Which is inferior when it comes to short-term outcomes: donation after cardiac death or donation after brain death?
DCD.
Short-term outcomes (such as rates of DGF and primary non-function) are inferior to those seen with brain dead donors. However, long-term outcomes of DCD organs (from donors <50 years old) are similar to those from standard deceased donors.
52
Uncontrolled and controlled donors after cardiac death are described as
**Uncontrolled donors** are either unsuccessfully resuscitated or present dead on arrival to hospital
**Controlled donors** suffer a cardiac arrest following the withdrawal of life support in the intensive care unit or operating room immediately prior to donation.
The duration of warm ischemia time is likely to be significantly greater in the setting of uncontrolled donation.
53
Donation after cardiac death can be sub-classified as (2)
Controlled
Uncontrolled
54
In order to maximize the utility of the deceased donor organ supply, deceased donor kidneys with this KDPI score are to be allocated to candidates with the highest posttransplant life expectancy
The KDPI is expressed as a percentile score with 0% and 100% signifying excellent quality and marginal organs, respectively. In order to maximize the utility of the deceased donor organ supply, deceased donor kidneys with a **KDPI < 20%** are to be allocated to candidates with the highest posttransplant life expectancy, as judged by the 4-variable estimated posttransplant survival (EPTS) score. Older candidates, for whom long waiting times represent a barrier to transplantation, who would previously have agreed to receipt of an ECD kidney, may now choose to accept deceased donor kidneys with a high KDPI value (>85%).
55
This is calculated using 10 donor characteristics thatg is used in the new Kidney Allocation System that has replaced the standard and expanded criteria deceased donor categories with a single pool of kidneys
In the US, the new Kidney Allocation System has replaced the standard and expanded criteria deceased donor categories with a single pool of kidneys graded using the **kidney donor profile index (KDPI)**. The KDPI score is calculated using 10 donor characteristics and is a modified version of the predictive tool first described by Rao et al.329
The KDPI is expressed as a percentile score with 0% and 100% signifying excellent quality and marginal organs, respectively. In order to maximize the utility of the deceased donor organ supply, deceased donor kidneys with a KDPI < 20% are to be allocated to candidates with the highest posttransplant life expectancy, as judged by the 4-variable estimated posttransplant survival (EPTS) score. Older candidates, for whom long waiting times represent a barrier to transplantation, who would previously have agreed to receipt of an ECD kidney, may now choose to accept deceased donor kidneys with a high KDPI value (>85%).
56
Survival of ECD kidneys is, on average, shorter for two general reasons:
Survival of ECD kidneys is, on average, shorter for two general reasons:
1. The baseline GFR of these kidneys is likely lower
2. Tend to be transplanted into older recipients, who have higher rates of posttransplant death
57
Expanded Criteria Donor kidneys are defined by donor characteristics that are associated with (4):
This includes donors who are:
1. 60 years or older
2. Donors aged 50 to 59 with two of the following criteria:
- CVA as cause of death
- history of hypertension
- terminal creatinine > 1.5 mg/dL
Donor characteristics that are associated with a 70% greater risk of allograft failure when compared to a reference group of non hypertensive donors of age 10 to 39 years, whose cause of death was not cerebrovascular accident (CVA) and whose terminal creatinine is less than 1.5 mg/dL
58
The best radiologic technique for determining the site of obstruction post transplant
**Percutaneous antegrade pyelography** is the best radiologic technique for determining the site of obstruction and can be combined with interventional endourologic techniques. In expert hands, endourologic techniques (e.g., balloon dilation, stenting) may be effective in treating ureteric stenosis and stricture
59
Ultrasound finding of urinary tract obstruction post transplant
Worsening hydronephrosis showed in serial scans
60
Intrinsic (3) and extrinsic (2) causes of urinary tract obstruction post KT
Intrinsic causes
1. poor implantation of the ureter into the bladder
2. intraluminal blood clots or slough material
3. fibrosis of the ureter due to ischemia or rejection
Extrinsic causes
1. enlarged prostate in elderly men (causing bladder outlet obstruction)
2. Compression by a lymphocele or other fluid collection
Rarely, calculi cause transplant urinary tract obstruction
61
Urinary tract obstruction can occur at any time after transplantation but most commonly occur when?
Early postoperative period
62
Urinary tract obstruction can occur at any time after transplantation but most commonly occur when?
Early postoperative period
63
Managemet of urine leaks post transplant
**Bladder catheter** may be inserted to decompress the urinary tract
many, however, require urgent **surgical exploration and repair**
64
This is the best test to demonstrate a bladder leak post transplant
Cystography
65
This allows precise diagnosis and localization of proximal urinary leaks post transplant
**Antegrade pyelography** allows precise diagnosis and localization of proximal urinary leaks
66
Urine leaks posttransplant occur at the level of (3)
Renal calyx
ureter
bladder
67
This drug has been shown to successfully treat and prevent recurrent atypical HUS post KT
**Eculizumab** has been shown to successfully treat and prevent recurrent atypical HUS and post-kidney transplant ‘prophylactic’ eculizumab represents a viable, if expensive, option for preventing disease recurrence
68
Transplantation should be deferred until this disease is quiescent for at least 6 months becaue the atypical form of this disease has high recurrence (as high as 80%)
Recurrence of classic (diarrhea-associated) HUS/TTP is uncommon. However, transplantation should still be deferred until the disease is quiescent for at least 6 months. In contrast, recurrence of **atypical (non–diarrhea-associated) HUS/TTP, particularly if inherited, has been reported to be as high as 80%**
69
Patients with recurrent anti-GBM disease with allograft dysfunction should be treated with (2)
Patients with allograft dysfunction should be treated with **plasmapheresis** and **cyclophosphamide**
70
Here, the recipient with abnormal type IV collagen produces antibodies against the previously “unseen” normal α5 chain NC1 domain in the basement membrane of the transplanted kidney.
De novo anti GBM disease can occur in recipients with **Alport syndrome**. Here, the recipient with abnormal type IV collagen produces antibodies against the previously “unseen” normal α5 chain NC1 domain in the basement membrane of the transplanted kidney.
Patients with allograft dysfunction should be treated with plasmapheresis and cyclophosphamide.
71
De novo anti GBM disease can occur in transplant recipients with
De novo anti GBM disease can occur in recipients with **Alport syndrome**. Here, the recipient with abnormal type IV collagen produces antibodies against the previously “unseen” normal α5 chain NC1 domain in the basement membrane of the transplanted kidney.
Patients with allograft dysfunction should be treated with plasmapheresis and cyclophosphamide.
72
In order to prevent recurrence of anti-GBM disease post transplant, these 2 criteria must be fulfilled
Before transplantation, patients with ESRD due to antiglomerular basement membrane (GBM) disease should generally be on **dialysis for at least 6 months** and have **negative anti-GBM serology**. If these criteria are fulfilled, posttransplant recurrence is rare.
73
Kidney biopsy finding of recurrent FSGS post transplant
This may not show FSGS lesions per se, but the electron microscopic demonstration of **diffuse foot process effacement is present**
74
Manifestion of recurrent FSGS post transplant
Proteinuria - hours to weeks after transplant
Because of the poor prognosis of delayed treatment, patients with primary FSGS should be monitored after transplantation for new-onset proteinuria. Early biopsy is indicated in those who develop proteinuria; this may not show FSGS lesions per se, but the electron microscopic demonstration of diffuse foot process effacement is present
75
Recurrence rate of primary FSGS post transplant
30% - spodic FSGS
rare - familial FSGS
76
The drug most commonly implicated in causing allergic interstitial nephritis in kidney transplant patients
**SMX-TMP** is the drug most commonly implicated in causing allergic interstitial nephritis in kidney transplant patients; other antibiotics including penicillins, cephalosporins, and quinolones can also be implicated.
77
What will you do if you suspect acute allergic interstitial nephritis?
Steroids
Stop suspected drug
TCMR, which cannot be ruled out, also responds to steroid
78
How do you differentiate acute allergic interstitial nephritis from T-cell-mediated rejection?
Fever and rash after ingestion of new drug - but this is rarely seen
Histology: mononuclear and eosinophil infiltraton of the transplanted kidney - seen in both
Acute allergic interstitial nephritis is a diagnosis of exclusion.
Polyomavirus infection - another Ddx
79
Most commonly implicated microorganisms in UTI among KT recipients (3):
Diagnosis requires urine culture, but empiric antibiotic treatment should be started immediately. Delay in treatment can lead to rapid clinical decline in the immunosuppressed patient. The most commonly implicated microorganisms are **gram-negative bacilli, coagulase-negative staphylococci, and enterococci**. Kidney function usually returns to baseline quickly with antimicrobial therapy and volume expansion. Recurrent pyelonephritis requires investigation to exclude underlying urologic abnormalities.
80
How can you differentiate acute pyelonephritis in KT versus acute rejection?
**Fever, allograft pain and tenderness, and leukocytosis are usually more pronounced** in acute pyelonephritis than in acute rejection.
81
UTI post transplant mostly occur when?
Urinary tract infections (UTIs) may occur at any period but are most frequent **shortly after transplantation** because of catheterization, stenting, and aggressive immunosuppression. Other risk factors for urinary tract infection (UTI) are anatomic abnormalities and neurogenic bladder.
82
Initial treatment for acute thrombotic microangiopathy
Switch CNI
may also switch off CNI then move to belatacept or mTori-based immunosuppression regimen
if fails to improve, may initiate plasma exchange
83
Causes of acute thtombotic microangiopathy (5)
Causes include
1. CNIs
2. Orthoclone OKT3
3. ABMR
4. Viral infections such as cytomegalovirus (CMV)
5. Recurrence of a previously undiagnosed primary disease
The presence of hepatitis C and anticardiolipin antibodies increases the risk.
84
Diagnosis of Acute de novo thrombotic microangiopathy is confirmed with
This diagnosis can be overlooked because thrombocytopenia and anemia occur commonly after transplantation in the setting for ATG induction therapy. The diagnosis is confirmed by **allograft biopsy**, which shows endothelial damage and, in severe cases, thrombosis of glomerular capillaries and arterioles
85
Manifestations of acute de novo thrombotic microangiopathy (6)
Acute de novo TMA after kidney transplantation is a rare but serious complication. It usually occurs in the early post-transplant period and is accompanied by **increasing plasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis,** and **low haptoglobin concentrations**
86
A rare but serious complication that occurs in the early post-transplant period and is accompanied by increasing plasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis, and low haptoglobin concentrations
Acute de novo TMA after kidney transplantation is a rare but serious complication. It usually occurs in the early post-transplant period and is accompanied by increasing plasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis, and low haptoglobin concentrations.
This diagnosis can be overlooked because thrombocytopenia and anemia occur commonly after transplantation in the setting for ATG induction therapy. The diagnosis is confirmed by allograft biopsy, which shows endothelial damage and, in severe cases, thrombosis of glomerular capillaries and arterioles
87
2 types of DSA and which has worse allograft outcomes
1. Preformed - formed pretransplant
2. De novo - occur de novo posttransplant
Worse allograft outcomes
DSA may be accompanied by 1) normal renal function and histology, 2)
normal renal function and ABMR histology (subclinical ABMR), 3) overt ABMR, or 4) chronic active ABMR
88
Gold standard for diagnosis of transplant rejection
Kidney biopsy
89
2 major weakness in transplant rejection monitoring and diagnosis:
There are two major weaknesses in transplant rejection monitoring and diagnosis in its current form.
1) Graft dysfunction (as evidenced by creatinine rise) may occur relatively late into a rejection episode, resulting in a delay in diagnosis and treatment
2) Kidney biopsy, the gold standard for rejection diagnosis, is expensive, invasive and has real risks
90
The standard target level of tacrolimus in the early posttransplant months and first posttransplant year to year-and-a-half.
The standard target level for tacrolimus **C0 is 8-12 ng/dL **in the early posttransplant months and **6-9 ng/dL** in the first posttransplant year to year–and-a-half.
We individualize our longer term tacrolimus targets aiming for a level at the lower or higher end of **5-8 ng/ mL** depending on immune risk, tolerability, and other clinical factors.
For patients with evidence of CNI toxicity and who are otherwise stable, compliant, and at low immunological risk, a target of **3-7 ng/mL** may be reasonable in the long term
91
In Tacrolimus monitoring, which correlate more with AUC? C0 or C2
C0
92
The standard target level for Cyclosporine A in early and late posttransplant in terms of C0 and C2:
The standard target level for CsA is **C0 of 150-300 ng/mL early and 100-200 ng/mL** late posttransplant or **C2 1400-1800 ng/mL early and 800-1200 ng/mL later**after transplantation
93
In Cyclosporine A monitoring, which correlate more closely with AUC? C0 or C2?
C2
94
C0 in drug dose monitoring means
Trough level, or measure level after the dosing interval (e.g. 12 hrs after dosing is given after the dosing interval
C2 - measured level 2 hours after dosing
95
According to brenner, how often will you monitor routine blood test post transplant?
Serum creatinine, basic chemistry panel, liver function tests, and CBC are routinely checked to screen for graft dysfunction and manifestations of drug toxicity. Drug levels for CNI, MMF, and mTORi are also monitored for adjustment of immunosuppressive drug dosing. The frequency of monitoring is greater immediately posttransplant, and gradually decreased. At our institution, **we monitor routine blood levels twice weekly during the first month, once a week during the second month, and once every two weeks during the 3rd-6th months posttransplant. Thereafter, we require monitoring on a monthly basis**. The frequency of monitoring is increased if there is graft dysfunction and subsequent treatment. BK plasma PCR monitoring is performed at set time points in the first two years posttransplant
96
The CDC assay is divided into 2 separate assays:
The test was subsequently refined and divided into two separate assays
1) with **donor T lymphocytes**, which exclusively express HLA class I antigen
2) with **donor B lymphocytes**, which express both HLA class I and II antigens
The addition of antihuman globulin to the assay increased
its sensitivity.
97
The ________, where donor lymphocytes were incubated with recipient serum, was first developed in the 1960s
The **complement dependent lymphocyte cytotoxicity (CDC) assay**, where donor lymphocytes were incubated with recipient serum, was first developed in the 1960s
98
ABO-incompatible protocols now mostly entail a relatively short but intensive pretransplant regimen consisting of ______, _______ and______ – continued until anti-A/B titres fall below a prespecified safe threshold (usually_____ or ____).
ABO-incompatible protocols now mostly entail a relatively short but intensive pretransplant regimen consisting of **rituximab, IVIg** and **plasmaphereis** – continued until anti-A/B titres fall below a prespecified safe threshold (usually **1:8 or 1:16**), some protocols also include additional posttransplant plasmapheresis or IVIg.
In patients with low baseline anti-A/B titers ABO-incompatible transplant has been shown to be safe with minimal pretreatment (1-2 weeks MMF)
99
Two broad categories of desensitization protocols
Desensitization protocols vary from center to center but fall into two broad categories
1)high-dose IVIg/anti-CD20-based, and
2) low dose IVIg/plasmapharesis-based regimens.
High-dose IVIg has been employed as a monotherapy and does effectively lower DSA titers and permit successful transplantation;58 however, a number of studies have suggested that IVIg alone (versus
IVIg plus plasmapharesis and rituximab or IVIg plus rituximab) is associated with a posttransplant rebound in DSA titres and increased incidence of ABMR. More recent reports have also described successful desensitization using newer agents such as the anti-IL-6 receptor antibody, tocilizumab, and the IgG-degrading enzyme (IdeS).
100
Do you maintain steroid on African-America KT recipients?
Yes. We usually maintain African-American kidney transplant recipients on chronic maintenance steroid even if unsensitized. This stems from data showing that African-Americans, perhaps because of an intrinsically more robust alloimmune response, appear to be at higher rejection risk in the absence of steroid. However, a newer study suggests that early steroid withdrawal may be safe in unsensitized African-American recipients when transplant is performed with lymphocyte depleting induction
101
Do you continue steroids form patients with ESRD from LN post KT?
Yes. We do not usually withdraw prednisone in patients with ESRD from lupus nephritis because of concern regarding a higher rejection risk and lupus nephritis recurrence
For each patient with IgA nephropathy, we weigh this potential benefit of remaining on steroid against the advantages of steroid withdrawal.128 There is little firm evidence on what to do with steroid in patients with ESRD from other GNs, although we will continue steroid therapy if it was being taken chronically pretransplant
102
Immunosuppression for patients with prior KT
We treat these patients as sensitized irrespective of their cPRA and therefore give **Thymoglobulin for induction** and **maintain on chronic triple immunosuppression**
103
According to brenner, the recipients of two haplotype matched sibling donated kidney transplants only requires this immunosuppression
The recipients of two haplotype matched sibling donated kidney transplants merit a special mention as these patients can expect excellent outcomes with relatively little immunosuppression. Our practice for these patients has been to use **steroid-only induction and low dose dual immunosuppression** usually with a CNI and antimetabolite thereafter.
104
Is the presence of preformed DSA an absolute contraindication for KT?
No. We try to avoid crossing immunological barriers; however, in the abscence of better alternative option, we do not consider the presence of low level preformed DSA to be a contraindication to transplant
Depending on the strength of the DSAat the time of transplant we either monitor the antibody closely post transplant, or administer high-dose IVIg in the immediate posttransplant period and repeat another dose around 4 weeks post transplant.
105
Which has greater prognostic significance for graft survival, high cPRA or preformed DSA?
Preformed DSA ( with or without high cPRA) versus a high cPRA (without DSA) has much greater prognostic significance for graft survival
106
All sensitized patients (cPRA ≥20%) are maintained on this immunosuppression therapy
Lifelong triple immunosuppresion with CNI, MMF, and steroid
107
Hypersensitized patients have cPRA of
≥98%
108
For cPRA ≥ 20%, this therapy is used for desensitization
Thymoglobulin induction therapy
if hypersensitized, PTA ≥ 98% or previously desensitized, additional administration of single dose of Rituximab (500mg) prior to discharge
109
cPRA level that is considered to be sensitized
cPRA ≥ 20%
110
Flow crossmatch result that is considered as a contraindication to KT in the abscence of pretransplant desensitization
Positive flow crossmatch (in the presence of DSA)
111
Most steroid withdrawal protocols wean steroids within _______ of transplant
3-6 months
112
This remains the first line of treatment for acute rejection
Corticosteroids
Steroid sparing strategies are a reasonable option for low immunological risk patients who are treated with modern era (tacrolimus/MMF) immunosuppression regimens.
113
The current package insert recommends use of this drug only in kidnet transplant patients who are documented anti-EBV antibody seropositive because of the risk of PTLD.
Belatacept
114
Human infusion potein that binds the ligands CD80 adn CD86
Belatacept
given as IV infusion
115
A selective co-stimulation blocker
Belatacept
116
Immunosuppressant that has been approved for treatment of advanced renal cell carcinoma
Everolimus (Affinitor)
117
Derived from sirolimus and has a shorter half-life
Everolimus (Zortress)
118
Coversion from CNI to this drug is associated with regressiin of Kaposi's sarcoma and reduction in the development of squamos cell skin cancers
Sirolimus
119
The presence of this before conversion from CNI to sirolimus is predictive of a a poor response and should be screened for prior to considering a switch to sirolimus
Proteinuria
120
Binds with FKBP12 then binds with mammalain target of rapamycin (mTOR)
Sirolimus
shares cytoplasmic binding protein with tacrolimus but does not interfere with calcineurin
Potentiates CNI nephrotoxicity
121
Macrocyclic antibiotic that has immunossuppressive properties
Sirolimus (Rapamune)
122
Enteric-coated slow release formulation of mycophenolic acid
Mycophenolate sodium (Myfortic)
decrease the GI sode effects
dose coversion of mycophenolate mofeltil to mycophenolate sodium is 250 mg to 180 mg
123
Dose of MMF when usd with calcineurin inhibitor nd steroids
1g BID
fixed dose regimen
124
In patients with MMF who are planning pregnancy, when will you switch MMF to azathioprine?
At least 6 weeks before attempting to conceive
MMF is associated with an increased risk of major fetal malformation
125
Most troublesome MMF side effects
Gastrointestinal - may require dose reduction
diarrhea
bloating
epigastric pain
nausea
may also cause neutropenia and, less frequently, anemia.
Alopecia - can be bothersome
not associated with nephrotoxicity or hypertension
126
Calcineurin inhibitor that do not interefere with the metabolism of MMF
Tacrolimus
Sirolimus also do not interfere with metabolism of MMF
Cyclosporine blocks the enteroihepatic recirculation of MMF, reducing the exposure of the drug by approximately 40%
127
The effects of this immunosuppressant are relatively lymphocyte-specific
Mycophenolate mofetil
lacking a purine salvage oathway, T and B cells rely exclusively on de novo purine synthesis
limits the pool of available guanine triphosphate --> prevents T and B lymphocyte replication adn suppresses both the cellular and humoral immune responses
128
Pro-drug that releases an inhibitor of inosine monophosphate dehydrogenase (IMPDH)
Mycophenolate mofetil (MMF)
Mycophenolate acid - inhibitor of the IMPGH
129
Co-administration of azathioprine with this drug will result to production of metabolically active substrates and may lead to potentially serious toxicity
Allopurinol
130
Most important side effect of azathioprine
Myelosuppression
131
Mainstay of transplant immunosuppression in the early 1960s
Azathioprine + prednisone
but now only used as an adjuvant medication to cyclosporine
132
Calcineurin inhibitor that is associated with greater neurotoxicity, higher incidence of postransplant DM, and gastrointestinal toxicity
Tacrolimus
133
Calcineurin ihibitor that is associated with gingival hyperplasia, hypertrichosis, and hyperlipidemia
Cyclosporine
These side effects are not seen in tacrolimus. Hypetension and nephrotoxicity is also milder in tacrolimus
134
Macrolide antibiotic that binds to the cytosolic FK506 binding protein (FKBP12)
Tacrolimus
135
Calcineurin inhibitor that is a lipophilic amino acid cyclic peptide
Cyclosporine
bind with cyclophilin while tacrolimus bind with FKBP
136
The cornerstone of transplant immunosuppression
Calcineurin inhibitors
137
A calcium dependent serine/threonine phosphatase that is involved in a diverse range of cellular function, including T–cell signal transduction
Calcineurin
138
Hemolysis is a side effect common in patients in this blood group that were treated with IVIg
Blood group A
139
Side effects of IVIg (5)
1. Infusion reaction
2. headache (common and troublesome)
3. aseptic meningitis
4. hemolysis (especially in patients with blood group A)
5. thrombosis (rarely)
140
Used in pretansplant as [part of both HLA- or ABO incompatible-desensitization protocols, induction in patients with preformed donor specific antibody and for treatment of antibody-mediated rejection (ABMR); also used for treatment of posttransplant viral infection (BK and parvovirus)
IVIg
Mechanism of action is not fully understood, but may include neutralization of circulating (ant-HLA) antibody, inhibition of complement, modulation of B-cell and antigen-presenting cell function, and cytokine inhibition
141
Immunusuppressive agent that is commonly employed in protocols for the treatment of frequently in combination with steroids, plasmapheresis, and/or IVIg; and is also an important element in many pretransplant desensitization protocols
Rituximab
Also used in treatmet of recurrent glomerular diseases such as membranous glomerulonephritis and FSGS
we usually premedicate with steroid, acitamenophen, and anti-histamine in order to decrease infusion-related side effects
hepatitis B prophylaxis also given in all patients treated with rituximab who have vidence of prior hepatitis B infection, irrespective of antibody titer
142
Chimeric anti-CD20 cytolytic monoclonal antibody that has been approved for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis
Rituximab
initially used in the transplant population for the treatment of post-transplant lymphoproliferative disease
143
Basiliximab treatment regimen
2 infusions of 20 mg
1. 1st: time of transplantation
2. 2nd: 3-4 days posttransplant
This regimen provid prophylaxis for 30 days posttransplant
144
Chimeric monoclonal IgG1 antibody directed against the alpha chain of the IL-2 receptor (CD25 antigen)
Basiliximab
Only IL-2 blocker available in the US
reduce the rate of rejection by 30-40% compared to placebo
less effective that Rabbit ATG and alemtuzumab in reducing the rate of rejection, but less infectious rate
145
Humanized monoclonal IgG1 antibody directed against the alpha chain of the IL-2 receptor (CD25 antigen)
Daclizumab
Withdrawn from the market in 2009
146
Development of this adverse effect is a main concern with the use of alemtuzumab
Autoimmune disease (especially thyroid-related)
Advantage of alemtuzumab:
1. Single dose treatment
2. lower cost
limited manufacturing (access is through Campath Distribution Program)
147
Humanized monoclonal antibody against CD52 that was originally developed to treat refractory B-cell CLL
Alemtuzumab (Campath)
May cause infusion first dose reaction, which can be avoided if the SQ route is used
148
First monoclonal antibody to be approved by the US FDA
Muromonab-CD3 (Orthoclone OKT3)
As a result of its side effects, the use of OKT3 decreased considerably following the emergence of alternative immunosuppressive agents, such as ATG and IL-2 blockers. Manufacture was discontinued in 2010.
149
A mouse anti-human monoclonal antibody against the T cell receptor-associated CD3 antigen
Muromonab-CD3 (Orthoclone OKT3)
As a result of its side effects, the use of OKT3 decreased considerably following the emergence of alternative immunosuppressive agents, such as ATG and IL-2 blockers. Manufacture was discontinued in 2010.
150
Dose of Rabbit-ATG
1-1.5 mg/kg/day
initial regimen of 7-14 days
shorter duration of 5 days has been demonstrated to be efficacious
ADR:
1. fever, chills, hypotension and cardiovascular events - usually mild
- must premidicate with steroid and antihistamine
- must be given as a slow infusion rate
2. serum sickness - fever, rash and arthralgia occurring 10-15 days after treatment
151
Anti-thymocyte globulin which is a gamma globulin derived from horses inoculated with human thymocytes
Atgam
152
Anti-thymocyte globulin which is derived from rabbits inoculated with Jurkat -cells
ATG-Fresenius
153
Anti-thymocyte globulin which is derived frim rabbits that inoculated with human thymocytes
Thymoglobulin
154
Difference between induction and maintenance immunosuppression
Induction - rapid achievement of profound immunosuppression
- at the time or transplant
- use of depleting agents
Maintenance - combination or oral agents that take advantage of additive sor synergestic immunosuuprressive effects of different drug categories to minimize their non-immunosuppressive side effects
a combination of calcineurin inhibitor, antiprpoliferative agent, and corticosteroids is the most common regiment
155
Immunosuppressant that causes posttransplant lyphoproliferative disorder in EBV seronegative, PML, and reactivation of TB
Belatacept
156
Immunosuppressant that blocks T-cell costimulation
Belatacept
157
Immunosuppressant that causes bone marrow suppression, proteinuria, mouth ulcers, hyperlipidemia, and interstitial pneumonitis
Sirolimus
158
Complex with FKBP and inhibits TOR (target of rapamycin) blocking lymphocyte proliferative response
SIrolimus
159
CMV disease is more common with this immunosuppressant
Mycophenolate mofetil
CMV disease is more common than in azathioprine
160
Immunosuppressant that is relatively lymphocyte selective
Mycophenolate mofetil
161
Immunosuppressant that inhibits de novo pathway or purine biosynthesis
Mycophenolate mofetil
Azathioprine also inhibits purine biosynthesis
162
Calcineurin inhibitor that more commonly cause DM but with less common cosmetic defect
Tacrolimus
Other ADR:
1. hypertension
2. hyperlipidemia
163
Calcineurin inhibitor that binds to cytoplasmic protein FKBP
Tacrolimus
Cyclosporine is also a calcieurin inhibitor.
164
Drug used in maintenance immunosuppresion that block synthesis of several cytokines including IL-2. It has multiple antiinflammatory effects.
Corticosteroids
165
3 T-cell immune activation signals
1. Foreign antigen / major histocompatibility complex is presented to the T-cell receptor of the recipient
2. Co-stimulatory T-cell-APC interaction for downstream signal transduction
3. T cell proliferation
166
Cells that play a central role in the recognition of the allograft as foreign and in the initiation of the rejection process
T lymphocyte
167
Preferred and most definitive treatment of lymphocoele post transplantation
Internal drainage of the lymphocoele into the peritoneal cavity
Percutaneous drainage - may cause recurrence
- may inject sclerosing agent to prevent recurrence
168
Complication of kidney transplantation that May compress the ureter which cause hydronephrosis, or obstruct lowel limb venous return which causes unilateral edema
Lymphocoele
169
Difference between lymphocoele and urinoma
Lymphocoele - lymphatic fluid collectin originating frpom either the severed ilial lymphatics or lymphatic drainage of the renal allograft itself
- mostly asymptomatic
- May compress the ureter which cause hydronephrosis, or obstruct lowel limb venous return which causes unilateral edema
- **high lymphocyte count; creatinine similar to serum**
Urinoma - **high creatinine than serum**
170
Vascular complication of transplantation that can lead to loss of lower limb
Distal thrombosis of the femoral artery or arterial dissection at the time of transplant
vert rare but devastating complication
171
This vascular complication of transplantation is a rare infectious complication that leads invariably to graft loss and associated with significant moratlity and morbidity
Pseudoaneurysm of the arterial anastomosis
Management:
Noninvasive treatment with covered stenting (if not severe)
transplant nephrectomy, vascular reconstruction, and/or excision with extraanatomical bypass is usually required
172
Causes of venous thrombosis after kidney transplantation (3)
1. Problems with the surgical anastomosis
2. extrinsic compression by a lymphocoele or a hematoma
3. deep venous thrombosis that extends in the iliac vein at the level of venous anastomosis
Contributing factor: thrombophilia
surgical exploration to attempt thrombectomy followed by anticoagulation can be performed but is rarely successful
173
Vascular complication that usually presents with local swelling, pain and hematuria after transplantation
Venous thrombosis
USD - decrease or absent blood flow in the renal vein and either absent or reversed diastolic arterial flow
174
Usual clue to renal artery thrombosis after transplantation
Sudden anuria
arterial thrombosis results in immediate warm ischemia
175
Risk factors for renal artery thrombosis (4)
1. Recipient arteriosclerosis
2. multiple arteries
3. Vasospasm
4. hypotension
renal artery thrombosis is usually related to anastomotic problem or kink in the artery
176
Acute and life threatening hemorrhagic complications in the immediate postoperative period after kidney transplantation usually involve
Anastomotic site
177
Alternative to static cold preservation for deceased donor kidneys
Hyothermic machine perfusion
1. Flushing of kidney allograft
2. renal artery connected to a perfusion pump that circulates a preservation solution
3. maintain temp at 1-100C
178
This organ preservation solution may be used for living donor kidneys with short ischemia times
heparinized lactated Ringer's with procaine
179
Ingredient of HTK solution that serves as buffer; ingredient taht are free radical scavengers
Histidine - buffer
Tryptophan and mannitol - free radical scavengers
180
Organ preservation solution that has low potassium and low sodium
HTK
K of 15 mmol/L
Na of 15 mmol/L
reduiced the risk for hyperkalemia after transplantation
181
Organ preservation solution that has low viscosity
HTK solution
182
Organ preservation solution that has high viscosity
University of Wisconsin
viscosity is 3x that of water, making it more difficult to flush
183
Ingredient of University of WIsconsin solution that buffers free radicals
Hydroxyethyl starch
184
Ingredient of University of WIsconsin solution that prevent cellular edema (2)
Lactobionate
Raffinose
185
Organ preservation solution that has an electrolyte composition similar to that of intracellular fluid
University of Wisconsin
high K concentration (120 mmol/L)
186
The 2 cold storage organ preservation solution most widely used in US
University of Wisconsin solution (Viaspan, UW)
Histidine-Tryptophan-Ketoglutarate (Custodiol, HTK)
187
The ingredients of all preservation solutions used in organ preservation are designed to: (3)
1. Minimize intracellular edema
2. preserve the integrity of the cells and tissue
3. buffer free radicals
188
A technique designed to minimize urinary reflux into the ureter and has become the preferred technique for neo-ureterocystostomy
Lich-Gregoir implantation of the ureter to the bladder
