CHAPTER 70 - CLINICAL MANAGEMENT OF THE ADULT KIDNEY TRANSPLANT RECIPIENT Flashcards
If acute CNI nephrotoxicity is suspected, our practice is to reduce the CNI dose and repeat a serum creatinine and drug level when?
within 48 to 96 hours
Indicators of diagnosis of acute CNI nephrotoxicity and acute rejection
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
The treatment of acute CNI nephrotoxicity is
dose reduction
Histologic findings of acute CNI nephrotoxicity
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
The best studied non-HLA antibody implicated in graft injury
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
Management of ABMR
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
Which has poorer prognosis? ABMR or TCMR?
Active ABMR
Diagnosis of active ABMR requires the presence of (3)
- 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
Therapeutic options for refractory T-cell mediated rejection (3)
- 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
Refractory TCMR is generally defined as
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
This is the most commonly used depleting agent for steroid-resistant TCMR
ATG
Steroid-resistant TCMR is defined somewhat arbitrarily asfailure of improvement in urine output or plasma creatininewithin _____ of starting pulse treatment
5 days
Treated with depleting antibodies (but allograft biopsy must be done first prior to treatment)
Treatment of uncomplicated TCMR
- 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.
The presence of this cells in theinfiltrate suggests severe rejection
Eosinophils
but allergic interstitial nephritis should also be considered
Histologic findings fall belowthe threshold for Banff 1A TCMR
Borderline TCMR
A fairly frequent finding.
We usually treat borderline rejection
Histologic findings characteristic of TCMR (3)
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
This is a widely used schema for classifying rejection
Banff classification
Definitive diagnosis of acute rejection
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
Acute rejection can occur anytime but mostly occurs when
1st 6 months posttransplant
Difference between renal artery thrombosis and renal vein thrombosis
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
The most common cause ofallograft loss in the first week.
Acute vascular thrombosis
Transplant renal artery or renal vein thrombosis usually occurs when?
in the first 72 hours but may be delayed for up to 10 weeks
These drugs will cayse functional preranal failure in the early posttransplant period
ACEi
ARBs
NSAIDs
Diarrhea is a common adverse effect of this immunosuppresant
Diarrhea is a common adverse effect of the MMF, especially when used with tacrolimus.
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
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
Intraoperative mean arterial pressure should be maintained ________ in the recipient.
greater than 70 mm Hg
Treating the donor with this medication prior to organ retrieval has been shown to reduce the rate of DGF
dopamine
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
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.
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.
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.
Management of hyperacute rejection
Transplant nephrectomy
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
Anti-HLA class I antibodies are formed in response to (3):
previous transplantation
blood transfusion
pregnancy
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)
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
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.
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.
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
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.
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
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
Delayed graft function is defined as
DGF is usually defined by the need for one or more dialysis treatments within the first posttransplant week
Excellent allograft function is manifested by (2):
Excellent allograft function is manifest by:
1. ample urine output
2. rapidly falling plasma creatinine concentration
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.
The principal reasons for sensitization (3)
Previous transplants
pregnancy
blood transfusion
This is responsible for more than 50% of graft failures in elderly
Death with a functioning allograft
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
In general, allograft survival rates are poorer in what ages?
In general, allograft survival rates are poorer in those at theextremes 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.
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.
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.
Donation after cardiac death can be sub-classified as (2)
Controlled
Uncontrolled
In orderto maximize the utility of the deceased donor organ supply,deceased donor kidneys with this KDPI score are to be allocatedto candidates with the highest posttransplant life expectancy
The KDPI isexpressed as a percentile score with 0% and 100% signifyingexcellent quality and marginal organs, respectively. In orderto maximize the utility of the deceased donor organ supply,deceased donor kidneys with a KDPI < 20% are to be allocatedto candidates with the highest posttransplant life expectancy,as judged by the 4-variable estimated posttransplant survival(EPTS) score. Older candidates, for whom long waiting timesrepresent a barrier to transplantation, who would previouslyhave agreed to receipt of an ECD kidney, may now choose toaccept deceased donor kidneys with a high KDPI value (>85%).
This is calculated using10 donor characteristics thatg is used in thenew Kidney Allocation System that has replacedthe standard and expanded criteria deceased donor categorieswith a single pool of kidneys
In the US, the new Kidney Allocation System has replacedthe standard and expanded criteria deceased donor categorieswith a single pool of kidneys graded using the kidney donorprofile index (KDPI). The KDPI score is calculated using10 donor characteristics and is a modified version of thepredictive tool first described by Rao et al.329
The KDPI isexpressed as a percentile score with 0% and 100% signifyingexcellent quality and marginal organs, respectively. In orderto maximize the utility of the deceased donor organ supply,deceased donor kidneys with a KDPI < 20% are to be allocatedto candidates with the highest posttransplant life expectancy,as judged by the 4-variable estimated posttransplant survival(EPTS) score. Older candidates, for whom long waiting timesrepresent a barrier to transplantation, who would previouslyhave agreed to receipt of an ECD kidney, may now choose toaccept deceased donor kidneys with a high KDPI value (>85%).
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 baselineGFR of these kidneys is likely lower
2. Tend to be transplanted into older recipients, who have higherrates of posttransplant death
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 a70% greater risk of allograft failure when compared to areference group of non hypertensive donors of age 10 to 39years, whose cause of death was not cerebrovascular accident(CVA) and whose terminal creatinine is less than 1.5 mg/dL
The bestradiologic technique for determining the site of obstruction post transplant
Percutaneous antegrade pyelography is the bestradiologic technique for determining the site of obstructionand can be combined with interventional endourologictechniques. In expert hands, endourologic techniques (e.g.,balloon dilation, stenting) may be effective in treating uretericstenosis and stricture
Ultrasound finding of urinary tract obstruction post transplant
Worsening hydronephrosis showed in serial scans
Intrinsic (3) and extrinsic (2) causes of urinary tract obstruction post KT
Intrinsic causes
1. poor implantation ofthe ureter into the bladder
2. intraluminal blood clots or sloughmaterial
3. fibrosis of the ureter due to ischemia or rejection
Extrinsic causes
1. enlarged prostate in elderlymen (causing bladder outlet obstruction)
2. Compressionby a lymphocele or other fluid collection
Rarely, calculicause transplant urinary tract obstruction
Urinary tract obstruction can occur at any time after transplantation but most commonly occur when?
Early postoperative period
Urinary tract obstruction can occur at any time after transplantation but most commonly occur when?
Early postoperative period
Managemet of urine leaks post transplant
Bladder catheter may be inserted to decompress the urinary tract
many, however, require urgent surgical exploration and repair
This is the best test to demonstrate abladder leak post transplant
Cystography
This allows precise diagnosis and localization of proximalurinary leaks post transplant
Antegrade pyelography allows precise diagnosis and localization of proximalurinary leaks
Urine leaks posttransplant occur at the level of (3)
Renal calyx
ureter
bladder
This drug has been shown to successfully treat and prevent recurrent atypical HUS post KT
Eculizumab has beenshown to successfully treat and prevent recurrent atypicalHUS and post-kidney transplant ‘prophylactic’ eculizumabrepresents a viable, if expensive, option for preventing diseaserecurrence
Transplantation should be deferred until this disease isquiescent 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 isquiescent for at least 6 months. In contrast, recurrence ofatypical (non–diarrhea-associated) HUS/TTP, particularly ifinherited, has been reported to be as high as 80%
Patients with recurrent anti-GBM disease with allograftdysfunction should be treated with (2)
Patients with allograftdysfunction should be treated with plasmapheresis andcyclophosphamide
Here, the recipient with abnormaltype IV collagen produces antibodies against the previously“unseen” normal α5 chain NC1 domain in the basementmembrane of the transplanted kidney.
De novo anti GBM disease can occur in recipientswith Alport syndrome. Here, the recipient with abnormaltype IV collagen produces antibodies against the previously“unseen” normal α5 chain NC1 domain in the basementmembrane of the transplanted kidney.
Patients with allograftdysfunction should be treated with plasmapheresis andcyclophosphamide.
De novo anti GBM disease can occur in transplant recipientswith
De novo anti GBM disease can occur in recipientswith Alport syndrome. Here, the recipient with abnormaltype IV collagen produces antibodies against the previously“unseen” normal α5 chain NC1 domain in the basementmembrane of the transplanted kidney.
Patients with allograftdysfunction should be treated with plasmapheresis andcyclophosphamide.
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 ondialysis for at least 6 months and have negative anti-GBMserology. If these criteria are fulfilled, posttransplant recurrence is rare.
Kidney biopsy finding of recurrent FSGS post transplant
This may not show FSGS lesions per se,but the electron microscopic demonstration of diffuse footprocess effacement is present
Manifestion of recurrent FSGS post transplant
Proteinuria - hours to weeks after transplant
Becauseof the poor prognosis of delayed treatment, patients withprimary FSGS should be monitored after transplantation fornew-onset proteinuria. Early biopsy is indicated in those whodevelop proteinuria; this may not show FSGS lesions per se,but the electron microscopic demonstration of diffuse footprocess effacement is present
Recurrence rate of primary FSGS post transplant
30% - spodic FSGS
rare - familial FSGS
The drug most commonlyimplicated in causing allergic interstitial nephritis in kidneytransplant patients
SMX-TMP is the drug most commonlyimplicated in causing allergic interstitial nephritis in kidneytransplant patients; other antibiotics including penicillins,cephalosporins, and quinolones can also be implicated.
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
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
Most commonly implicated microorganisms in UTI among KT recipients (3):
Diagnosis requires urine culture, but empiricantibiotic treatment should be started immediately. Delay intreatment 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 baselinequickly with antimicrobial therapy and volume expansion.Recurrent pyelonephritis requires investigation to excludeunderlying urologic abnormalities.
How can you differentiate acute pyelonephritis in KT versus acute rejection?
Fever,allograft pain and tenderness, and leukocytosis are usuallymore pronounced in acute pyelonephritis than in acuterejection.
UTI post transplant mostly occur when?
Urinary tract infections (UTIs) may occur at any period butare most frequent shortly after transplantation because ofcatheterization, stenting, and aggressive immunosuppression. Other risk factors for urinary tract infection (UTI) are anatomic abnormalities and neurogenic bladder.
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
Causes of acute thtombotic microangiopathy (5)
Causes include
1. CNIs
2. Orthoclone OKT3
3. ABMR
4. Viral infectionssuch as cytomegalovirus (CMV)
5. Recurrence of apreviously undiagnosed primary disease
The presence ofhepatitis C and anticardiolipin antibodies increases the risk.
Diagnosis of Acute de novo thrombotic microangiopathy is confirmed with
This diagnosis can be overlookedbecause thrombocytopenia and anemia occur commonlyafter transplantation in the setting for ATG induction therapy.The diagnosis is confirmed by allograft biopsy, which showsendothelial damage and, in severe cases, thrombosis ofglomerular capillaries and arterioles
Manifestations of acute de novo thrombotic microangiopathy (6)
Acute de novo TMA after kidney transplantation is a rarebut serious complication. It usually occurs in the earlypost-transplant period and is accompanied by increasingplasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis, and lowhaptoglobin concentrations
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 rarebut serious complication. It usually occurs in the earlypost-transplant period and is accompanied by increasingplasma creatinine and lactate dehydrogenase levels, thrombocytopenia, falling hemoglobin level, schistocytosis, and lowhaptoglobin concentrations.
This diagnosis can be overlookedbecause thrombocytopenia and anemia occur commonlyafter transplantation in the setting for ATG induction therapy.The diagnosis is confirmed by allograft biopsy, which showsendothelial damage and, in severe cases, thrombosis ofglomerular capillaries and arterioles
2 types of DSA and which has worse allograft outcomes
- Preformed - formed pretransplant
- De novo - occur de novo posttransplant
Worse allograft outcomes
DSA may beaccompanied by 1) normal renal function and histology, 2)
normal renal function and ABMR histology (subclinicalABMR), 3) overt ABMR, or 4) chronic active ABMR
Gold standard for diagnosis of transplant rejection
Kidney biopsy
2 major weakness in transplant rejection monitoring and diagnosis:
There are two major weaknesses in transplant rejectionmonitoring and diagnosis in its current form.
1) Graftdysfunction (as evidenced by creatinine rise) may occurrelatively late into a rejection episode, resulting in a delayin diagnosis and treatment
2) Kidney biopsy, the goldstandard for rejection diagnosis, is expensive, invasive andhas real risks
The standard target level of tacrolimus in the early posttransplant months and first posttransplant year to year-and-a-half.
The standard target levelfor tacrolimus **C0 is 8-12 ng/dL **in the early posttransplantmonths and 6-9 ng/dL in the first posttransplant year toyear–and-a-half.
We individualize our longer term tacrolimustargets aiming for a level at the lower or higher end of 5-8 ng/mL depending on immune risk, tolerability, and otherclinical factors.
For patients with evidence of CNI toxicityand who are otherwise stable, compliant, and at low immunological risk, a target of 3-7 ng/mL may be reasonable inthe long term
In Tacrolimus monitoring, which correlate more with AUC? C0 or C2
C0
The standard target levelfor Cyclosporine A in early and late posttransplant in terms of C0 and C2:
The standard target levelfor CsA is C0 of 150-300 ng/mL early and 100-200 ng/mL late posttransplant or C2 1400-1800 ng/mL early and800-1200 ng/mL laterafter transplantation
In Cyclosporine A monitoring, which correlate more closely with AUC? C0 or C2?
C2
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
According to brenner, how often will you monitor routine blood test post transplant?
Serum creatinine, basic chemistry panel, liver function tests, and CBCare routinely checked to screen for graft dysfunction andmanifestations of drug toxicity. Drug levels for CNI, MMF,and mTORi are also monitored for adjustment of immunosuppressive drug dosing. The frequency of monitoring is greaterimmediately posttransplant, and gradually decreased. At ourinstitution, we monitor routine blood levels twice weeklyduring 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 monthlybasis. The frequency of monitoring is increased if there isgraft dysfunction and subsequent treatment. BK plasma PCRmonitoring is performed at set time points in the first twoyears posttransplant
The CDC assay is divided into 2 separate assays:
The test was subsequently refined and divided into twoseparate assays
1) with donor T lymphocytes, which exclusively express HLA class I antigen
2) with donor Blymphocytes, which express both HLA class I and II antigens
The addition of antihuman globulin to the assay increased
its sensitivity.
The ________, wheredonor lymphocytes were incubated with recipient serum,was first developed in the 1960s
The complementdependent lymphocyte cytotoxicity (CDC) assay, wheredonor lymphocytes were incubated with recipient serum,was first developed in the 1960s
ABO-incompatible protocols now mostlyentail a relatively short but intensive pretransplant regimenconsisting of ______, _______ and______– continueduntil anti-A/B titres fall below a prespecified safe threshold(usually_____or ____).
ABO-incompatible protocols now mostlyentail a relatively short but intensive pretransplant regimenconsisting of rituximab, IVIg and plasmaphereis – continueduntil anti-A/B titres fall below a prespecified safe threshold(usually 1:8 or 1:16), some protocols also include additionalposttransplant plasmapheresis or IVIg.
In patients with lowbaseline anti-A/B titers ABO-incompatible transplant hasbeen shown to be safe with minimal pretreatment (1-2 weeksMMF)
Two broad categories of desensitization protocols
Desensitization protocols varyfrom center to center but fall into two broad categories
1)high-dose IVIg/anti-CD20-based,and
2) low dose IVIg/plasmapharesis-basedregimens.
High-dose IVIg has beenemployed as a monotherapy and does effectively lower DSAtiters and permit successful transplantation;58 however, anumber of studies have suggested that IVIg alone (versus
IVIg plus plasmapharesis and rituximab or IVIg plus rituximab) is associated with a posttransplant rebound in DSAtitres and increased incidence of ABMR. More recent reportshave also described successful desensitization using neweragents such as the anti-IL-6 receptor antibody, tocilizumab,and the IgG-degrading enzyme (IdeS).
Do you maintain steroid on African-America KT recipients?
Yes. We usually maintain African-American kidney transplant recipients on chronic maintenancesteroid even if unsensitized. This stems from data showingthat African-Americans, perhaps because of an intrinsicallymore robust alloimmune response, appear to be at higherrejection risk in the absence of steroid. However, a newerstudy suggests that early steroid withdrawal may be safe inunsensitized African-American recipients when transplant isperformed with lymphocyte depleting induction
Do you continue steroids form patients with ESRD from LN post KT?
Yes. We do not usuallywithdraw prednisone in patients with ESRD from lupusnephritis because of concern regarding a higher rejectionrisk and lupus nephritis recurrence
Foreach patient with IgA nephropathy, we weigh this potentialbenefit of remaining on steroid against the advantages ofsteroid withdrawal.128 There is little firm evidence on whatto do with steroid in patients with ESRD from other GNs,although we will continue steroid therapy if it was beingtaken chronically pretransplant
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 tripleimmunosuppression
According to brenner, the recipients of two haplotype matched sibling donatedkidney transplants only requires this immunosuppression
The recipients of two haplotype matched sibling donatedkidney transplants merit a special mention as these patientscan expect excellent outcomes with relatively little immunosuppression. Our practice for these patients has been to usesteroid-only induction and low dose dual immunosuppressionusually with a CNI and antimetabolite thereafter.
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.
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
All sensitized patients (cPRA ≥20%) are maintained on this immunosuppression therapy
Lifelong triple immunosuppresion with CNI, MMF, and steroid
Hypersensitized patients have cPRA of
≥98%
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
cPRA level that is considered to be sensitized
cPRA ≥ 20%
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)
Most steroid withdrawal protocols wean steroids within _______ of transplant
3-6 months
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.
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
Human infusion potein that binds the ligands CD80 adn CD86
Belatacept
given as IV infusion
A selective co-stimulation blocker
Belatacept
Immunosuppressant that has been approved for treatment of advanced renal cell carcinoma
Everolimus (Affinitor)
Derived from sirolimus and has a shorter half-life
Everolimus (Zortress)
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
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
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
Macrocyclic antibiotic that has immunossuppressive properties
Sirolimus (Rapamune)
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
Dose of MMF when usd with calcineurin inhibitor nd steroids
1g BID
fixed dose regimen
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
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
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%
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
Pro-drug that releases an inhibitor of inosine monophosphate dehydrogenase (IMPDH)
Mycophenolate mofetil (MMF)
Mycophenolate acid - inhibitor of the IMPGH
Co-administration of azathioprine with this drug will result to production of metabolically active substrates and may lead to potentially serious toxicity
Allopurinol
Most important side effect of azathioprine
Myelosuppression
Mainstay of transplant immunosuppression in the early 1960s
Azathioprine + prednisone
but now only used as an adjuvant medication to cyclosporine
Calcineurin inhibitor that is associated with greater neurotoxicity, higher incidence of postransplant DM, and gastrointestinal toxicity
Tacrolimus
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
Macrolide antibiotic that binds to the cytosolic FK506 binding protein (FKBP12)
Tacrolimus
Calcineurin inhibitor that is a lipophilic amino acid cyclic peptide
Cyclosporine
bind with cyclophilin while tacrolimus bind with FKBP
The cornerstone of transplant immunosuppression
Calcineurin inhibitors
A calcium dependent serine/threonine phosphatase that is involved in a diverse range of cellular function, including T–cell signal transduction
Calcineurin
Hemolysis is a side effect common in patients in this blood group that were treated with IVIg
Blood group A
Side effects of IVIg (5)
- Infusion reaction
- headache (common and troublesome)
- aseptic meningitis
- hemolysis (especially in patients with blood group A)
- thrombosis (rarely)
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
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
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
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
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
Humanized monoclonal IgG1 antibody directed against the alpha chain of the IL-2 receptor (CD25 antigen)
Daclizumab
Withdrawn from the market in 2009
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)
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
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.
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.
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
Anti-thymocyte globulin which is a gamma globulin derived from horses inoculated with human thymocytes
Atgam
Anti-thymocyte globulin which is derived from rabbits inoculated with Jurkat -cells
ATG-Fresenius
Anti-thymocyte globulin which is derived frim rabbits that inoculated with human thymocytes
Thymoglobulin
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
Immunosuppressant that causes posttransplant lyphoproliferative disorder in EBV seronegative, PML, and reactivation of TB
Belatacept
Immunosuppressant that blocks T-cell costimulation
Belatacept
Immunosuppressant that causes bone marrow suppression, proteinuria, mouth ulcers, hyperlipidemia, and interstitial pneumonitis
Sirolimus
Complex with FKBP and inhibits TOR (target of rapamycin) blocking lymphocyte proliferative response
SIrolimus
CMV disease is more common with this immunosuppressant
Mycophenolate mofetil
CMV disease is more common than in azathioprine
Immunosuppressant that is relatively lymphocyte selective
Mycophenolate mofetil
Immunosuppressant that inhibits de novo pathway or purine biosynthesis
Mycophenolate mofetil
Azathioprine also inhibits purine biosynthesis
Calcineurin inhibitor that more commonly cause DM but with less common cosmetic defect
Tacrolimus
Other ADR:
1. hypertension
2. hyperlipidemia
Calcineurin inhibitor that binds to cytoplasmic protein FKBP
Tacrolimus
Cyclosporine is also a calcieurin inhibitor.
Drug used in maintenance immunosuppresion that block synthesis of several cytokines including IL-2. It has multiple antiinflammatory effects.
Corticosteroids
3 T-cell immune activation signals
- Foreign antigen / major histocompatibility complex is presented to the T-cell receptor of the recipient
- Co-stimulatory T-cell-APC interaction for downstream signal transduction
- T cell proliferation
Cells that play a central role in the recognition of the allograft as foreign and in the initiation of the rejection process
T lymphocyte
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
Complication of kidney transplantation that May compress the ureter which cause hydronephrosis, or obstruct lowel limb venous return which causes unilateral edema
Lymphocoele
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
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
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
Causes of venous thrombosis after kidney transplantation (3)
- Problems with the surgical anastomosis
- extrinsic compression by a lymphocoele or a hematoma
- 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
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
Usual clue to renal artery thrombosis after transplantation
Sudden anuria
arterial thrombosis results in immediate warm ischemia
Risk factors for renal artery thrombosis (4)
- Recipient arteriosclerosis
- multiple arteries
- Vasospasm
- hypotension
renal artery thrombosis is usually related to anastomotic problem or kink in the artery
Acute and life threatening hemorrhagic complications in the immediate postoperative period after kidney transplantation usually involve
Anastomotic site
Alternative to static cold preservation for deceased donor kidneys
Hyothermic machine perfusion
- Flushing of kidney allograft
- renal artery connected to a perfusion pump that circulates a preservation solution
- maintain temp at 1-100C
This organ preservation solution may be used for living donor kidneys with short ischemia times
heparinized lactated Ringer’s with procaine
Ingredient of HTK solution that serves as buffer; ingredient taht are free radical scavengers
Histidine - buffer
Tryptophan and mannitol - free radical scavengers
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
Organ preservation solution that has low viscosity
HTK solution
Organ preservation solution that has high viscosity
University of Wisconsin
viscosity is 3x that of water, making it more difficult to flush
Ingredient of University of WIsconsin solution that buffers free radicals
Hydroxyethyl starch
Ingredient of University of WIsconsin solution that prevent cellular edema (2)
Lactobionate
Raffinose
Organ preservation solution that has an electrolyte composition similar to that of intracellular fluid
University of Wisconsin
high K concentration (120 mmol/L)
The 2 cold storage organ preservation solution most widely used in US
University of Wisconsin solution (Viaspan, UW)
Histidine-Tryptophan-Ketoglutarate (Custodiol, HTK)
The ingredients of all preservation solutions used in organ preservation are designed to: (3)
- Minimize intracellular edema
- preserve the integrity of the cells and tissue
- buffer free radicals
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
