Clinical Case Conference
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Transcript Clinical Case Conference
Clinical Case Conference
REBIN TITUS
Presenting history
44-year-old, Hispanic male with a history of ESRD,
most likely secondary to his diabetes and
hypertension, on hemodialysis since March 2008
He also has coronary artery disease status-post stent
placement in 2008
Admitted for a scheduled transplant from a living,
healthy donor
No complaints on presentation
Past Medical History
ESRD, possibly secondary to diabetes and
hypertension.
Diabetic neuropathy.
Left arm shunt in November of 2008.
Cholecystectomy in 2008.
Coronary artery disease status-post stenting in the
left anterior descending with single vessel disease
in 2008.
Kidney stones.
Erectile dysfunction.
History (contd.)
Social History: The patient does not drink or smoke.
He is unemployed. He lives in Lubbock.
Family History: Positive for hypertension in the
mother and father, diabetes in the father, and colon
cancer in a grandfather. No h/o ESRD
Medications
Aspirin,
Atenolol.
Sertraline.
PhosLo.
Calcitriol.
Enalapril.
Neurontin.
Lantus 50 units at night.
Allergies: None
PE
Vitals: T 97.8: P 66: R 18 :BP 144/76: Pox: 96% on
RA
Gen appearance: Comfortable, in no distress
HEENT: PERRLA, normal conjunctivae, moist
MM
Neck: Supple, no lymphadenopathy
Lungs: CTAB
CVS: S1, S2, RRR, no M/R/G
Abd: Soft, BS +, NT/ND
Ext: No C/C/E; pulses positive
Labs
WBC 6/8: Hgb 11.3: Plt 134K
BMP: Na 140, K 5.1, Cl 98, HCO3 24, BUN 53, Cr 12,
Ca 8.5, Glu 148, Phos 6.9
LFTs negative
Day of Surgery
Was dialysed that night (as per his usual schedule)
Was taken for surgery in the am.
Living donor kidney transplanted to the rt iliac
fossa with EBL approx 350 cc and no
intraoperative complication
POD # 1, 2
Doing well, good urine output, mild pain at site
Started on sirolimus/mycophenelate/prednisone
Creatinine down to 7.7, then 5.9 the next day
POD # 3
Continues to do well
Producing >3 L of urine
Cr slightly up to 6.2, BUN 51
Ordered renal ultrasound which showed good flow
with no hydronephrosis, but with elevated resistive
indices (1.0) and velocities at the level of the lobar
arteries (peak syst vel 47 cm/sec)
POD # 3
Later that day, spikes a temp of 102 degrees. Reports
painful incision site. Pancultured and started on
Zosyn
Cultures negative
POD # 4
Fall in urine output (2.2 L, 30 cc/hr), but responds to
fluids
Creatinine up to 7.6, BUN 70
Concern for accelerated acute rejection, renal flow
scan ordered
Repeat cross matching the same
POD # 4
Was started on thymoglobulin
Acutely developed flash pulmonary edema
Thymoglobulin rate cut by half and 100 mg IV lasix
given, but did not respond
He was emergently dialysed, and 5L fluid was
ultrafiltered
POD # 5
Status improved, still on venti mask
Creatinine down to 5, BUN 40
Urine output not improving, still at about 40cc/hr
Renal scan with good flow and questionable function
POD # 6
Required ultrafiltration again, still on 8L O2
Urine output still about 30-100 cc/hour (1260cc/24
hrs)
Continued Rx with thymoglobulin, along with
mycophenalate/methylprednisone (sirolimus held)
Creatinine up to 5.7
POD # 7
Urine output further decreasing
Respiratory status now improved
Is now clinically depressed
Repeat renal scans and color dopplers unyielding
Decision made to biopsy
POD # 8
Biopsy unsuccessful, patient refused further
attempts
Now oliguric, creatinine 7.5, BUN 96
Continued immune suppression with thymoglobulin
POD # 9-20
Pt’s urine ouput slowly starts to increase
Creatinine continues to rise with peak at 12.2, BUN
88 (though rate of increase less precipitous)
Supportive measures continued, had to be dialyzed
one more time secondary to fluid (POD #11)
Immune suppression continues for a total of 11
doses of thymoglobulin along with MMF and
prednisone. Tacrolimus started toward the end
POD # 9-20
Renal scan continues to show good flow, but
abnormal function
Ultrasound with elevated resistive indices (0.95-1.0),
but with normal velocities
POD # 9-20
Provigil and ambien started for his depression
Was transfused 2 units of PRBC’s, amongst other
supportive measures
T-cell subsets show adequate immune suppression
Urine output continues to improve, in spite of
rising creatinine
No further need for dialysis
Discharged on POD # 20
Renal Transplant
The most common complication of renal
transplantation is allograft dysfunction.
The overall one year unadjusted survival of a renal
allograft is approximately 92 percent for a nonextended criteria deceased donor kidney and
approximately 96 percent for a living donor kidney
(there is wide inter-center variability)
Risk factors for lower survival
Second or third transplant
Prior sensitization with more than 50 percent panel
reactivity
Delayed graft function
Number and severity of rejection episodes
Donor age less than five or greater than 60 years
Greater degrees of HLA mismatching
Allograft dysfunction at discharge (plasma
creatinine above 2 mg/dL)
Delayed graft function (DGF)
Any newly transplanted kidney that does not
function well
Mostly oliguric and requiring dialysis during the first
week of transplantation
Need for accurate and timely recognition and to
differentiate from infection and drug toxicity
Rejection can be mimicked by various infections
such as BK virus-induced nephropathy
Differential diagnosis of DGF
Acute tubular necrosis (ATN)
Intravascular volume contraction
Hyperacute and acute antibody mediated rejection (AMR)
Accelerated rejection
Urinary tract obstruction due to ureteral necrosis or
hematoma
Urine leak
Thrombosis of the renal artery or vein
Nephrotoxicity
Thrombotic microangiopathy (TMA)
ATN
Post ischemic ATN is the most common cause for
DGF. Diagnosis of exclusion.
Risk factors include:
Cold ischemia time >24 hours, especially with
cyclosporine induction therapy
Prior sensitization in re-transplanted patients
The type of dialysis performed immediately prior to
transplantation
Other risk factors
Higher donor age
Preservation of the allograft in Eurocollins solution
Severe vascular disease in the donor or recipient
Sirolimus therapy
Laparoscopy
Pathophysiology of posttransplant ATN
In the short term, it is relatively benign, and
resolves spontaneously
Thought to be post ischemic, ischemiareperfusion injury with increased
concentration of oxygen free radicals
Oliguria caused by decreased GFR, tubular
obstruction with cellular debris and increased
interstitial pressure
May impact long term graft prognosis
Usually requires only supportive therapy
Early Transplant Rejection
Accelerated acute rejection
Early cell-mediated rejection
Antibody-mediated rejection
Accelerated acute rejection
Can occur immediately posttransplant-hyperacute
rejection; or it may be delayed several days
Caused by preformed donor specific antibodies, such
as ABO isoagglutinins, anti-endothelial antibodies
and anti-HLA antibodies
Diagnosis mostly made in the OR and frequently
results in allograft loss within the first 24 hours.
Prompt surgical exploration and intra-op biopsy if
needed to determine viability
Accelerated acute rejection
Usually oliguric or anuric
Fever, graft tenderness
Renal scan with little or no uptake
Early cell-mediated rejection
Latter part of the first transplant week or typically
somewhat later
Differentiated from accelerated by renal scan which
shows decreased but persistent flow
Diagnosis by biopsy
Pathology
Biopsy shows interstitial infiltration with
mononuclear cells and occasionally eosinophils, and
disruption of the tubular basement membranes
(tubulitis) by the infiltrating cell
Immunohistology shows an increased number of
infiltrating MHC class II positive and IL-2 receptor
positive mononuclear cells, when compared to
controls
Histology
Acute cellular rejection in a renal transplant showing diffuse
interstitial infiltrate of mononuclear cells, some of which are
actively invading the tubules
Antibody-mediated rejection
Humoral rejection
Typically in the first few weeks
Asymptomatic rise in creatinine
Diagnosis made by biopsy with diffuse C4d staining
Pathology
Biopsy shows capillary endothelial swelling,
arteriolar fibrinoid necrosis, fibrin thrombi in
glomerular capillaries, and frank cortical necrosis in
severe cases.
Differentiated from acute cellular rejection by C4d
staining
Histology
Renal transplant biopsy with antibody mediated rejection:
Immunofluorescence with C4d monoclonal antibody showing diffuse
peritubular capillary deposition
Categories for the Banff classification system
Category 1: Normal — A histologically normal biopsy.
Cateogry 2: Antibody-mediated changes —It is due to documentation
of circulating antidonor antibody, and C4d or allograft pathology.
C4d deposition without morphologic evidence of acute rejection
Acute antibody-mediated rejection
Histologic type (grade) include the following:
Type I - An acute tubular necrosis-like histology (C4d positive), with
minimal inflammation
Type II - A capillary-glomerulitis, with margination and/or
thromboses (C4d positive)
Type III - Arterial-transmural inflammation/fibrinoid changes (C4d
positive)
Chronic active antibody-mediated rejection
Banff classification system
Category 3: Borderline changes
Category 4: T-cell mediated rejection
Acute T cell mediated rejection
Type IA — Significant interstitial inflammation (>25 percent of
parenchyma affected, i2 or i3) and foci moderate tubulitis (t2).
Type IB — Significant interstitial inflammation (>25 percent of
parenchyma affected, i2 or i3) and severe tubulitis (t3)
Type IIA — Mild to moderate arteritis (v1).
Type IIB — Severe arteritis, which is associated with greater than 25
percent loss of the luminal area (v2)
Type III — Transmural arteritis, and/or arterial fibrinoid alterations,
and necrosis of medial smooth muscle cells occurring in association
with lymphocytic inflammation of the vessel (v3).
Chronic active T-cell-mediated rejection
Banff classification system
Category 5: Interstitial fibrosis and tubular atrophy,
without evidence of any specific etiology — a.k.a chronic
allograft nephropathy.
Grade
I. Mild interstitial fibrosis and atrophy of tubules (<25
percent of cortical area)
II. Moderate interstitial fibrosis and atrophy of tubules (25
to 50 percent of cortical area)
III. Severe interstitial fibrosis and atrophy of tubules (>50
percent of cortical area)
Category 6: Other
Treatment of renal allograft rejection
Once acute rejection is confirmed, the possibility of
inadequate immunosuppression must be addressed.
Factors that can influence:
Aggressive weaning
Inadequate dosing, especially of mycophenolate
mofetil
Failure to recognize drugs that promote cytochrome
P450 metabolism and decrease levels of drugs like
tacrolimus, sirolimus, and cyclosporine
Options for treatment
Pulse steroids
Antibodies (monoclonal or polyclonal)
Manipulation of baseline immunosuppression
Other therapies
Pulse steroids
Pulse methylprednisolone, 3 to 5 mg/kg, given
intravenously for three to five days
Can be used as intensification of maintenance
immunosuppression therapy
Usually the only additional treatment added if the
rejection is Banff class 1A or 1B
Complications: Increased susceptibility to infection,
especially oral candidiasis. Other issues include
hyperglycemia, hypertension, peptic ulcers, and
psychiatric disturbances including euphoria and
depression.
Antibodies
Polyclonal anti T-cell antibodies are prepared by immunizing
rabbits or horses with human lymphoid cells derived from the
thymus (called antithymocyte globulin [ATG]) or cultured B
cell lines.
ATG can be used both for prophylaxis against and for the
primary treatment of acute rejection.
The reversal rate has been between 75 and 100 percent in
different series, with the plasma creatinine concentration
returning to baseline several days to a week after initiating
therapy.
In a small study, compared with steroids, antibodies more
effectively reversed a first acute rejection (RR of 0.57, 95% CI
0.38-0.87) and prevented allograft loss (RR of 0.74, 95% CI
0.58-0.95
Side effects of ATG
Fever and chills during the initial ATG infusion
Anaphylactic reactions, including respiratory distress and
hypotension
Pre-ATG administration of the concurrently given pulse
steroids can significantly reduce infusion-related reactions.
Pruritic skin rash (20 percent)
Presumed antiplatelet antibody-induced thrombocytopenia of
varying severity (50 percent)
CMV and herpes infections
Post-transplant lymphoproliferative disease
ATG does not induce a host antibody response to the rabbit or
horse serum (like OKT3).
OKT 3
OKT3 was the first mouse antibody licensed for use
in humans
Directed against the CD3 antigen that is closely
associated with the T cell receptor
Inhibition of cell-mediated immunity via
modulation/clearing of CD3+ T cells.
OKT3 has been used as the primary treatment of
acute rejection and as rescue therapy for resistant
rejection in kidney transplantation
Side effects
Infection
Lymphoproliferative disease associated with Epstein
Barr virus
First-dose reaction
Pulmonary edema
Hemolytic-uremic syndrome
Other therapies
Alemtuzumab (Campath-1H) is a humanized anti-CD52
panlymphocytic (both B and T cells) monoclonal
antibody that is approved for the treatment of chronic
lymphocytic leukemia. Has been reported in a few
limited studies, to be effective in the treatment of acute
rejection
IL-2 receptor blockers like basiliximab or daclizumab are
indicated for induction in renal transplantation, there are
no studies reporting their use in the treatment of acute
rejection.
Additional rescue therapy for refractory rejection can be
the addition of tacrolimus of MMF to antibody therapy
Antibody-mediated rejection (AMR)
Preliminary data show that patients with AMR may
respond to treatment with plasmapheresis,
tacrolimus, and MMF, or plasmapheresis plus IVIg,
and/or immunoadsorption
Follow up
Continues to improve.
Creatinine finally started to downtrend, now is 7.2
Urine output improved
No need for further dialysis
Thank you for your attention