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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
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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
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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
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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
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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
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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