Dosing Strategies in Renal Transplant Recipients: Case Studies

1
Dosing Strategies in Renal Transplant
RecipientsCase Studies

• Harold C. Yang, MD
• Medical Director, Transplantation
• Pinnacle Health at Harrisburg
• Harrisburg, Pennsylvania

2
Optimizing Renal Allograft Function Over The Long
Term

• Long-term renal allograft function is dependent
  on optimizing immunosuppressive management in the
  early post-operative period with an emphasis on
• Immediate graft function
• Preventing acute rejection/early recognition and
  treatment of acute rejection
• Preventing chronic rejection

3
Experience at Pinnacle Health Systems,
Harrisburg,Pennsylvania

• Inception of program
• March 2000 to June 30, 2003
• 209 consecutive kidney transplant recipients
• 100 cadaveric transplants
• 109 living donor transplants
• Mean age 48.812.6 years
• All patients followed-up for a minimum of 1 year

Report available at www.ustransplant.org.
4
Immunosuppressive Regimen

• Tacrolimus
• starting dose 0.07 mg/kg bid
• target blood levels 10-15 ng/ml for the first
  month, 5-10 ng/ml thereafter
• Mycophenolate mofetil (MMF)
• 1000 mg bid for the first two weeks, 500 mg bid
  thereafter
• Corticosteroids
• 100 mg bid on day 1, 90 mg bid on day 2, 80 mg
  bid on day 3, etc. until a dose of 10 mg/day is
  reached

Report available at www.ustransplant.org.
5
Immunosuppressive Regimen(continued)

• Induction with daclizumab or basiliximab
• daclizumab 1 mg/kg intravenously prior to
  surgery and two weeks following transplantation
• basiliximab 20 mg intravenously prior to surgery
  and 20 mg again on days 3, 4 or 5
• The rate of oliguric acute tubular necrosis is
  less than 10
• Patients are given 1.0-1.5 mg/kg of Thymoglobulin
  per day until their serum creatinine is lt3.0 mg/dL

Report available at www.ustransplant.org.
6
Patient Outcomes at 1 Year
Report available at www.ustransplant.org.
7
Renal Function at 1 Year

• Mean serum creatinine at 1 year
  posttransplantation was 1.360.52 mg/dL
• Just 21.0 of patients had a serum creatinine
  gt1.5mg/dL

Report available at www.ustransplant.org.
8
Comparative Studies Design

• Prospective, randomized, multicentre, parallel
  group study
• 361 adult recipients of first cadaveric or living
  donor kidney transplants in 27 US centres
• Antilymphocyte induction used in patients with
  delayed graft function

Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
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Comparative Studies Dosing Regimens
Tacrolimus

• 0.150.20 mg/kg/day in 2 divided doses
• Target trough levels 816 ng/mL (first 3 months)
• 515 ng/mL (months 46)

MMF

• 2 g/day in two divided doses

Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
10
Comparative Studies Dosing Regimens
Sirolimus

• 6 mg loading dose
• 2 mg/day thereafter
• Target trough levels 412ng/mL

Corticosteroids

• 500 mg (peri-op), 200mg/day
• 20 mg/day (days 114)
• 15 mg/day (day 30)
• 10 mg/day (day 60)
• 510 mg/day (by month 6)

Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
11
Delayed Graft Function (DGF) and Acute Tubular
Necrosis (ATN)
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
12
Acute Rejection at 3 Months
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
13
Patient and Graft Survival at 3 Months
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
14
Renal Function Mean Serum Creatinine
Mmonth Wweek
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
15
Mean Serum Creatinine in Patients With DGF
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
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Laboratory Values at 3 Months (Mean SD)
Tacrolimus/ sirolimus
Tacrolimus/ MMF
P
SCr (mg/dL) Patients without DGF 1.61
0.75 1.50 0.56 .29 Patients with DGF 2.12
1.21 1.70 0.61 .06 WBC 7.67 2.76 7.02
2.63 .03 Cholesterol (mg/dL) 227 65 196
44 lt.0001 HDL (mg/dL) 56 16 53
20 .0092 LDL (mg/dL) 114 39 103
36 .02 Triglycerides (mg/dL) 281 303 204
231 lt.0001 Systolic blood pressure 137 18 132
18 .01 Diastolic blood pressure 81 12 77
11 .0006
Yang HC. Nephrol Dial Transplant. 200318 Suppl
1i16-20.
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Tacrolimus/MMF vs Ciclosporin microemulsion/MMF
Study design

• Randomized, multicentre, three-arm, parallel
  group
• 223 adult recipients of first cadaveric kidney
  transplants in 15 US centres
• Antilymphocyte induction only used in patients
  with delayed graft function

Randomized
Tacrolimus Azathioprine Corticosteroids (n76)
Ciclosporin microemulsion MMF 2g/day
Corticosteroids (n75)
Tacrolimus MMF 2g/day Corticosteroids (n72)
Johnson C, et al. Transplantation.
200069834-841.
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Outcomes at 1 Year Posttransplant
Ciclosporin-ME MMF (n75)
Tacrolimus MMF (n72)
Tacrolimus Azathioprine (n76)
15 (20.0)
11 (15.3)
13 (17.1)
Biopsy-confirmed acute rejection
10 (13.3)
8 (11.1)
9 (11.8)
Death or graft loss
Johnson C, et al. Transplantation.
200069834-841.
19
Renal Function at 1 Year Posttransplant
P.03
Johnson C, et al. Transplantation 200069834-841.
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Long-term ResultsStudy Completion at 3 Years
Deathsa
4 (5.3) 4 (5.6) 7 (9.3) 11 (14.5) 10
(13.9) 13 (17.3) 5 (6.6) 4 (5.6) 1
(1.3) 56 (73.7) 54 (75.0) 54 (72.0) 36
(47.4) 40 (55.6) 36 (48.0)
Graft loss
Lost to follow-up
Patients completing 36 months
On randomized tx at 36 months
a Death with a functioning graft
Gonwa T, et al. Transplantation.
2003752048-2053.
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Probability of Biopsy-Confirmed Acute Rejection
at 3 Years
Probability of biopsy-confirmed acute rejection
30.8
25.0
18.2
Months from randomization
Gonwa T, et al. Transplantation.
2003752048-2053.
22
Probability of Overall Graft Survival at 3 Years
79.7
Probability of patient or graft survival
79.6
73.0
Months from randomization
Gonwa T, et al. Transplantation.
2003752048-2053.
23
Graft Survival at 3 Years for Patients With DGF
and Antilymphocyte Therapy
Tacrolimus azathioprine
Ciclosporin MMF
Tacrolimus MMF
84.1
71.6
Probability of patient or graft survival
49.9
0
3
6
12
15
18
21
24
27
30
33
36
9
Months from randomization
P.02
Gonwa T, et al. Transplantation.
2003752048-2053.
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Renal Function at 3 Years Posttransplant
1.6
1.4
1.4
Median serum creatinine (mg/dL)
51.0
38.3
35.8
patients gt1.5mg/dL
56.1
59.3
62.3
Median creatinine clearance (mL/min)
Gonwa T, et al. Transplantation.
2003752048-2053.
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Conclusions

• Good immunosuppressive management in the early
  post-transplant period is key to long-term graft
  survival and function
• Tacrolimus whether combined with MMF or
  sirolimus adjunctive therapy is associated with
• excellent patient survival and graft survival
• low rate of biopsy-proven acute rejection
• excellent renal function

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Conclusions (contd)

• Tacrolimus MMF is superior to cyclosporin
  microemulsion MMF, resulting in
• improved renal function, as assessed by median
  serum creatinine
• improved graft survival in patients with DGF
• Long-term use of tacrolimus maintains good renal
  function
• improved renal function observed at 1 year with
  tacrolimus/MMF was preserved at 3 years
  posttransplant

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Case 1 Presentation

• 27-year-old, 70 kg, African American female
• An increase in serum creatinine 3 months after
  cadaveric transplantation from 1.0-1.2 mg/dL to
  1.6-1.8 mg/dL
• Her hemoglobin and hematocrit have remained
  stable and her bicarbonate level is normal
• No somatic complaints and feels better than ever
  before
• Immunosuppression regimen
• prednisone, 10 mg daily
• mycophenolate mofetil, 1500 mg twice a day
• tacrolimus, 5 mg twice a day.
• Her last tacrolimus level was 8 ng/mL

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Case 1 Our Approach

• Obtain a duplex ultrasound to rule out mechanical
  causes of an elevated creatinine, including
  obstruction and fluid collections
• The duplex component would assess resistive
  indices. In this case the indices were equivocal
  at .7-.8
• Given a normal ultrasound and therapeutic
  tacrolimus levels we would proceed to biopsy
• Biopsy in this instance failed to demonstrate any
  evidence of rejection
• The tacrolimus dose was reduced to 4 mg twice a
  day
• Serum creatinine dropped back to the patients
  baseline

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Case 2 Presentation

• 55-year-old, 85 kg, Caucasian male
• An increase in his baseline serum creatinine from
  low 1s to low 2s 10 years after cadaveric
  transplantation
• All other parameters have remained stable
• No constitutional symptoms and his urine output
  is stable
• Immunosuppression regimen
• prednisone, 5 mg a day
• azathioprine, 100 mg a day
• cyclosporin, 250 mg twice a day

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Case 2 Our Approach

• Obtain a duplex ultrasound
• In this case the ultrasound was completely normal
• Proceed to biopsy
• Biopsy was remarkable for no evidence of acute
  rejection, but
• compared to a biopsy soon after transplant there
  was increased interstitial fibrosis with minimal
  vascular changes
• The patient was switched from azathioprine and
  cyclosporin to
• mycophenolate mofetil, 500 mg twice a day
• tacrolimus, 4 mg twice a day aiming for a blood
  trough level of 5-10 ng/mL

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Case 2 Follow-up

• One year following the switch the patients serum
  creatinine is in the mid 1s and stable.
• His creatinine clearance has increased from the
  high 20s to low 40s.

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Case 3 Presentation

• 20-year-old, 65 kg, Caucasian male
• An increase in his serum creatinine from 1.4-1.5
  mg/dL to 1.9-2.0 mg/dL, 6 months after
  living-related transplantation from his mother
• His hemoglobin and hematocrit are stable and his
  bicarbonate is normal
• He has no complaints
• Immunosuppression regimen
• prednisone, 10 mg a day
• mycophenolate mofetil, 750 mg twice a day
• tacrolimus, 7 mg twice a day

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Case 3 Our Approach

• A duplex ultrasound of the kidney was completely
  normal
• A biopsy was scheduled
• Before the biopsy the patients serological and
  urinary titers of polyoma BKV came back
• Serological titer 49,800
• Urinary titer 9.8 X 108
• Mycophenolate mofetil was discontinued
• Started on leflunomide, 40 mg once a day for two
  weeks
• At two weeks leflunomide dose was reduced to 20
  mg once a day

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Case 3 Follow-up

• A repeat polyoma titer at 1 month
• serological titer 15,000
• urinary titer 1,800,000
• Repeat polyoma titer at 2 months
• serological titer not detected
• urinary titer 757,000
• The patient maintained on 20 mg leflunomide
• At 6 months he redeveloped serologic evidence of
  polyoma virus at titers of 2000
• Leflunomide dose increased to 40 mg for 1month
  until serologic evidence of polyoma disappeared
• Currently maintained on leflunomide, 20 mg/day

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Case 4 Presentation

• 39-year-old Caucasian male underwent
  living-unrelated kidney transplantation from his
  wife
• His fasting lipid profile the day following
  surgery
• Total cholesterol 255 mg/dL
• Triglycerides490 mg/dL
• HDL 32 mg/dL
• LDL 125 mg/dL
• His medications at the time of discharge
• prednisone, 10 mg a day
• mycophenolate mofetil, 1000 mg twice a day
• tacrolimus, 6 mg twice a day
• Patients lipid profile 1 month following
  surgery
• Total cholesterol 311 mg/dL
• Triglycerides 260 mg/dL H
• HDL 38 mg/dL
• LDL 221 mg/dL

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Case 4 Our Approach

• He was started on rosuvastatin, 5 mg a day
• At 6 months his repeat lipid profile was
• Total cholesterol 174 mg/dL
• Triglycerides 191 mg/dL
• HDL 35 mg/dL
• LDL 110 mg/dL
• Without our knowledge the patient let his
  prescription run out
• His repeat lipid profile at 9 months was
• Total cholesterol 273 mg/dL
• Triglycerides 277 mg/dL
• HDL 35 mg/dL
• LDL 182 mg/dL
• Rosuvastatin was reinstated and his lipid profile
  returned to his 6 month levels