IMMUNOSUPRESSION ---
A LIVER TRANSPLANTATION SUCCESS STORY.
DR. Thomas E Starzl did first liver transplantation in 1963.
Since then Liver transplantation has evolved like anything. From initial one
year survival rates of 20% now we have reached up to 5 year survivals of more
than 90%.
It is a fascinating story about its evolution. What is the
prime reason for this Success.
Yes, techniques have improved, Yes ICU care has improved but
the prime reason for this Phenomenal Success is development in IMMUNOSUPRESSION DRUGS.
As we all know whenever some foreign subject enters our
body, it tries to react against it. So, whenever other person’s liver enters
our body. It reacts against the foreign liver also. To stop this we need to
suppress body’s immunity and here comes precisely role of immunosuppressive
drugs.
So, Let us go in past and start our journey from 1963 from
where liver transplantation started and see how immunosuppression and liver
transplantation success have travelled hand in hand.
Precyclosporine Era :
In 1967 in the following research paper Dr.Thomas Starzl
reported his first extended survival (1 year) after liver transplantation. This
was before an important immunosuppression drug cyclosporine was invented.
•
Corticosteroids and azathioprine were used in
combination as immunosupressants by Starzl et al. in his first 5 transplants.
•
The majority of the Colorado (place were
dr.starzl was doing liver transplantation) series from 1963 to 1976 received
corticosteroids, azathioprine, and antilymphocyte globulin.
•
Survival in the Early and Late Phases of the
Colorado Experience (Follow-up to January 1979)
•
Primary cause of death was rejection (reaction
of body against liver)in 20% of cases
•
Time period
|
No of patients
|
One year survival
|
1963-1976
|
111
|
28%
|
As you can see one year survival in 111 patient at that time was only
28%.
· Cyclosporin
Era:
Dr.Starzl
immediately used this drug in liver transplantation and published his results
in 14 patients.
As you can
see he showed that one year survival rate was almost 100% in patients for whom
cyclosporine with steroid drug prednisolone was used.
In 1988 he
published his experience with 1000 liver transplants in which cylosporin was
used and showed 5 year survival of almost 70% in patients whom cyclosporine
compared to around just 20% in patients using earlier immunosuppressant drugs
like azathioprine.
Now
something about cyclosporine:
•
Can be
administered intravenously, although it is usually given orally as a tablet or
an oral suspension
•
After oral
administration, cyclosporine is variably absorbed in the jejunum and enters the
lymphatic system.
•
Peak blood levels
are achieved in two to four hours.
•
Cyclosporine
levels should be monitored frequently in the peritransplant period (typically
daily), with decreasing frequency as graft function stabilizes and rejection
becomes less of a threat.
•
Initial dosage 10
to 15 mg/kg/day divided into 2 doses. For any immunosuppressant its blood level
has to be monitored so that it gives adequate immunosuppression while avoiding
its toxic effects.
•
•
Cyclosporin level
in the blood goals:
•
Week 1-2 250-350 ng (nanogram)/mL
•
Weeks 3-4 200-300
•
Weeks 5-24 150-250 ng/mL
•
Weeks 25+ 100-200 ng/mL
•
Distant – can
tolerate levels <100
Adverse effects:
•
Hypertension
•
Renal dysfunction
•
Hirsutism
•
Hyperkalemia
•
Gingival
hyperplasia
•
Hypomagnesemia
•
Neurologic
toxicity
Tacrolimus:
(latest and most widely used drug):
Its success
results were first published in New England Journal of medicine in 1994
As you can see there was no difference in survival between
tacrolimus and cyclosporin. So absolutely you will be tempted to question then
why tacrolimus is a better drug for preventing rejection?? (Damage due to
reaction of body against foreign liver)
But as you can see from the above graft proportion of
patients who developed rejection were much less in tacrolimus group and also
proportion of patents who require another drug for rejection was also much less
in the tacrolimus group.
•
Initial dose 0.1 to 0.15 mg/kg/day orally
•
Blood level Goals (variable per patient/disease)
–
Early Post-OLT – 10-15 ng/ml
–
3-6 Months – 8-10
–
>6 Months – 5-7 (variable)
•
Tacrolimus dosing should be individualized.
•
start with a low dose (0.5 to 1 mg every
•
12 hours) on postoperative day one, and aim for
a level of 7 to 10 ng/mL by the end of the first week.
•
Often with the addition of an auxiliary agent
like mycophenolate mofetil or a monoclonal antibody
Adverse effects:
•
Posttransplant diabetes mellitus
•
Nausea, vomiting, diarrhea
•
Hyperkalemia
•
Tremor
•
Hypertension
•
Hypomagnesemia
•
Headache
•
Renal dysfunction
Tripple Therapy ;
Now a days triple therapy is used for any liver
transplantation, that is adding of mycophenolate to tacrolimus and steroid
(prednisolone). Why it is effective??
AS you can see from this research patient survival and graft
survival was higher when another drug
mycophenolate was added to the tacrolimus and steroids.
Freedom from rejection is also much higher with triple drug
therapy.
As you can see from each and every graft here that as we
progressed from precyclosporinera to cyclosproin aera and to tacrolimus and to
the present triple drug therapy how liver transplantation survival rates have
improved and rejection rate have decreased.
Liver transplant success story is a truly success story of
imuunosupressants.
Will post in another post about other drugs like sirolimus,
monoclonal antibodies how to use various immunosuppressant in different
situations.
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