Download Cyclosporin Nephrotoxicity

Cyclosporin Nephrotoxicity

Some of the indications for the use of
cyclosporin include the prevention of
graft rejection in renal transplant
recipients and autoimmune diseases.
How cyclosporin nephrotoxicity is
manifested

Long term usage of Cyclosporin generally
may results in Cyclosporin Nephrotoxicity

Short term usage at high dosages can also
cause Cyclosporin Nephrotoxicity
Characterised by:









Renal dysfunction,
Reduced GFR ,
Reduced renal blood flow,
Rise in serum creatinine,
Decrease in renal clearance,
Rise in RAS,
Arteriolopathy of afferent ateriole,
Vascular dysfunction and
Elevated BUN.
Monitoring procedures:
Biochemical monitoring:





Radioimmunoassay
fluorescent polarization
Immunoassays
homogeneous immunoassays
high-performance liquid chromatography–
mass spectrometry
Clinical Monitoring:








Renal function tests
Liver function tests
BUN
Bilirubin
Trough cyclosporin blood concentration
Renal biopsy
Blood pressure
FBC
Explain whether it is
possible to distinguish
between the adverse renal
effects of cyclosporin and
graft rejection.
Similarly…




Increase in Creatinine Serum
Decrease in GFR
Decrease in Creatinine Clearance
Increase in BUN
However…
Renal Transplant Rejection Cyclosporin Nephrotoxicity
Acute onset
Fever
Variable onset
No fever
Rapid rise in Creatinine
Gradual rise in Creatinine
No change in serum Urate
level
No change in serum
magnesium level
Urate Retention
Cyclosporin A trough level
<150 ng/ml
Cyclosporin A level >
400 ng/ml
Reduced serum magnesium
1/ Cyclosporine-Sparing Effect
 The
introduction of one or more
agents with Cyclosporine in order to
achieve the therapeutic drug
concentration at lower doses.
2/ Benefits Associated




Vast reduction in cost
(Cyclosporine is very expensive)
Reduced side effects
(toxicity is a major issue to contend with)
3/ Agents typically used




Azole antifungals: Fluconazole,
Ketoconazole and Itraconazole
Ca2+ channel blockers: Verapamil,
Diltiazem and Nicardipine
Other immunosuppressants such as
Siromilus or Mycophenolate Mofetil
Macrolide antibiotics such as erythromycin
(rarely used)
4/ Azole Antifungals MOA





Include Ketoconazole, Fluconazole and
Itraconazole
Have the ability to increase the blood
cyclosporine concentration by two means:
Firstly via inhibition of the CYP3A4 enzyme,
responsible for the metabolism of cyclosporine,
and
Decreasing the clearance of cyclosporine from
the body
Results in a 70 to 85% reduction in cyclosporine
dose required
5/ Ca2+ Channel Blockers MOA
Include Diltiazem, Verapamil and Nicardipine
 Similar MOA to azoles but have minimal
ability to decrease the clearance of
cyclosporine in comparison
 As a result the effectiveness of these agents
is smaller, with a 30-50% reduction in
cyclosporine dose achieved.
6/ Other Immunosuppressants



Include Siromilus and Mycophenolate
Mofetil
Work synergistically with cyclosporine,
inhibiting lymphocyte activation and
proliferation.
Effect is very powerful and the immune
system becomes quickly weakened.
7/ Most effective agents

Ketoconazole and Diltiazem appear to be
the best candidates when considering the
two mot important issues; financial
pressures and the patients' well being.
Mathematical Calculations of
Renal Function.

Why these approaches have been
developed?
Ideal marker to measure CL





Physically inert
Filtered freely at the glomerulus
Neither secreted, reabsorbed, synthesised,
nor metabolised by the kidney
Stable production rate
Cl depends only on glomerular filtration
Inulin (sinsitrin)


Exogenous marker of GFR
Precise measurement
Method:


Intravenous infusion
Urine collections
Problems:

$$, time, not feasible in clinical setting.
Radioactive markers



Exogenous markers
125I- iothalamate
99mTc- DTPA
Problems:


Not readily available
Time consuming
Creatinine



By-product of muscle
Predominately eliminated by glomerular
filtration
Inexpensive
Problems:

Poor sensitivity, specificity.
Method

24-hr urine collection:
To determine creatinine clearance
CrCl (mL/min): Ucr * Vurine
Scr * T

Serum creatinine concentration
24 hr urine collection
Problems:



Incomplete urine collections
Serum creatinine concentrations obtained
at incorrect times
Collection time errors can produce
erroneous measured creatinine clearance
values.
Quick Methods to estimate CrCl


Equations postulated by clinicians to
predict GFR.
From serum creatinine values and patient
characteristics in various populations.
Cockcroft and Gault equation
Clcr(male) = BW *(140-age) / 72*Crserum
Clcr(female) = above equation*0.85
BW (body weight) - Kg
Age - years
Crserum - mg/dL
Note: formula different for men and women because of gender dependent
differences in muscle mass.
Cockcroft and Gault equation
Assumptions:
Stable renal function
 Actual weight within 30% of IBW.
(Normal muscle mass).
 Crserum< 4.5mg/dL

Limitations:

18 yrs and older.
Jelliffe multistep equation
Estimate urinary Cr excretion rate
E(male) = LBW(29.3 – (0.203 * age))
E(female) = LBW(25.1 – (0.175 * age))
Correct E for non reanl Cr excretion in chronic renal failure
E(corrected) = E(1.035 – (0.0337 * Crserum(avg))
Correct E for rising serum Cr
E = E – (4 * LBW * (Crserum1 – Crserum2))/Time
Calc normalised CrCl
CrCl/1.73m2 = (E * 0.12) / (Crserum * BSA)
Jelliffe multistep equation
Asumptions:


Avg. BSA for a 70kg male is 1.73m2
Clcr value obtained must then be multiplied
by BSA/1.73 to obtain the patients’ Clcr in
absolute terms (ie mL/min).
Limitations:

Muscle mass must be in the avg range.
Swartz CrCl eqution
Clcr = (k * Ht) / Crserum
Clcr in mL/min/1.73m2
Ht- height in cm
Crserum- mg/mL
K = 0.45 if age < 1 year
K = 0.55 if age 1-12 years.

BSA normalised to 1.73m2
Salazar and Corcoran equation
Clcr(male) = (137-age)*((0.2858*Wt) + (12.1*Ht2))
51*Crserum
Clcr(female) = (146-age)*((0.287*Wt) + (9.74*Ht2))
60 *Crserum
Ht:height in metres
Wt: weight in kg
Age in years.

A specific measure for obese people
References:




Pathology The Chinese University of Hong Kong, Chemical Pathology in Organ Transplantation, Department of
Chemical, 2000
http://www.transplantbuddies.org/library/tdm.html. Visited 23/3/04
. Johnston, Atholl * . Chusney, Gary + . Schutz, Ekkehard ++ . Oellerich, Michael ++ . Lee, Terry D. +. Holt, David
W. +. Monitoring Cyclosporin in Blood: Between-Assay Differences at Trough and 2 Hours Post-dose (C2).
Therapeutic Drug Monitoring. 25(2):167-173, April 2003.
Morris, Raymond G.. Lam, Ada K.. Cyclosporin Monitoring in Australasia: Survey of Laboratory Practices in
2000. Therapeutic Drug Monitoring. 24(4):471-478, August 2002.