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 Variable onset

Fever No fever

Rapid rise in Creatinine Gradual rise in Creatinine

No change in serum Urate level

Urate Retention

No change in serum magnesium level

Reduced serum magnesium

Cyclosporin A trough level <150 ng/ml

Cyclosporin A level > 400 ng/ml

1/ Cyclosporine-Sparing EffectThe 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 MOAInclude 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 collectionProblems:

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 equationClcr(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 equationAssumptions: Stable renal function Actual weight within 30% of IBW.

(Normal muscle mass). Crserum< 4.5mg/dL

Limitations: 18 yrs and older.

Jelliffe multistep equationEstimate 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))/TimeCalc normalised CrCl

CrCl/1.73m2 = (E * 0.12) / (Crserum * BSA)

Jelliffe multistep equationAsumptions: 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 equtionClcr = (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 equationClcr(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.