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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 .

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Cyclosporin Nephrotoxicity

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  1. Cyclosporin Nephrotoxicity

  2. Some of the indications for the use of cyclosporin include the prevention of graft rejection in renal transplant recipients and autoimmune diseases.

  3. 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

  4. 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.

  5. Monitoring procedures: Biochemical monitoring: • Radioimmunoassay • fluorescent polarization • Immunoassays • homogeneous immunoassays • high-performance liquid chromatography–mass spectrometry

  6. Clinical Monitoring: • Renal function tests • Liver function tests • BUN • Bilirubin • Trough cyclosporin blood concentration • Renal biopsy • Blood pressure • FBC

  7. Explain whether it is possible to distinguish between the adverse renal effects of cyclosporin and graft rejection.

  8. Similarly… • Increase in Creatinine Serum • Decrease in GFR • Decrease in Creatinine Clearance • Increase in BUN

  9. However…

  10. 1/ Cyclosporine-Sparing Effect • The introduction of one or more agents with Cyclosporine in order to achieve the therapeutic drug concentration at lower doses.

  11. 2/ Benefits Associated • Vast reduction in cost • (Cyclosporine is very expensive) • Reduced side effects • (toxicity is a major issue to contend with)

  12. 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)

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. Mathematical Calculations of Renal Function. • Why these approaches have been developed?

  18. 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

  19. Inulin (sinsitrin) • Exogenous marker of GFR • Precise measurement Method: • Intravenous infusion • Urine collections Problems: • $$, time, not feasible in clinical setting.

  20. Radioactive markers • Exogenous markers • 125I- iothalamate • 99mTc- DTPA Problems: • Not readily available • Time consuming

  21. Creatinine • By-product of muscle • Predominately eliminated by glomerular filtration • Inexpensive Problems: • Poor sensitivity, specificity.

  22. Method • 24-hr urine collection: To determine creatinine clearance CrCl (mL/min): Ucr * Vurine Scr * T • Serum creatinine concentration

  23. 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.

  24. Quick Methods to estimate CrCl • Equations postulated by clinicians to predict GFR. • From serum creatinine values and patient characteristics in various populations.

  25. 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.

  26. 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.

  27. 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)

  28. 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.

  29. 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

  30. 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

  31. 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. +. MonitoringCyclosporin 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.. CyclosporinMonitoring in Australasia: Survey of Laboratory Practices in 2000.Therapeutic Drug Monitoring. 24(4):471-478, August 2002.

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