cyclosporin nephrotoxicity l.
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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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slide2
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
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
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
Monitoring procedures: Biochemical monitoring:
  • Radioimmunoassay
  • fluorescent polarization
  • Immunoassays
  • homogeneous immunoassays
  • high-performance liquid chromatography–mass spectrometry
clinical monitoring
Clinical Monitoring:
  • Renal function tests
  • Liver function tests
  • BUN
  • Bilirubin
  • Trough cyclosporin blood concentration
  • Renal biopsy
  • Blood pressure
  • FBC
slide7
Explain whether it is possible to distinguish between the adverse renal effects of cyclosporin and graft rejection.
similarly
Similarly…
  • Increase in Creatinine Serum
  • Decrease in GFR
  • Decrease in Creatinine Clearance
  • Increase in BUN
1 cyclosporine sparing effect
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
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
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
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
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
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
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
Mathematical Calculations of Renal Function.
  • Why these approaches have been developed?
ideal marker to measure cl
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
Inulin (sinsitrin)
  • Exogenous marker of GFR
  • Precise measurement

Method:

  • Intravenous infusion
  • Urine collections

Problems:

  • $$, time, not feasible in clinical setting.
radioactive markers
Radioactive markers
  • Exogenous markers
  • 125I- iothalamate
  • 99mTc- DTPA

Problems:

  • Not readily available
  • Time consuming
creatinine
Creatinine
  • By-product of muscle
  • Predominately eliminated by glomerular filtration
  • Inexpensive

Problems:

  • Poor sensitivity, specificity.
method
Method
  • 24-hr urine collection:

To determine creatinine clearance

CrCl (mL/min): Ucr * Vurine

Scr * T

  • Serum creatinine concentration
24 hr urine collection
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
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
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 equation26
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
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 equation28
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
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
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
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.