Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy.
BACKGROUND
Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment.


METHODS
One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18).


RESULTS
Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method.


CONCLUSIONS
This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.
Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. mweir@medicine.umaryland.edu
M R
MR
Weir
M T
MT
Ward
S A
SA
Blahut
D K
DK
Klassen
C B
CB
Cangro
S T
ST
Bartlett
J C
JC
Fink
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D019703:Calcineurin / Q000009:adverse effects*; D002908:Chronic Disease; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D009173:Mycophenolic Acid; D016559:Tacrolimus