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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Transplant Congress 2009

Boston, Massachusetts / May 30-June 3, 2009

Kidney transplant recipients are enjoying increasing longevity and studies indicate that immunosuppressive effects of calcineurin inhibitors (CNIs) provide equivalent short-term outcomes in graft and patient survival.

USRDS Data Analysis

Dr. Robert S. Woodward, Chair in Health Economics, University of New Hampshire, Durham, and colleagues addressed CNI long-term outcomes and clinical differences in a data analysis from the United States Renal Data System (USRDS) on all first single-organ renal transplants that took place between 1998 and 2002.

This analysis was carried out when Medicare was the primary payer and when maintenance immunosuppression was based on either microemulsion cyclosporine (CsA) alone or tacrolimus alone. Dr. Woodward indicated that as the analysis took place when the two agents had approximately equal market share, there were approximately equal numbers of patients on each of the two CNI-based regimens.

Patients were stratified into three cohorts: those diagnosed with diabetes prior to transplantation (pre-existing diabetes); those without pre-existing diabetes but who developed new-onset diabetes within the first three years after transplantation (NODAT); and those who did not develop diabetes within that period after transplantation.

In total, 10,104 patients in the USRDS data set had pre-existing diabetes, while 14,712 transplant recipients did not. Out of the 14,712 patients who did not have pre-existing diabetes prior to transplantation, 5700 in total developed NODAT while 9000 did not. Investigators then developed Kaplan-Meier plots to calculate both patient and graft survival over five years. They also performed a Cox proportional hazards multivariate regression analysis to confirm the size and significance of the adverse long-term effects of both CNIs on death-censored graft and patient survival as well as graft and patient survival not censored by death.

Results from these analyses indicated that 44.3% of tacrolimus patients developed NODAT within the first three years post-transplant compared with 33.1% of their CsA counterparts (P<0.001). “This is a result that is not new and which has been reported in a number of places elsewhere,” Dr. Woodward observed. In contrast, there was no difference between the two CNIs in either patient or graft survival that was not death-censored, i.e. that was not affected by patient survival, as Dr. Woodward explained.

“We did find a significant difference greater than P=0.01 - in death-censored graft survival no matter what statistical test we used, with lower graft survival in the tacrolimus cohort at a difference of about 2%,” he noted. That 2% - on top of a 20% CsA graft failure five years post-transplant—translated to about a 10% difference in death-censored graft failure in favour of CsA, he added. On Cox proportional hazards multivariate regression analysis, the difference in death-censored graft failures was roughly equivalent, where tacrolimus had a 9% greater risk of graft failure (P=0.05).

Other significant variables that emerged from the same analysis were slightly more predictable. If patients received a living donor, the risk of graft failure was lower. However, in African American patients, the risk of graft failure was higher, if they were under 35 years old at the time of transplantation, or if they had more HLA mismatches. “Using the USRDS registry data during a period that was roughly comparable in CsA and tacrolimus use, we found that CsA-based regimens were associated with a better death-censored graft survival,” Dr. Woodward concluded.

In a related poster, Dr. Woodward and colleagues computed daily average accumulated Medicare payments per patient for three years prior to transplantation and five years after transplantation. Claims were adjusted to 2002 dollars (USD).

“During the three years before transplantation, patients with and without diabetes cost Medicare approximately $39,000 and $33,000 average accumulated Medicare payments per year, respectively,” they reported. Overall, the average accumulated Medicare payments did not differ by CNI-based immunosuppression among kidney transplant recipients who did not develop diabetes within five years post-transplant. In contrast, the five-year average accumulated Medicare payment for patients who developed NODAT within five years post-transplantation was $14,457 higher for tacrolimus than for CsA, $153,452 vs. $138,995 (P<0.01). Patients with pre-existing diabetes also had the highest five-year average accumulated Medicare payments and the cost of treating these patients with tacrolimus was $10,056 higher than with CsA, investigators added. BK-associated Nephropathy: DIRECT Study

The BK member of the polyomavirus family infects between 80 to 90% of the general population, where it largely remains latent. On transplantation, immunosuppression allows the virus to surface with high levels detectable in the urine (>10 million copies/mL) in approximately 40% of kidney transplant patients (range 20 to 60%). Unchecked BK virus then becomes detectable in the blood, viremia occurring in approximately 15 to 20% of recipients. “The disease is diagnosed histologically in up to 10% of patients with a median time to diagnosis of nine months post-transplant,” as confirmed by Prof. Hans Hirsch, University Hospital, Basel, Switzerland, “and of those in whom [invasive tissue disease] is diagnosed, roughly half eventually lose their graft.”

In the largest prospective assessment of BK nephropathy yet undertaken, the DIRECT study (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring versus Tacrolimus) was a six-month, open-label, randomized multicentre study designed to define glucose abnormalities in de novo renal transplant recipients receiving either CsA microemulsion or tacrolimus along with other immunosuppressive agents.

From this cohort of 682 patients, BKV DNA load was analyzed in urine and plasma at month 1, 2, 3 and 6 and again at a follow-up visit at month 12. “We did both univariate analysis as well as multivariate regression modelling,” Prof. Hirsch indicated, into which they included a variety of explanatory variables that might affect the presence of both BK viruria and viremia.

Results from real-time PCR analyses indicated that the cumulative incidence of viruria by month 12 was 37% while the cumulative incidence of high-level viruria (>107 copies/mL) was roughly half that. The cumulative incidence of viremia at the same 12-month follow-up visit was 23% and the incidence of high-level viremia (>104 copies/mL) was slightly more than half at about 15%. BK viruria and viremia were less likely among patients in the CsA arm (Table 1). Table 1. Incidence of BK Viruria and Viremia

As Prof. Hirsch also observed, biopsy-proven acute rejection (BPAR) was more likely to occur after month 6 in viremic patients than non-viremic patients, where the incidence of BPAR reached 13% for viremic patients vs. 6.2% for non-viremic individuals. “By univariate analysis, BK viremia at month 6 was associated with higher cumulative steroid exposure and more BPAR,” he confirmed, “while by multivariate analysis, CsA was associated with a lower risk of high-level viruria as well as high-level viremia in patients with HLA mismatches of less than 4, male gender and white race.”