Preservation of graft function in low-risk living kidney transplant recipients treated with a combination of sirolimus and cyclosporine

The use of sirolimus (SRL) in combination with full doses of cyclosporin A (CsA) results in reduced one-year kidney allograft function, which is associated with shorter long-term allograft survival. We determined the effect of reduced CsA exposure on graft function in patients receiving SRL and prednisone. Ninety recipients of living kidney transplants receiving SRL (2 mg/day, po) were compared to 35 recipients receiving azathioprine (AZA, 2 mg kg-1 day-1, po). All patients also received CsA (8-10 mg kg-1 day-1, po) and prednisone (0.5 mg kg-1 day-1). Efficacy end-point was a composite of biopsy-confirmed acute rejection, graft loss, or death at one year. Graft function was measured by creatinine, creatinine clearance, and graft function deterioration between 3 and 12 months (delta1/Cr). CsA concentrations in patients receiving SRL were 26 percent lower. No differences in one-year composite efficacy end-point were observed comparing SRL and AZA groups (18 vs 20 percent) or in the incidence of biopsy-proven acute rejection (14.4 and 14.3 percent). There were no differences in mean ± SD creatinine (1.65 ± 0.46 vs 1.60 ± 0.43 mg/dl, P = 0.48) or calculated creatinine clearances (61 ± 15 vs 62 ± 13 ml/min, P = 0.58) at one year. Mean ± SD delta1/Cr (-11 ± 17 vs -14 ± 15 percent, P = 0.7) or the percentage of patients with >20 percent (26 vs 31 percent, P = 0.6) or >30 percent delta1/Cr (19 vs 17 percent, P = 1) did not differ between the two groups. The use of 2-mg fixed oral doses of SRL and reduced CsA exposure was effective in preventing acute rejection and preserving allograft function.

Preservation of graft function in low-risk living kidney transplant recipients treated with a combination of sirolimus and cyclosporine.

The use of sirolimus (SRL) in combination with full doses of cyclosporin A (CsA) results in reduced one-year kidney allograft function, which is associated with shorter long-term allograft survival. We determined the effect of reduced CsA exposure on graft function in patients receiving SRL and prednisone. Ninety recipients of living kidney transplants receiving SRL (2 mg/day, po) were compared to 35 recipients receiving azathioprine (AZA, 2 mg kg-1 day-1, po). All patients also received CsA (8-10 mg kg-1 day-1, po) and prednisone (0.5 mg kg-1 day-1). Efficacy end-point was a composite of biopsy-confirmed acute rejection, graft loss, or death at one year. Graft function was measured by creatinine, creatinine clearance, and graft function deterioration between 3 and 12 months (delta1/Cr). CsA concentrations in patients receiving SRL were 26% lower. No differences in one-year composite efficacy end-point were observed comparing SRL and AZA groups (18 vs 20%) or in the incidence of biopsy-proven acute rejection (14.4 and 14.3%). There were no differences in mean +/- SD creatinine (1.65 +/- 0.46 vs 1.60 +/- 0.43 mg/dl, P = 0.48) or calculated creatinine clearances (61 +/- 15 vs 62 +/- 13 ml/min, P = 0.58) at one year. Mean +/- SD delta1/Cr (-11 +/- 17 vs -14 +/- 15%, P = 0.7) or the percentage of patients with >20% (26 vs 31%, P = 0.6) or >30% delta1/Cr (19 vs 17%, P = 1) did not differ between the two groups. The use of 2-mg fixed oral doses of SRL and reduced CsA exposure was effective in preventing acute rejection and preserving allograft function.

Long-term kidney transplant outcomes in patients receiving oil-based or microemulsion formulations of cyclosporine.

UNLABELLED: In the last 20 years long-term experience with cyclosporine use in kidney transplantation has increased, allowing a more precise identification of its benefits. METHODS: We performed a retrospective analysis of 1619 kidney transplants that received cyclosporine-based immunosuppressive therapy. Patients were divided into three groups (1) oil-based cyclosporine (SIM) with trough monitoring (GI, n=617); (2) microemulsion formulation (NEO) with trough monitoring (GII, n=962); and (3) NEO with C2 monitoring (GIII, n=40). Information was obtained on transplant demography; adjunctive immunosuppressive agent; living (LD) versus cadaveric (CAD) recipients; delayed graft function; any treated acute rejection; graft function at 3, 6, and 12 months, patient and graft survival, as well as causes of graft loss and death. RESULTS: At 15 years follow-up, patient and graft survival were 67.5% and 41.6%, being superior, among LD versus CAD recipients (patient: 78.7% vs 57.7%, P<.001; graft: 56.4% vs 30.5%, P<.001). In LD (54% vs 32%, P<.001) and CAD (69% vs 55%, P<.001) NEO reduced the incidence of AR and improved 8-year patient (LD: 81.8% vs 94.7%; CAD: 66.4 vs 79.9%, P<.01) and graft survival (LD: 58.3 vs. 80%; CAD: 40.2% vs. 59.5%, P<.01), compared to SIM. Overall 8-year graft survival was inferior among patients with increased 1-year creatinine values (< or =1.5, 1.6-2.5 and >2.5 mg/dL) level (74% vs 63.9% vs 22.4%, P<.001) or change in Cr (< or =0.1, 0.2-0.4, >0.5 mg/dL) level (73.1% vs 61.9% vs 37.2%, P<.001). In patients at the same level of graft function, those receiving NEO showed superior 8-year patient and graft survival compared with SIM. CONCLUSION: Compared to SIM, NEO reduced the incidence of acute rejection and produced superior long-term patient and graft survival.

Predictive value of urinary retinol binding protein for graft dysfunction after kidney transplantation.

UNLABELLED: High concentrations of retinol binding protein (RBP) are found in the urine of patients with tubulointerstitial injury. We evaluated the predictive value of urinary RBP (RBPu) for development graft dysfunction after kidney transplantation. METHODS: Serum creatinine and RBPu were prospectively measured at months 3, 6, and 12 in 221 kidney transplant patients. Baseline graft function was defined as the lowest serum creatinine value during the first 3 months after transplantation. Graft dysfunction was assessed at 1 year as a >-20% or >-30% change in the inverse creatinine ((Delta)1/Cr) compared to baseline value at month 3. RESULTS: Among 183 patients with normal graft function (Cr 0.6 mg/L (95% CI = -13% to -1.3%, P =.018). The percentage of patients with >-20% or >-30% (Delta)1/Cr was higher among patients with RBPu > 0.6 mg/L (34% vs 47%, P =.042; 21% vs 34%, P =.035). RBPu > 0.6 mg/L was the only variable independently associated with >-30% (Delta)1/Cr at 1 year, with an odds ratio (OR) of 1.95 (95% CI 0.99 to 3.80, P =.05). CONCLUSIONS: RBPu may serve as a surrogate marker for graft dysfunction early after transplantation for patients with normal graft function, allowing early institution of intervention therapies to prolong allograft survival.

Interleukin-2 gene polymorphism is associated with renal but not cardiac transplant outcome.

It was recently shown that IL-2 gene single nucleotide polymorphism (SNP) at position -330 (G-->T) is related to in vitro cytokine production levels, with the T/T and T/G genotypes being associated with low production and the G/G genotype associated with high production. The objective of this study was to investigate a possible influence of this polymorphism on renal and cardiac allograft outcomes. IL-2 SNP G-T (-330) was determined by PCR-RFLP in 67 recipients of heart allografts and in 63 recipients of renal grafts from HLA-haplo-identical, related donors. A higher frequency of the T/T genotype was observed in renal transplant patients who experienced at least one acute rejection episode during the first 3 months after transplantation than in those without rejection during this period (80% vs 49%, respectively, P <.05). Accordingly, the same genotype tended to be more frequent in renal recipients with a 6-month serum creatinine level above 1.5 mg/dL (median value for the whole group of kidney recipients) than in patients with lower creatinine levels (79% vs 45%, P <.08). Regarding cardiac transplant recipients, no associations were observed concerning acute rejection or graft survival. The finding of the association of T/T but not T/G genotype with acute kidney rejection was unexpected considering that both genotypes were shown to be associated with equal (low) IL-2 in vitro production. Further studies are necessary not only to dissect the nature of IL-2 T/T genotype association with kidney rejection, but also to explain why this genotype does not apparently influence cardiac allograft outcome.

Safety and efficacy of sirolimus in kidney transplant patients and in patients with coronary artery disease undergoing angioplasty.

UNLABELLED: We show the key results of our 4-year experience with sirolimus in kidney transplant patients and in nontransplanted patients undergoing coronary angioplasty. METHODS: Recipients of one-haplotype living-related kidney allografts were randomized to receive sirolimus (2 mg/d, n = 35) or azathioprine (2 mg/kg per day, n = 35). Recipients of fully mismatched living kidney allografts (n = 55) received sirolimus (2 mg/day). High-risk recipients of black ethnicity (n = 68) were randomized to target whole-blood trough sirolimus concentrations between 8 and 12 ng/mL or 15 to 20 ng/mL. All kidney transplant patients received cyclosporine and prednisone. Sirolimus/cyclosporine pharmacokinetic studies were performed in 40 patients receiving 2 mg (n = 20) or 5 mg (n = 20) of sirolimus 7 days after transplantation. In the coronary intervention study, 12 patients at high risk for in-stent restenosis received sirolimus for 28 days after angioplasty. RESULTS: The incidence of biopsy-confirmed acute rejection was 11.4% in recipients of one-haplotype living-related kidney allografts, 16.4% in recipients of fully mismatched living kidney allografts, and 15% (8 to 12 ng/mL) and 4% (15 to 20 ng/mL) in high-risk recipients of black ethnicity. Cyclosporine exposure was higher after morning administration compared to evening administration. There were poor correlations between sirolimus and cyclosporine exposures. The 4-month follow-up angiography revealed no restenosis (stenosis diameter > 50%), a late loss of 0.56 +/- 0.40 mm, and a loss index of 0.33 +/- 0.30. The follow-up 3D-intravascular ultrasound restudy showed an in-stent relative volumetric obstruction of 9.9 +/- 5.5%. Sirolimus in highly effective in preventing kidney allograft acute rejection and in-stent coronary restenosis.