Mean Glomerular Volume After Renal Transplantation in Patients Receiving Sirolimus and Cyclosporine A Compared With Elimination of Cyclosporine A at 3 Months

Abstract

Glomerular enlargement after renal transplantation is associated with kidney allograft preservation. Increased glomerular size in donor biopsies is associated with donor age and with increased serum creatinine during follow-up, suggesting that older donors with larger glomeruli have exhausted their capacity for further glomerular adaptation (1). Allografts from younger donors with smaller glomeruli experience further increase of glomerular size after transplantation (2), which is associated with an improvement of renal function. The use of anticalcineurinic agents is associated with vasoconstriction and decreased glomerular filtration rate (GFR) (3). Sirolimus (SRL) has allowed withdrawing cyclosporine A (CsA) early after transplantation as it has been observed in the Rapamune Maintenance Regimen (RMR) study in which a steady improvement of GFR was observed in patients in the CsA withdrawal arm in comparison with the CsA maintenance group (4). We hypothesized that amelioration of GFR in patients after CsA withdrawal is related to glomerular size increase after transplantation. Sixty-four patients from a substudy (5) of the RMR trial conducted in Spain and Portugal with a donor and 1-year paired biopsies were reviewed. Details of the RMR study design and clinical results were published elsewhere (4–6). Of the 64 patients reviewed for this study, only 15 contained at least 10 glomerular sections in both biopsies (6 randomized to CsA elimination at 3 months and 9 maintained with CsA and SRL during the first year). Banff acute and chronic scores were blindly evaluated by a central pathologist. Vg was estimated according to the Weibel and Gomez formula using the mean glomerular area evaluated with an optical pen. Absolute differences between chronic Banff scores and mean glomerular volume (Vg) in both biopsies were calculated. Unpaired comparisons between means were done by Mann-Whitney U test and paired comparisons by Wilcoxon t test. The Vg in the donor and 1-year protocol biopsies in both groups is shown in Figure 1. In the CsA withdrawal group, a significant glomerular enlargement was observed (2.15±0.73× 106 μ3 in the donor and 2.66±0.78×106 μ3 in the 1-year biopsy, P=0.009) whereas in patients maintaining CsA, Vg decreased (2.87±0.81×106 μ3 in the donor and 2.27±0.70×106 μ3 in the 1-year biopsy, P=0.026). The Vg difference between the 1-year and the donor biopsy was significantly different between treatment arms (+0.51±0.31 vs. −0.60± 0.66×106 μ3, P=0.002).FIGURE 1.: Mean glomerular volume in donor and 1-year biopsies from patients randomized to cyclosporine A (CsA) maintenance or elimination at 3 months. Thin lines represent evolution of individual kidneys, and thick lines represent the mean for each group. SRL, sirolimus; P, prednisone.There was a positive correlation between Vg in the donor and 1-year biopsies (R=0.53; P=0.042), and this relationship was closer in patients eliminating CsA at 3 months (R=0.92, P=0.009) than in those maintaining CsA during the first year (R=0.65, P=0.059). The capsular tuft volume fraction was not different between both groups in the donor biopsy (0.58±0.13 vs. 0.61±0.07), whereas in the 1-year biopsy, it was lower in the CsA maintaining group (0.55±0.11 vs. 0.66± 0.34; P=0.045). Glomerular enlargement was associated with a lower progression of chronic lesions (Banff chronic score −0.7±1.0 vs. 2.5±1.7, P<0.01), whereas acute lesions at 1 year were not different between groups. Our data suggest that CsA prevents glomerular adaptation after transplantation and may contribute to explain why estimated GFR was superior in the CsA withdrawal group at 1 and 3 years of follow-up (4). In our study, it is important to remark that in patients receiving CsA and SRL during the first year, glomerular size significantly decreased, which may be the result of a synergistic effect of CsA and SRL impairing glomerular adaptation after renal transplantation by two different mechanisms: renal ischemia and inhibition of glomerular hypertrophy. This hypothesis is further sustained by the observation that 1-year capsule tuft volume fraction was lower in CsA- and SRL-treated patients. The higher degree of chronic tubulointerstitial damage observed in patients treated with CsA and SRL may constitute a third mechanism contributing to the impeded glomerular adaptation in patients receiving CsA and SRL. We have previously shown that interstitial inflammation and interstitial fibrosis are two major predictors of glomerular adaptation after transplantation (7). Thus, worse preservation of interstitial structure in CsA maintenance group may also account for the lack of glomerular adaptation because of peritubular capillary damage associated with interstitial fibrosis and inflammation. In summary, despite the number of cases included is low and consequently, these results should be interpreted with caution, we show that in stable grafts, the combination of CsA and SRL prevents glomerular enlargement after transplantation when compared with CsA withdrawal and SRL continuation. Joana Sellarés1 Francesc Moreso2 Juan Carlos Ruiz3 Daniel Seron2 1 Nephrology Department Hospital Universitari Bellvitge L'Hospitalet, Barcelona, Spain 2 Nephrology Department Hospital Vall d'Hebron Universitat Autonoma Barcelona Barcelona, Spain 3 Nephrology Department Hospital Universitario Marqués de Valdecilla Santander, Spain