Understanding Bone Damage After Kidney Transplantation: A Retrospective Monocentric Cross Sectional Analysis.

BACKGROUND: Kidney transplantation (KT) immunosuppression may induce bone tissue damage with bone mineral density (BMD) loss increasing bone fractures risk. Steroid therapy is considered the major player, but others factors are still under review. PATIENTS AND METHODS: We designed an observational retrospective cohort study to evaluate bone damage after KT. The prevalence of osteopenia, osteoporosis, bone fractures, and the associated risk factors were investigated. The following parameters were recorded before transplantation and at the last follow-up: demographic indexes, cumulative steroid dose (CSD), dialytic and transplantologic age, previous nephropathy, femoral and lumbar BMD, fractures, immunosuppressors, calcemia, phosphoremia, rejection episodes, estimated glomerular filtration rate, and parathyroid hormone and vitamin D levels. Stata software (Stata Corporation, College Station, Texas, United States) was used for the statistical analysis, to perform the Fisher's exact test, Kruskal-Wallis test, Student t test, as well as univariate and multivariate analyses. RESULTS: The analyzed cohort was composed of 297 patients (65.3% males and 34.7% females). Sixty percent of KT patients had normal BMD, 24% had osteopenia, and 15% had osteoporosis. Twelve percent were victims of bone fractures (8.4% minor, 2% femoral, and 1.7% vertebral). A significant correlation (P <.05) was observed for both osteopenia and osteoporosis with menopause, transplantologic age, CSD, previous glomerulonephritis, and mammalian target of rapamycin (mTOR) inhibitors treatment (imTOR). CONCLUSION: This study confirms the correlation between CSD (both before and after transplantation) and post-transplantation bone damage. It also shows that a large fraction of these patients had normal BMD related with a low steroid dose in our protocols. This correlation between imTOR assumption and osteoporosis deserves attention and warrants further in vitro analyses to be performed.

Effects of continuous erythropoietin receptor activator (CERA) in kidney transplant recipients.

Erythropoietin-stimulating agents (ESAs) are commonly used to treat anemia in kidney transplant recipients (KTRs). Since 2007, continuous erythropoietin receptor activator (CERA) has been one of the newest recombinant ESAs to treat anemia in dialysis and nondialysis patients with chronic kidney disease. The efficacy of CERA to manage anemia has not been extensively evaluated in KTRs. We evaluated safety, efficacy, and satisfaction among KTRs treated with CERA. We enrolled 19 anemic KTRs (60 ± 9.3 y) who were treated with short-acting ESA for ≥24 weeks. They were shifted to the equivalent dose of CERA and followed for 24 weeks. We measured serum hemoglobin, hematocrit, creatinine, iron, ferritin, and transferrin. To investigate tolerance to and satisfaction with short-acting ESA and CERA, questionnaires were administered to the patients before shifting to CERA and at the end of the follow-up. After 6 months, CERA induced an increase in hemoglobin levels (12.3 ± 0.8 vs 11.2 ± 1.1 g/dL; P = .002, CERA vs short-acting ESA, respectively). In 2 patients treatment was discontinued because the hemoglobin increased to >13 g/dL. No significant differences were observed in serum iron and creatinine between short-acting ESA and CERA throughout the study. The questionnaires showed better compliance to CERA treatment with reduced pain at the injection site, which led subjects to prefer CERA to short-acting ESA. In summary, CERA showed better control of anemia compared with short-acting ESA. It was preferred by the majority of patients, mainly because of the reduced number of monthly injections. Our results demonstrated CERA to be effective, safe, and well tolerated in the management of anemia in KTRs.

Sirolimus prevents short-term renal changes induced by ischemia-reperfusion injury in rats.

BACKGROUND: Ischemia-reperfusion (I/R) is present at various degrees in kidney transplants. I/R plays a major role in early function and long-term survival of renal allograft. The purpose of our study was to determine if immunosuppressants modulate I/R in a model that separates I/R from all immune responses. METHODS: Sprague-Dawley rats with monolateral renal I/R received daily cyclosporine (A), tacrolimus (B), sirolimus (C) or saline (D). Sham-operated rats received saline (E). After 30 days, glomerular filtration rate for each kidney was measured by inulin clearance. Kidney injury was examined, and TGF-ß, fibronectin and metalloproteases were evaluated by real-time PCR, Western blot and zymography. RESULTS: Sirolimus, but not cyclosporine and tacrolimus, prevented a glomerular filtration rate decrease in I/R kidneys (403 ± 303 vs. 1,006 ± 484 µl/min, p < 0.05; 126 ± 170 vs. 567 ± 374 µl/min, p < 0.05; 633 ± 293 vs. 786 ± 255; A, B and C group, respectively, I/R vs. contralateral kidneys). Sirolimus reduced ED-1+ cell infiltrate, interstitial fibrosis and intimal thickening of small vessels observed in I/R kidneys of controls and calcineurin inhibitor-treated rats. Tacrolimus and cyclosporine increased fibronectin and TGF-ß expression and matrix deposition. Only sirolimus increased metalloprotease activity. CONCLUSIONS: Sirolimus but not calcineurin inhibitors prevented I/R-induced kidney injury.

Effects of sirolimus on human mesangial cells.

Mesangial cell (MC) proliferation and production of extracellular matrix or loss of MC are both central findings in a number of renal proteinuric diseases. However, the role of MC as components of the glomerular filtration barrier and whether MC alterations induce changes in the glomerular filtration barrier leading to proteinuria are still matters of debate. The effects of Sirolimus (SRL) in proteinuric nephropathies is controversial: some papers have indicated a reduction and others, an increase in proteinuria after sirolimus treatment. Considering the pivotal role of MC in the pathogenesis of many chronic nephropathies, we evaluated the effect of SRL on cultured human MC. We treated primary human MC cultures with SRL, or platelet-derived growth factor (PDGF) or SRL + PDGF, or dimethylsulfoxide, the SRL vehicle, as a control. PDGF was used to activate MC. After 48 hours treatment, MC showed a significant growth increase that was significantly reduced by SRL (P < .01). Apoptosis, determined by the TUNEL assay and flow cytometry, was not modified by the treatments at 24 hours. SRL treatment increased significantly the number of alpha-smooth muscle actin-positive cells compared with controls (P < .05). Cells treated with SRL and SRL + PDGF showed significant changes in morphology with increased mean cell surface, perimeter, and maximum diameter (P < .01) but not protein content. Furthermore, MC treated with SRL showed decreased migration through polycarbonate membranes. The changes induced by SRL may help to explain some of the in vivo effects observed in SRL-treated patients.