Giuseppe Sileno

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-β, 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-β expression and matrix deposition. Only sirolimus increased metalloprotease activity. Conclusions: Sirolimus but not calcineurin inhibitors prevented I/R-induced kidney injury.

Costimulatory Pathways in Kidney Transplantation: Pathogenetic Role, Clinical Significance and New Therapeutic Opportunities

Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.

Hemodialysis vascular access: everything you always wanted to know about it (but were afraid to ask).

Vascular accesses are essential for effective dialysis treatment. Arteriovenous fistulas, grafts and central venous catheters are the options available to the nephrologist, but they all have their pros and cons. All of the 3 types of vascular access share the same complications but at different rates, and their costs vary enormously, with on balance the arteriovenous fistula being the best choice. Nevertheless, recently the number of incident patients starting dialysis treatment with a venous catheter as vascular access has been steadily increasing. This is true even for more advanced countries such as the United States, where despite the efforts made to promote the use of fistulas, their prevalence is still low compared with Europe. Moreover, nowadays nephrologists are required to master technical skills that once were those of surgeons and to perform interventions to preserve the patency of the access. The aim of this paper is to review the prevalence, benefits and complications of the different vascular accesses in light of the most recent findings.

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.

Selective bilirubin removal: a treatment of jaundice-related kidney injury?

To the Editor: van Slambrouck et al.1 proposed the term bile cast nephropathy to describe the high prevalence of tubular bile casts in the kidneys of patients with jaundice and renal injury of different origin, suggesting a potential direct nephrotoxicity of bilirubin. This observation not only highlights an important pathogenetic mechanism, but also leads to hypothesize that bilirubin removal per se could improve renal function in jaundiced patients. Recently, we had the possibility to explore this intriguing hypothesis.

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.

Selective bilirubin removal as treatment of jaundice-related kidney injury

Severe hyperbilirubinemia is often associated with acute kidney injury (AKT). Considering the potential renal toxicity of bilirubin, it is possible that bilirubin removal per se could represent a way to improve renal function in patients experiencing jaundice-related AKI. Here we present the case of a 47-year-old male patient, who was admitted due to severe jaundice and ascites. The patient presented a history of idiopathic myelofibrosis, associated with liver disease with stable bilirubin values of about 4 mg/dL. At admission, blood tests showed plasma bilirubin of 45 mg/dL, normal liver enzymes and AKI (creatinine 2.1 mg/dL vs a previous value of 0.7 mg/dL). Instrumental examinations and liver biopsy showed a picture of diffuse inflammatory cholangitis. During hospitalization, bilirubin levels further raised (up to 59.7 mg/dL) and, simultaneously, kidney function declined. We excluded functional causes of renal failure and hepatorenal syndrome and thus, suspecting a bilirubin-associated nephrotoxicity, we decided to treat the patient with plasma adsorption perfusion (PAP), a technique based on plasma adsorption by a bilirubin-specific adsorbent. After the treatment plasma bilirubin, as well as creatinine serum levels, progressively decreased. Unfortunately, about 10 days after the beginning of PAP the patient died of septic shock. This case represents an additional proof of the potential nephrotoxicity of bilirubin, suggesting that PAP could be a valuable therapeutic option in patients with jaundice-related AKI.