Gianluca Fasoli

Risk Factors for Chronic Renal Dysfunction in Cardiac Allograft Recipients

Renal dysfunction is one of the most common and threatening complications in heart transplant recipients. Even if ciclosporin seems to play a central role in inducing renal damage, other factors may concur or predispose to renal injury. In order to identify factors responsible for renal dysfunction, we retrospectively studied a cohort of 114 cardiac transplant recipients during a follow-up period of at least 3 years. The patients had a normal renal function before and 0.5 months after heart transplantation. Doubling of baseline serum creatinine or attainment of serum creatinine steadily above 176.8 µmol/l (2.0 mg/dl) was used as criterion to define the end-point renal dysfunction. A series of clinical and laboratory variables were obtained from the patients’ charts at different time intervals, and their prognostic value for the occurrence of renal dysfunction was calculated by Cox proportional hazards models. 23 out of 114 patients reached the end point after a median time period of 21 months. High serum triglyceride, alanine aminotransferase, alkaline phosphatase, ciclosporin, urea, glucose, and hemoglobin levels were shown to be associated with the development of renal dysfunction. Four variables, i.e., triglyceride, ciclosporin, urea, and alkaline phosphatase, had an independent prognostic value. Our results confirm a role for ciclosporin in inducing renal dysfunction and identify hyperlipidemia and an increased plasma urea level as risk factors for renal dysfunction in heart transplant recipients.

Hyperkalemia-induced ECG abnormalities in patients with reduced renal function.

Hyperkalemia is a potentially lethal condition to be aware of in the presence of ECG abnormalities especially in patients with reduced renal function. However, ECG abnormalities are not always dependent on the degree ofhyperkalemia but may be aggravated by the rapidity of the development of hyperkalemia and by associated electrolyte disorders. We describe 3 patients with renal failure and different ECG changes induced by hyperkalemia. More severe changes were observed when hyperkalemia developed rapidly, but not in presence of electrolyte disorders. Even minor ECG abnormalities must alarm physicians in patients with renal failure since severe hyperkalemia is not always associated with critical ECG changes.

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.

Renal diseases in haemophilic patients: pathogenesis and clinical management

Haemophilia A and B are genetic X‐linked bleeding disorders, caused by mutations in genes encoding factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV and HIV infections. Different clinical problems arise from this important change in history of patients with haemophilia. In particular, ageing‐related diseases, such as diabetes, hypertension and cancer, and chronic viral infections are emerging as new challenges in this patient population. Among the different types of chronic illnesses, renal diseases are of special interest as they involve some difficult management issues. In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly complicated, because only few data are available. In this review, we discuss the pathogenesis of renal damage in patients with haemophilia, especially in those with blood‐transmitted viral infections, and the major issues about the management of renal diseases, including problems related to dialytic treatment and kidney transplantation, providing practical algorithms to guide the clinical decision‐making process.

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.