COVID-19: The Dysregulated Response to Infection - Why Consider Polymethylmethacrylate Membrane in Hemodialysis Patients?

Since SARS-CoV-2 spread through China at the end of 2019, COVID-19 has been probably the most difficult challenge in the last decades for healthcare systems all around the world, still representing a danger for fragile patients with different comorbidities. Chronic dialysis patients affected by COVID-19 experienced severe disease with a higher mortality rate compared to the general population. Morbidity and mortality of this severe acute respiratory syndrome depend on both acute respiratory failure and systemic immunological involvement with consequent inflammation-mediated injury. Indeed, the most important determining factor of COVID-19 severity is the strength of the so-called "cytokine storm" associated with SARS-CoV-2 infection. Therefore, this severe infection varies clinically from an asymptomatic condition to a generalized and violent inflammatory response and acute respiratory distress syndrome, with consequent pulmonary interstitial edema and a high risk of multi-organ failure. The use of extracorporeal therapies targeting cytokine clearance to improve patients' outcomes has been widely debated, especially in end-stage kidney disease's patients on maintenance dialysis or in individuals affected by acute kidney injury admitted to intensive care units. Different studies were conducted to demonstrate how specific dialyzers could decrease the COVID-19 inflammatory state. The aim of this narrative review was to summarize main studies about this topic, focusing primarily on the role of polymethylmethacrylate dialyzer and underlining pros and cons of this sorbent.

Updates on C3 Glomerulopathy in Kidney Transplantation: Pathogenesis and Treatment Options.

C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement's alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigger the alternative complement pathway. In this review, we summarize the impact of C3 glomerulopathy on kidney grafts and present the latest treatment options. The most widely used treatments for the disease include corticosteroids and mycophenolate mofetil, which are already used chronically by kidney transplant recipients; thus, additional treatments for C3 glomerulopathy are required. Currently, several studies using anti-complement drugs (i.e., eculizumab, Ravalizumab, avacopan) for C3 glomerulopathy in kidney transplant patients are ongoing with encouraging results.

Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies.

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.

Immunosuppressive therapy and oral anticoagulation in kidney transplant recipients: Direct oral anticoagulants versus vitamin-k antagonists.

BACKGROUND: direct oral anticoagulants (DOACs) are an alternative to conventional antagonist of vitamin-K (AVK). However, immune suppressive drugs (ISDs) may interfere with DOACs pharmacokinetic. AIM OF THIS STUDY: evaluate safety and efficacy profile of DOACs compared to AVK in kidney transplant recipients (KTRs) treated with ISDs. METHODS: a multi-center study from 4 Italian University hospitals enrolling consecutive KTRs on DOACs or AVK was carried out. Sixty-six patients on DOACs were compared with fifty patients on AVK with similar clinical features. Serial evaluation of renal function and serum levels of ISDs during 18 months follow-up (FU) was performed. RESULTS: Mean age of DOACs patients was 67±9 and mean eGFR was 58,3± 30,4mL/min/1.73m2. ISDs included tacrolimus (n=47, 71%), cyclosporin (n=13, 20%), everolimus (n=10, 7%) and sirolimus (n=4, 6%). After 14 days of DOACs therapy initiation there was a slight increase of serum levels of tacrolimus (+0.19±0.67 p=0.80) and cyclosporine (+0.12±0.25 p=0.94) not statistically significant. Levels of Tacrolimus and cyclosporin were stable at serial evaluation during 18-months follow-up. There were no thromboembolic events among patients treated with DOACs or AVK and no differences in term of major bleeding (6% vs 4% p=0.69), at long-term follow-up. There was no difference in term of eGFR decline from start therapy to 18 months FU between DOACs vs AVK therapy (-3.9±1 vs -3.8±2 p=0.82). CONCLUSION: DOACs have similar safety and efficacy than AVK among KTRs treated with ISDs. However, careful evaluation of potential drug interaction and ISDs serum levels is needed.

Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus.

Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.

Role of Complement in Regulating Inflammation Processes in Renal and Prostate Cancers.

For decades, the complement system, the central pillar of innate immune response, was recognized as a protective mechanism against cancer cells and the manipulation of complement effector functions in cancer setting offered a great opportunity to improve monoclonal antibody-based cancer immunotherapies. Similarly, cellular senescence, the process of cell cycle arrest that allow DNA and tissue repair has been traditionally thought to be able to suppress tumor progression. However, in recent years, extensive research has identified the complement system and cellular senescence as two main inducers of tumour growth in the context of chronic, persistent inflammation named inflammaging. Here, we discuss the data describing the ambivalent role of senescence in cancer with a particular focus on tumors that are strongly dependent on complement activation and can be understood by a new, senescence-related point of view: prostate cancer and renal cell carcinoma.