Antineoplastic treatment class modulates COVID-19 mRNA-BNT162b2 vaccine immunogenicity in cancer patients: a secondary analysis of the prospective Vax-On study.

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.

The social cost of chronic kidney disease in Italy.

This study aims to estimate the mean annual social cost per patient with chronic kidney disease (CKD) by stages 4 and 5 pre-dialyses and cost components in Italy. The multicenter cross-sectional study included all adult outpatients in charge of the 14 main Nephrology Centers of Tuscany Region during 7 weeks from 2012 to 2013. Direct medical costs have been estimated using tariffs for laboratory tests, diagnostic exams, visits, hospitalization and prices for drugs. Non-medical costs included expenses of low-protein special foods, travel, and formal and informal care. Patients' and caregivers' losses of productivity have been estimated as indirect costs using the human capital approach. Costs have been expressed in Euros (2016). Totals of 279 patients in stage 4 and 205 patients in stage 5 have been enrolled. The estimated mean annual social cost of a patient with CKD were €7422 (±€6255) for stage 4 and €8971 (±€6503) for stage 5 (p < 0.05). Direct medical costs were higher in stage 5 as compared to stage 4; direct non-medical costs and indirect costs accounted, respectively, for 41 and 5 % of the total social cost of CKD stage 4 and for 33 and 9 % of CKD stage 5. In Italy, the overall annual social cost of CKD was €1,809,552,398 representing 0.11 % of the Gross Domestic Product. Direct non-medical costs and indirect costs were weighted on the social cost of CKD almost as much as the direct medical cost. Patients, their families and the productivity system sustain the burden of the disease almost as much as the healthcare system.

The biological response to online hemodiafiltration.

The biologic response to uremia and to the associated chronic inflammation is an active area of research. Among the different modalities developed in the technology field of chronic renal replacement, hemodialfiltration has evolved consistently. On-line production of substitution fluid by 'cold sterilization' of dialysis fluid by ultrafiltration gives access to virtually an unlimited amount of sterile and non-pyrogenic intravenous grade solution. Today, on line HDF is already a widespread, accepted treatment. Here, we will review the main mechanisms through which on line hemodialfiltration acts and the biological response observed in relation to the immune system dysfunction and the anemia associated to chronic kidney disease.

Safety and effects on the lipid and C-reactive protein plasma concentration of the association of ezetimibe plus atorvastatin in renal transplant patients treated by cyclosporine-A: a pilot study.

Ezetimibe (E) is a new cholesterol adsorption inhibitor which prevents the adsorption of dietary and biliary cholesterol by binding to a recently described cholesterol transporter. This pilot study was performed to evaluate the safety and the low-density lipoprotein (LDL)-C and C-reactive protein lowering efficacy of atorvastatin (A) and of the association of A plus E in five renal transplant patients with hypercholesterolemia and mild renal functional impairment receiving cyclosporine-A (CsA). Patients received for three periods, each of 3 weeks, A at a dose of 20 mg/day; A at a dose of 10 mg/day and finally, A 10 mg plus E 10 mg daily. The medications were well-tolerated and no important clinical or laboratory (muscle enzyme, creatinine clearance and CsA concentration) abnormalities were observed throughout the study period. A alone lead to target LDL-C values only in two of five patients and did not significantly reduce the mean CRP values. The combination of E plus A produced the lowest lipid levels and significantly reduced CRP mean values and allowed all patients to attain target levels of LDL-C: total cholesterol decreased from 240 +/- 42 (mean +/- S.D.) to 171 +/- 34 mg/dl, LDL-C from 129 +/- 32 to 87 +/- 21 mg/dl, plasma triglycerides from 330 +/- 54 to 194 +/- 71 mg/dl and CRP from 6.2 +/- 1.9 to 3.9 +/- 2.4 mg/l (P < 0.05 for all). This pilot study suggests that the co-administration of E and A at 10 mg/day in renal transplant patients receiving CsA is well-tolerated and effective in reducing important cardiovascular risk factors.

C-reactive protein in patients on chronic hemodialysis with different techniques and different membranes.

In hemodialysis patients, C-reactive protein (CRP), an acute-phase reactant, is a sensitive and independent marker of malnutrition, anemia, and cardiovascular mortality. The aim of the present study was to evaluate CRP levels in plasma samples from long-term hemodialysis patients on different extracorporeal modalities and dialyzed with different membranes, at baseline and after 6 months. Two hundred and forty-seven patients were recruited in eight hospital-based centers. All patients had been on their dialytic modality for at least 3 months and were prospectively followed in their initial dialytic modality for 6 months. Patients were treated with conventional bicarbonate dialysis (N = 127) or hemodiafiltration (N = 120). Patients treated with conventional bicarbonate dialysis were dialyzed with different membranes: Cuprophane (N = 51), low-flux cellulose modified membrane (N = 37) and synthetic membranes (N = 39). Hemodiafiltration was performed in post-dilution mode with polysulfone (N = 66) and polyacrylonitrile (N = 54) membranes. Analysis of baseline CRP values in the clinically stable patients showed that an unexpectedly high proportion (47%) of the patients had CRP values higher than 5 mg/l (upper limit in normal subjects). The mean +/- S.D. CRP values were significantly higher (P < 0.05) in hemodiafiltration with infusion volumes < 10 l per session (14.6+/-3.1 mg/l) than in standard hemodialysis (5.1 +/- 2.1 mg/l) and hemodiafiltration with infusion volumes > 20 l per session (4.9 +/- 2.1 mg/l). These values did not significantly change after 6 months of follow-up. Concerning the membranes, the highest levels of CRP were observed in patients dialyzed with Cuprophane with a significant increase from 15.1 +/- 3.6 to 21.2 +/- 3.1 mg/l after 6 months (P < 0.05); a significant reduction of CRP levels was observed in patients dialyzed with polysulfone in the same follow-up period (from 13.5 +/- 2.9 to 8.1 +/- 2.4 mg/l; P < 0.05). The CRP increase following low volume HDF can be related to back-filtration of bacterial derived contaminants.; moreover, an important effect on CRP of the hemodialysis membrane is observed and new synthetic membranes can be used to decrease these levels.

Treatment with 1,25-dihydroxyvitamin D3 preserves glomerular slit diaphragm-associated protein expression in experimental glomerulonephritis.

In this study, we investigated the effect of 1,25(OH)2D3 on proteinuria and on the alteration of slit diaphragm-associated proteins induced by anti-Thy 1.1 in Wistar rats. Four groups of animals were studied: group I, anti-Thy 1.1 treated rats; group II, anti-Thy1.1 treated group that at day 2, after the onset of overt proteinuria, started the treatment with 1,25(OH)2D3; group III, normal control rats injected with vehicle alone; group IV, rats that received only 1,25(OH)2D3. At day 2, in group I and II, before the administration of 1,25(OH)2D3, protein excretion was significantly increased when compared to controls. Overt proteinuria was maintained until day 14 in group I whereas in group II protein excretion was significantly reduced from day 3 to day 14. Moreover, treatment with 1,25(OH)2D3 abrogated podocytes injury, detected as desmin expression and loss of nephrin and zonula occludens-1 (ZO-1), two slit diaphragm-associated proteins, and glomerular polyanion staining, that were observed in group I. In conclusion, these results suggest that 1,25(OH)2D3 administrated with a therapeutic regiment may revert proteinuria, counteracting glomerular podocyte injury.

[Anti-cytokine therapy: present status and future perspectives in nephrology]. / Terapia anti-citochinica: stato dell'arte e prospettive future.

The increasing understanding of the role of cytokines in chronic inflammatory disease, autoimmunity and neoplastic disease has led to a new generation of therapeutic agents, the anti-cytokine blocking agents. In this article, we review current knowledge of two different available approaches: the use of Thalidomide and the anti-cytokine antibody immune therapy. Thalidomide is an immunodulatory and antiangiogenic drug; the most pronounced effect of this drug is the inhibition of tumor necrosis factor-alpha (TNF-alpha ) production. A few years after its withdrawal from the European and Canadian markets due to severe teratogenic effects, the unexpected activity of Thalidomide in reactive lepromatous leprosy stimulated further study. After some confirmatory placebo-controlled trials, multiple researches are now in progress to evaluate the optimal dose of Thalidomide in several autoimmune and neoplastic diseases. Both passive and active immunization can safely, transiently and effectively be used, as documented by animal experimentation and confirmed by clinical trials. Novel anti-cytokine therapeutic compounds, based on passive antibody immunization, are now available to treat rheumatoid arthritis and have been shown to help in Crohn's disease and in several other autoimmune diseases, and to control neoangiogenesis in cancer patients. The durability of the benefit, safety and pharmacoeconomic issues will determine whether this early success will prove to be a major breakthrough in the treatment of these painful and incurable diseases and eventually of other chronic inflammatory conditions in uremic patients.

Inhibitory activity of the white wine compounds, tyrosol and caffeic acid, on lipopolysaccharide-induced tumor necrosis factor-alpha release in human peripheral blood mononuclear cells.

The objective of this study was to assess whether tyrosol and caffeic acid are able to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release. TNF is one of the most important cytokines involved in inflammatory reactions. The results show that both tyrosol and caffeic acid are able to inhibit LPS-induced TNF-alpha release from human monocytes, even at low doses. Their mechanisms of action are discussed and we conclude that high doses of the two compounds are not required to achieve effective inhibition of inflammatory reactions due to TNF-alpha release.

Effect of some white wine phenols in preventing inflammatory cytokine release.

Some well-known antioxidant phenols present in extravirgin olive oil have also been found in white wine. Both tyrosol and caffeic acid are phenols that are present not only in extravirgin olive oil, but also in wine, especially white wine. Their antioxidant properties are well known, but their biological effects have not yet been elucidated. In a previous study we found that these substances were able to inhibit tumor necrosis factor alpha release. The present study was carried out to assess whether these compounds are able to inhibit other inflammatory cytokines, such as interleukin-1 beta and interleukin-6. The results show that low concentrations of these phenols, which can be found in the bloodstream after intake of moderate quantities of white wine, exert significant inhibitory activity on the release of several inflammatory cytokines.

Vascular calcifications as a footprint of increased calcium load and chronic inflammation in uremic patients: a need for a neutral calcium balance during hemodialysis?

Cardiovascular complications caused by an accelerated atherosclerotic disease represent the largest single cause of mortality in chronic renal failure patients. The rapidly developing atherosclerosis of the uremic syndrome appears to be caused by a synergism of different mechanisms, such as malnutrition, oxidative stress and genetic factors. Recent studies provide evidence that chronic inflammation plays an important role in the pathogenesis of cardiovascular diseases. Hyperphosphatemia and an increased calcium-phosphate ion product have also been associated with an increased risk of death. Cardiovascular calcifications secondary to increases in phosphate and calcium load in dialysis patients might exert an important contribution to the excess cardiovascular mortality and morbidity in dialysis patients. Elevated serum levels of plasma C-reactive protein (CRP) are associated with the extent and severity of the atherosclerotic processes as well as with an increased risk of experiencing myocardial infarction and sudden cardiac death in apparently healthy subjects. In patients affected by pre-dialytic renal failure increased levels of CRP and IL-6 were recorded in 25% of our population; CRP and IL-6 were inversely related with renal function. These data suggest the activation--even in the predialytic phase of renal failure--of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome. In recent years we have investigated the hypothesis that the chronic inflammatory state of the uremic patient could be at least in part due to the dialytic technique. We have shown that the increase of CRP in stable dialysis patients may be due to the stimulation of monocyte/macrophage by backfiltration of dialysate contaminants. During conventional dialysis, a positive calcium balance and a concomitant inflammatory state may act as cofactors in the development of cardiovascular calcifications. We suggest that this hypothesis should be verified by clinical studies. A reevaluation of the ideal calcium levels in the dialysate is warranted: a neutral intradialytic calcium balance is probably more appropriate, although not easily attainable.

C reactive protein in patients with chronic renal diseases.

Base-line serum levels of plasma C-reactive protein (CRP) are predictive of future myocardial infarction and sudden cardiac death in apparently healthy subjects, suggesting the hypothesis that chronic inflammation might be important in the pathogenesis of atherothrombosis. CRP production is mediated by several inflammatory mediators: interleukin 6 (IL-6) is currently felt to be the major cytokine influencing the acute phase response. CRP and other acute phase proteins are elevated in dialysis patients and cardiovascular diseases represent the single largest cause of mortality in chronic renal failure patients. Little information is available, however regarding CRP and IL-6 plasma levels in pre-dialysis renal failure. Plasma CRP was determined by a modification of the laser nephelometry technique; IL-6 by immunoassay (RD System); and fibrinogen, serum albumin, cholesterol, triglycerides, hematocrit, white blood cell count, erythrocytic sedimentation rate (ESR) and urinary protein levels by standard laboratory techniques. Results were obtained in 102 chronic pre-dialysis patients whose mean age was 53+/-5.8 years with a mean creatinine clearance (C(Cr)) of 52+/-37 mL/min). CRP was greater than 5 mg/L in 25% of the global population. CRP and IL-6 were 4.0+/-4.6 mg/L and 5.8+/-5.6 pg/mL, respectively and were not significantly correlated (r=0.11, p=n.s.). CRP and IL-6 were however related with renal function (CRP versus C(Cr) r=-0.40 p <0.001; IL- 6 versus C(Cr) r=-0.45; p <0.001). When patients were divided in two groups according to renal function, CRP resulted 7.4+/-6.3 mg/L in the group of patients with a C(Cr) lower than 20 mL/min (n=32) and 2.76+/-4.35 in the group of patients with a C(Cr) higher than 20 mL/min (n = 70) (p <0.0001). CRP and IL-6 were positively related with ESR (r=0.32 and 0.46 respectively). Serum albumin levels were not significantly different in the two groups of patients (3.2+/-0.4 versus 3.0+/-0.5 g/dL). CRP and serum albumin were not significantly related (r=0.17). CRP and IL-6 correlated positively with ESR (r=0.32 and 0.46 respectively). In pre-dialysis patients we have demonstrated an increase in both CRP and IL-6 that occurs as renal function decreases. These data provided evidence of the activation - even in the predialysis phase of renal failure - of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome.

Echocardiographic ultrasonic tissue characterization in a case of Fabry's disease following renal transplantation.

We report a case of Fabry's disease where stabilization of progressive cardiac involvement was recorded in a 29-yr-old Caucasian man, to our knowledge, for the first time by ultrasonic tissue characterization echocardiography after 1 yr of successful renal transplantation. Three echocardiographic evaluations have been made: the first 3 months before, the second 6 months after, and the third 1 yr after kidney transplantation. The myocardial structural damage - evaluated by integrated backscatter index - shows a persistence of the impairment of intrinsic myocardial contractility at septum level, probably due to coexistent hypertensive status, which is able to induce per se alterations of myocardial textural parameters. On the other hand, the cyclic variation index at posterior free wall, which is less dependent on strictly hemodynamic factors than the septum, appears quite normal at the third observation. These data could reflect the improvement of the ultrastuctural myocardial findings in relation to renal transplantation, which could correct not only renal failure but also the enzymatic deficiency by replacement of alpha-galactosidase A through the transplanted kidney.

Effects of 1,25(OH)2D3 in experimental mesangial proliferative nephritis in rats.

BACKGROUND: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D3, is a potent immunomodulatory agent on several cell types such as monocytes and mesangial cells. Recruitment of inflammatory cells, as well as stimulation of resident cells and mesangial matrix accumulation are key features of various experimental and human glomerular diseases. Here we show that 1,25(OH)2D3 attenuates the morphologic and functional alterations in anti-Thy-1.1. nephritis, an experimental model of mesangial proliferative glomerulonephritis. METHODS: The anti-Thy-1.1 group (group I) comprised 24 rats that at day 0 received 0.5 mL of saline containing 400 microg of monoclonal antibodies (mAb) anti-Thy-1.1 IgG. The anti-Thy-1.1 treated with 1,25(OH)2D3 group (group II) were 24 rats given 1,25(OH)2D3 at the dose of 25 ng/100 g body wt/day, from day -3 to day 14. At day 0, the rats received 400 microg of anti-Thy-1.1 monoclonal IgG. The control group (group III) comprised 12 rats injected with vehicle alone; the control group treated with 1,25(OH)2D3 (group IV)-12 rats were given 1,25(OH)2D3 as in group II without mAb administration. Proteinuria and urinary interleukin-6 excretion were measured daily. Blood urea nitrogen and creatinine, creatinine clearance, calcium, and phosphate were measured at days 0, 4, 7, and 14. In addition to conventional periodic acid-Schiff staining, binding of anti-Thy-1.1 IgG and C3b complement fraction, His48- and ED1-positive cells were studied by immunofluorescence. Mesangial proliferation was studied by the proliferating cell nuclear antigen (PCNA) technique. Apoptosis was evaluated by the TUNEL assay. RESULTS: The anti-Thy-1.1 treated with 1,25(OH)2D3 group versus the anti-Thy-1.1 alone group showed a significant reduction in urinary protein (at day 7, 424 +/- 228 vs. 66 +/- 30 mg/mg urinary creatinine, P = 0.02) and interleukin-6 excretion (at day 3, 537 +/- 360 pg/mL vs. 110 +/- 34 pg/mg urinary creatinine, P = 0.015), reduced glomerular diameters (at day 7, 283 +/- 38 vs. 261 +/- 48 microm, P < 0.01), decreased neutrophil (at day 4, 20 +/- 12 His48-positive cells/glomerulus vs. 3.7 +/- 1.3 His48-positive cells/glomerulus, P < 0.001), and monocyte accumulation (day 7, 4.9 +/- 2.9 ED1-positive cells/glomerulus vs. 2.8 +/- 2.9 ED1-positive cells/glomerulus, P < 0.05), and attenuated glomerular cells proliferation (day 7, 13 +/- 3.2 PCNA-positive cells/glomerulus vs. 9.4 +/- 3 PCNA-positive cells/glomerulus, P < 0.01). Apoptosis showed a biphasic behavior with an early peak at day 4 in the anti-Thy-1.1 group (2.3 +/- 2.2 TUNEL-positive cells/glom) related to cellular lysis and a late peak at day 14 related to the recovery phase. CONCLUSIONS: 1,25(OH)2D3 can reduce glomerular hypercellularity, inflammatory infiltration in anti-Thy-1.1 nephritis, preserving the apoptotic response of the reparative phase.

Resveratrol, a polyphenol found in wine, reduces ischemia reperfusion injury in rat kidneys.

Reactive oxygen species have been implicated in the pathophysiology of renal ischemia reperfusion injury. Antioxidants including polyphenolics have been found to protect renal cells from the cellular injury induced by ischemia and reperfusion. Resveratrol, a stilbene polyphenol found in grapes and red wine, has recently been found to protect isolated rat heart from ischemia reperfusion injury. This study was sought to determine if resveratrol could also protect renal cells from ischemic injury. Male Wistar rats were treated with control, resveratrol (0.23 microg/kg), vehicle used to solubilize resveratrol, and resveratrol plus L-NAME (15 mg/kg body wt), a nitric oxide blocker. Our results demonstrated that resveratrol administration reduced the mortality of ischemic rats from 50% to 10% and renal damage was reduced as indicated by histologic examination and serum creatinine level. The short-term administration of resveratrol also inhibited renal lipid peroxidation induced by ischemia and reperfusion both in cortex and in medulla. Electron paramagnetic resonance detected an increased formation of nitric oxide in the resveratrol-treated kidney that was reduced to the baseline value after treating the rats with L-NAME in addition to resveratrol. The results suggest that resveratrol reduced the renal ischemia reperfusion injury through a nitric oxide-dependent mechanism.

Alterations of the cytokine network in hemodialysis.

This study focuses on the mechanisms responsible for monocyte activation and enhanced cytokine production in hemodialysis. Particular emphasis is given to recent recognition of a link between cytokine production and chronic inflammation following long-term complications in today's hemodialysis population, namely cardiovascular disease and malnutrition.