Combined use of handgrip strength and hemoglobin as markers of undernutrition in patients with stage 3-5 chronic kidney disease.

BACKGROUND AND AIMS: The early identification of undernourished patients with CKD could help instating appropriate nutritional intervention before the full development of the threatening condition known as Protein Energy Wasting (PEW). Handgrip strength (HGS) and blood hemoglobin (Hb) concentration are two parameters considered representative of nutritional status but not included among the criteria for PEW diagnosis. In the present work we investigated whether they could help identifying CKD patients at risk of undernutrition. METHODS AND RESULTS: We performed a two-step cluster analysis to classify a cohort of 71 stage 3-5 CKD patients, none of which with PEW, according to their Hb concentration and dominant-hand HGS. Two clusters were finely separated using this method. When we compared the two groups for main body composition and nutritional variables by using t-test statistics or Mann-Whitney test, as appropriate, we found significant differences in PhA, ECW/TBW, ASMI, serum iron. Then we stratified our population by gender and performed cluster analysis as well. PhA, ECW/TBW were still significantly different in the two clusters both in M and in F, while serum iron concentration only in males and ASMI only in females. CONCLUSION: These results suggest that either in male than in female Hb concentration and HGS may distinguish two subgroups of CKD patients with different nutritional status and disease severity. Patient belonging to either of these cluster can be easily identified by using the HGS/Hb ratio which represents the HGS normalized per gr Hb.

Could Alcohol Abuse and Dependence on Junk Foods Inducing Obesity and/or Illicit Drug Use Represent Danger to Liver in Young People with Altered Psychological/Relational Spheres or Emotional Problems?

Recent data show that young people, mainly due to the pressure of some risk factors or due to disrupted interpersonal relationships, utilise greater reward value and display greater sensitivity to the reinforcing properties of "pleasurable stimuli", specifically in those situations in which an enhanced dopamine release is present. Alcoholic beverages, foods rich in sugar and fat, and illicit drug use are pleasurable feelings associated with rewards. Research shows that there is a link between substance abuse and obesity in brain functioning. Still, alcohol excess is central in leading to obesity and obesity-related morbidities, such as hepatic steatosis, mainly when associated with illicit drug dependence and negative eating behaviours in young people. It is ascertained that long-term drinking causes mental damage, similarly to drug abuse, but also affects liver function. Indeed, beyond the pharmacokinetic interactions of alcohol with drugs, occurring in the liver due to the same metabolic enzymes, there are also pharmacodynamic interactions of both substances in the CNS. To complicate matters, an important noxious effect of junk foods consists of inducing obesity and obesity-related NAFLD. In this review, we focus on some key mechanisms underlying the impact of these addictions on the liver, as well as those on the CNS.

Steatosis, Steatohepatitis and Cancer Immunotherapy: An Intricate Story.

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed.

Neurobiology of coronaviruses: Potential relevance for COVID-19.

In the first two decades of the 21st century, there have been three outbreaks of severe respiratory infections caused by highly pathogenic coronaviruses (CoVs) around the world: the severe acute respiratory syndrome (SARS) by the SARS-CoV in 2002-2003, the Middle East respiratory syndrome (MERS) by the MERS-CoV in June 2012, and Coronavirus Disease 2019 (COVID-19) by the SARS-CoV-2 presently affecting most countries In all of these, fatalities are a consequence of a multiorgan dysregulation caused by pulmonary, renal, cardiac, and circulatory damage; however, COVID patients may show significant neurological signs and symptoms such as headache, nausea, vomiting, and sensory disturbances, the most prominent being anosmia and ageusia. The neuroinvasive potential of CoVs might be responsible for at least part of these symptoms and may contribute to the respiratory failure observed in affected patients. Therefore, in the present manuscript, we have reviewed the available preclinical evidence on the mechanisms and consequences of CoVs-induced CNS damage, and highlighted the potential role of CoVs in determining or aggravating acute and long-term neurological diseases in infected individuals. We consider that a widespread awareness of the significant neurotropism of CoVs might contribute to an earlier recognition of the signs and symptoms of viral-induced CNS damage. Moreover, a better understanding of the cellular and molecular mechanisms by which CoVs affect CNS function and cause CNS damage could help in planning new strategies for prognostic evaluation and targeted therapeutic intervention.

Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria.

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.

Prevalence of obesity and obesity-associated muscle wasting in patients on peritoneal dialysis.

BACKGROUND AND AIMS: A progressive decrease in muscle mass until full-blown sarcopenia may occur in patients on peritoneal dialysis (PD) and worsen their life quality and expectancy. Here we investigate the prevalence of obesity and obesity-associated muscle wasting in PD patients. PATIENTS AND METHODS: The study design was observational, cross sectional. Body composition was assessed with BIA and BIVA in 88 PD patients (53.4 ± 13.1 years; 67% male). Patients with obesity and/or with reduced muscle mass were identified using FMI and SM/BW cutoff values, respectively. Inflammatory status was assessed by measuring CRP and fibrinogen blood levels. RESULTS: A total of 44.3% of the patients showed a reduced muscle mass (37.5% moderate and 6.8% severe). The prevalence of obesity was 6.1%, 81.8%, and 100% in patients with normal, moderately, and severely reduced muscle mass, respectively (p < 0.05). Of the total, 15.2% of the patients with normal muscle mass, 18.4% of those with moderately reduced muscle mass, and 66.7% of those with severely reduced muscle mass had diabetes. The prevalence of severe muscle mass loss was higher in those with diabetes than in those without diabetes (22.2% vs. 2.8%, p < 0.05). Patients with obesity-associated muscle wasting showed higher fibrinogen (613.9 ± 155.1 vs. 512.9 ± 159.5 mg/dL, p < 0.05) and CPR (1.4 ± 1.3 vs. 0.6 ± 0.8 mg/dL, p < 0.05) blood concentrations than those with normal body composition. CONCLUSION: Obesity and diabetes were strongly associated with muscle mass loss in our PD patients. It remains to be established whether prevention of obesity with nutritional interventions can halt the occurrence of muscle mass loss in patients on PD.

Comparison of the everolimus concentrations measured in whole blood with everolimus QMS or sirolimus CMIA.

Few years ago, it was proposed that everolimus blood levels could be determined with the commercially available sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA). More recently, a highly specific microsphere system (QMS) has been approved by FDA for therapeutic drug monitoring in humans. Aim of the present study was to compare the results of everolimus assay performed with everolimus QMS and with sirolimus CMIA. The two methods were compared with Passing-Bablok regression and Bland-Altman plot analysis. The Passing-Bablok regression analysis showed that although the results obtained with the two techniques were significantly correlated, CMIA-measured differed from QMS-measured everolimus concentrations by both a systematic and a proportional error. Specifically, at blood levels lower than 5 ng/mL CMIA were lower than QMS-measured everolimus concentrations. On the opposite, at everolimus blood concentrations higher than 10 ng/mL CMIA-estimated values became progressively higher than QMS-measured everolimus concentrations. The analysis of the Bland Altman plot showed a less than optimal agreement of the two tests (5.59% of the data point outside the ±1.96 SD interval). Moreover, the relationship between the difference between EveroQMS and EveroCMIA and their average was clearly concentration dependent with positive and negative values at concentration values lower and higher than 5 ng/mL respectively. In conclusion, our finding showed that the values of everolimus concentrations measured with sirolimus CMIA differ from those detected with the FDA-approved everolimus QMS further suggesting that sirolimus CMIA should not be used anymore for everolimus therapeutic drug monitoring.

Effect of a Short-Course Treatment with Synbiotics on Plasma p-Cresol Concentration in Kidney Transplant Recipients.

OBJECTIVE: We evaluated whether a short-term course with synbiotics may lower plasma p-Cresol concentrations in kidney transplant patients (KTRs) who accumulate this uremic toxin both because of increased production by their dysbiotic gut microbiome and because of reduced elimination by the transplanted kidneys. METHODS: Thirty-six KTRs (29 males, mean age 49.6 ± 9.1 years) with transplant vintage > 12 months, stable graft function, and no episode of acute rejection or infection in the last 3 months were enrolled in this single-center, parallel-group, double-blinded, randomized (2:1 synbiotic to placebo) study. Synbiotic (Probinul Neutro, CadiGroup, Rome, Italy) or placebo was taken at home for 30 days, as 5 g powder packets dissolved in water three times a day far from meals. The main outcome measure was the decrease in total plasma p-Cresol measured by high-performance liquid chromatography at baseline and after 15 and 30 days of placebo or synbiotic treatment. RESULTS: After 15 and 30 days of treatment, plasma p-Cresol decreased by 40% and 33% from baseline (both p < 0.05), respectively, in the synbiotic group, whereas it remained stable in the placebo group. After 30 days of treatment, no significant change was observed in either group in renal function, glycemia, plasma lipids, or albumin concentration. Treatment was well tolerated and did not induce any change in stool characteristics. CONCLUSION: The results of this pilot study suggest that treatment with synbiotics may be effective to lower plasma p-Cresol concentrations in KTRs. Prospective larger scale, longer term studies are needed to establish whether cardiovascular prognosis could also be improved with this nutritional intervention.

Emerging Role of the Spleen in the Pharmacokinetics of Monoclonal Antibodies, Nanoparticles and Exosomes.

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been traditionally ascribed to the spleen in these fundamental pharmacokinetic processes was definitely marginal. However, due to its high blood flow and to the characteristics of its microcirculation, this organ would be expected to be significantly exposed to large, new generation drugs that can hardly penetrate in other tissues with tight endothelial barriers. In the present review, we examine the involvement of the spleen in the disposition of monoclonal antibodies, nanoparticles and exosomes and the possible implications for their therapeutic efficacy and toxicity. The data that we will review lead to the conclusion that a new role is emerging for the spleen in the pharmacokinetics of new generation drugs, hence suggesting that this small, neglected organ will certainly deserve stronger attention by pharmacologists in the future.

Evidence That Skeletal Muscles Modulate HDL-Cholesterol in Metabolic Healthy Young Adults.

The aim of this study was to investigate whether skeletal muscle (SM) mass correlates with plasma lipids in metabolic healthy young adults. The study was designed as a retrospective observational monocentric study. Data on plasma lipids and SM mass of subjects attending our institution from 1999 to 2014 were analyzed. Inclusion criteria were being 18-45 years old and in apparently good health. SM mass was evaluated by bioelectrical impedance analysis (BIA) using the equation proposed by Janssen and normalized to height as skeletal muscle index (SMI: SM mass/height2). The association between SMI and plasma lipids levels was examined using a crude and adjusted linear regression model including age, sex, BMI and waist circumference as additional covariates. The study population consisted of 450 subjects (273 females) without metabolic syndrome (12.2% with normal body weight, 33.1% overweight, and 54.7% with obesity). SMI, total-cholesterol, LDL-cholesterol, and Triglycerides were higher, whereas HDL-cholesterol was lower in overweight and obese patients as compared with normal weight subjects. SMI was inversely associated with HDL-cholesterol in female patients with obesity but not in male patients with obesity, in normal- or over-weight subjects (p < 0.05). These results suggest that changes in SM mass occurring in obesity could have a role in worsening lipid profile with special reference to HDL-cholesterol.

Resting state networks in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is typically described as a neurologic disorder affecting a cerebral network comprising the hippocampus proper and several anatomically related extrahippocampal regions. A new level of complexity was recently added to the study of this disorder by the evidence that TLE also appears to chronically alter the activity of several brain-wide neural networks involved in the control of higher order brain functions and not traditionally linked to epilepsy. Recently developed brain imaging techniques such as functional magnetic resonance imaging (fMRI) analysis of resting state connectivity, have greatly contributed to these observations by allowing the precise characterization of several brain networks with distinct functional signatures in the resting brain, and therefore also known as "resting state networks." These significant advances in imaging represent an opportunity to investigate the still elusive origins of the disabling cognitive and psychiatric manifestations of TLE, and could have important implications for its pathophysiology and, perhaps, its therapy. Herein we review recent studies in this field by focusing on resting state networks that have been implicated in the pathophysiology of psychiatric disorders and cognitive impairment in patients with epilepsy: the default mode network, the attention network, and the reward/emotion network.

Effects of a diet rich in N-3 polyunsaturated fatty acids on systemic inflammation in renal transplant recipients.

OBJECTIVE: n-3 Polyunsaturated fatty acids (PUFAs) supplementation reduces systemic inflammation and improves renal and cardiovascular prognosis in kidney transplant recipients. However, patient compliance is poor because bad-tasting fish oils are used as an n-3 PUFA source. Therefore, we explored whether the beneficial effects of n-3 can be obtained by administering a diet based on n-3-rich foods. METHODS: Sixty kidney transplant recipients were assigned to 2 different groups: the CON group (n = 28), which continued with their usual diet, and the DIET group (n = 32), which followed an n-3-rich diet for 6 months. Twenty-six patients in the DIET group and 24 in the CON group completed the study. End points of the study were changes in n-3 PUFAs intake, n-6:n-3 PUFAs ratio, systemic inflammation markers, and renal function during the 6 months of the dietary treatment. RESULTS: Three and 6 months after the beginning of the study, n-3 PUFA intake was significantly higher and the n-6:n-3 PUFA ratio was markedly lower than baseline in the DIET group. Plasma total cholesterol, triglycerides, C-reactive protein, and interleukin (IL)-6 decreased as well. IL-6 mRNA levels in peripheral blood mononuclear cells were also lower than at the beginning of the study. Proteinuria and microalbuminuria were reduced by 50% with respect to the baseline, whereas glomerular filtration rate (GFR) was unchanged. No change in the aforementioned parameters was observed in the CON group throughout the study. CONCLUSION: In long-term kidney transplant recipients a naturally n-3 PUFA-rich dietary plan causes an increase in n-3 PUFA intake, decreases systemic inflammation and proteinuria, and improves plasma lipid pattern.

The changing landscape of voltage-gated calcium channels in neurovascular disorders and in neurodegenerative diseases.

It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca(2+) in neurons. Also, some of them as L-type channels are essential for Ca(2+)-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the "harmless" VGCCs may become "toxic" for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca(2+) when: a) their density or activity increases because of aging, chronic hypoxia or exposure to ß-amyloid peptides or b) Ca(2+)-dependent action potentials carry high Ca(2+) loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca(2+). This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca(2+)-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia.

Transcriptional regulation of ncx1 gene in the brain.

The ubiquitous sodium-calcium exchanger isoform 1 (NCX1) is a -bidirectional transporter that plays a relevant role under physiological and pathophysiological conditions including brain ischemia by regulating intraneuronal Ca(2+) and Na(+) homeostasis. Although changes in ncx1 protein and transcript expression have been detected during stroke, its transcriptional regulation is still largely unexplored. Here, we reviewed our recent findings on several transcription factors including cAMP response element-binding protein (CREB), nuclear factor kappa B (NF-κB), and hypoxia-inducible factor-1 (HIF-1) in the control of the ncx1 gene expression in neuronal cells.

Genetically modified mice as a strategy to unravel the role played by the Na(+)/Ca (2+) exchanger in brain ischemia and in spatial learning and memory deficits.

Because no isoform-specific blocker of NCX has ever been synthesized, a more selective strategy to identify the role of each antiporter isoform in the brain was represented by the generation of knockout and knockin mice for the different isoforms of the antiporter.Experiments performed in NCX2 and NCX3 knockout mice provided evidence that these two isoforms participate in spatial learning and memory consolidation, although in an opposite manner. These new data from ncx2-/- and ncx3-/- mice may open new experimental avenues for the development of effective therapeutic compounds that, by selectively inhibiting or activating these molecular targets, could treat patients affected by cognitive impairment including Alzheimer's, Parkinson's, Huntington's diseases, and infarct dementia.More importantly, knockout and knockin mice also provided new relevant information on the role played by NCX in maintaining the intracellular Na(+) and Ca(2+) homeostasis and in protecting neurons during brain ischemia. In particular, both ncx2-/- and ncx3-/- mice showed an increased neuronal vulnerability after the ischemic insult induced by transient middle cerebral artery occlusion.As the ubiquitous deletion of NCX1 brings about to an early death of embryos because of a lack of heartbeat, this strategy could not be successfully pursued. However, information on the role of NCX1 in normal and ischemic brain could be obtained by developing conditional knockout mice lacking NCX1 in the brain. Preliminarily results obtained in these conditional mice suggest that also NCX1 protects neurons from ischemic cell death.Overall, the use of genetic-modified mice for NCX1, NCX2, and NCX3 represents a fruitful strategy to characterize the physiological role exerted by NCX in CNS and to identify the isoforms of the antiporter as potential molecular targets for therapeutic intervention in cerebral ischemia.

Probiotics and Prebiotics: Any Role in Menopause-Related Diseases?

PURPOSE OF REVIEW: The aim of this review is to provide an overview of the menopause-related changes in microbiota and their role in the pathogenesis of menopause-related diseases. In addition, evidence on probiotic supplementation as a therapeutic strategy is discussed. RECENT FINDINGS: The human microbiota is a complex community that lives in a mutualism relationship with the host. Menopause is associated with dysbiosis, and these changes in the composition of microbiota in different sites (gut, vaginal, and oral microbiota) might play a role in the pathogenesis of menopause-related diseases (i.e., osteoporosis, breast cancer, endometrial hyperplasia, periodontitis, and cardiometabolic diseases). The present review highlights the pivotal role of microbiota in postmenopausal women health, in particular it (a) may increase intestinal calcium absorption thus preventing osteoporosis, (b) is associated with reduced risk of breast cancer and type 1 endometrial hyperplasia, (c) reduces gingival inflammation and menopausal periodontitis, and (d) beneficially affects multiple cardiometabolic risk factors (i.e., obesity, inflammation, and blood glucose and lipid metabolism). However, whether oral probiotic supplementation might be used for the treatment of menopause-related dysbiosis requires further clarification.

A Pharmacovigilance Study on the Safety of Axicabtagene Ciloleucel Based on Spontaneous Reports from the EudraVigilance Database.

During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells.

Identification of Drugs Acting as Perpetrators in Common Drug Interactions in a Cohort of Geriatric Patients from Southern Italy and Analysis of the Gene Polymorphisms That Affect Their Interacting Potential.

BACKGROUND: Pharmacogenomic factors affect the susceptibility to drug-drug interactions (DDI). We identified drug interaction perpetrators among the drugs prescribed to a cohort of 290 older adults and analysed the prevalence of gene polymorphisms that can increase their interacting potential. We also pinpointed clinical decision support systems (CDSSs) that incorporate pharmacogenomic factors in DDI risk evaluation. METHODS: Perpetrator drugs were identified using the Drug Interactions Flockhart Table, the DRUGBANK website, and the Mayo Clinic Pharmacogenomics Association Table. Allelic variants affecting their activity were identified with the PharmVar, PharmGKB, dbSNP, ensembl and 1000 genome databases. RESULTS: Amiodarone, amlodipine, atorvastatin, digoxin, esomperazole, omeprazole, pantoprazole, simvastatin and rosuvastatin were perpetrator drugs prescribed to >5% of our patients. Few allelic variants affecting their perpetrator activity showed a prevalence >2% in the European population: CYP3A4/5*22, *1G, *3, CYP2C9*2 and *3, CYP2C19*17 and *2, CYP2D6*4, *41, *5, *10 and *9 and SLC1B1*15 and *5. Few commercial CDSS include pharmacogenomic factors in DDI-risk evaluation and none of them was designed for use in older adults. CONCLUSIONS: We provided a list of the allelic variants influencing the activity of drug perpetrators in older adults which should be included in pharmacogenomics-oriented CDSSs to be used in geriatric medicine.

Pharmacomicrobiomics of Classical Immunosuppressant Drugs: A Systematic Review.

The clinical response to classical immunosuppressant drugs (cIMDs) is highly variable among individuals. We performed a systematic review of published evidence supporting the hypothesis that gut microorganisms may contribute to this variability by affecting cIMD pharmacokinetics, efficacy or tolerability. The evidence that these drugs affect the composition of intestinal microbiota was also reviewed. The PubMed and Scopus databases were searched using specific keywords without limits of species (human or animal) or time from publication. One thousand and fifty five published papers were retrieved in the initial database search. After screening, 50 papers were selected to be reviewed. Potential effects on cIMD pharmacokinetics, efficacy or tolerability were observed in 17/20 papers evaluating this issue, in particular with tacrolimus, cyclosporine, mycophenolic acid and corticosteroids, whereas evidence was missing for everolimus and sirolimus. Only one of the papers investigating the effect of cIMDs on the gut microbiota reported negative results while all the others showed significant changes in the relative abundance of specific intestinal bacteria. However, no unique pattern of microbiota modification was observed across the different studies. In conclusion, the available evidence supports the hypothesis that intestinal microbiota could contribute to the variability in the response to some cIMDs, whereas data are still missing for others.