Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas.

BACKGROUND/AIMS: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. METHODS: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. RESULTS: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased -density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. CONCLUSION: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.

Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview.

Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD-mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.

Vitamin D: A Bridge between Kidney and Heart.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) are highly prevalent conditions, each significantly contributing to the global burden of morbidity and mortality. CVD and CKD share a great number of common risk factors, such as hypertension, diabetes, obesity, and smoking, among others. Their relationship extends beyond these factors, encompassing intricate interplay between the two systems. Within this complex network of pathophysiological processes, vitamin D has emerged as a potential linchpin, exerting influence over diverse physiological pathways implicated in both CKD and CVD. In recent years, scientific exploration has unveiled a close connection between these two prevalent conditions and vitamin D, a crucial hormone traditionally recognized for its role in bone health. This article aims to provide an extensive review of vitamin D's multifaceted and expanding actions concerning its involvement in CKD and CVD.

Diet and Other Modifiable Factors in Long-Term Decline of Kidney Function: Observational and Population-Based Cohort Study.

BACKGROUND: Lower physical activity, lower alcohol intake, higher protein intake, higher sodium intake, and lower potassium intake related to greater kidney function decline over time, according to previous studies. The present study aimed to analyze the cumulative effects of these factors. METHODS: This prospective, observational, population-based cohort study included 3039 adult examinees of the Gubbio study who participated in the baseline exam and 15-year follow-up exam. Kidney function was evaluated as estimated glomerular filtration rate (eGFR). Habitual physical activity in leisure time and habitual alcohol intake were assessed by questionnaires; dietary intakes of protein, sodium, and potassium were assessed by urinary markers. Based on previous reports, each one of the five modifiable factors was scored 0 for the tertile associated with smaller eGFR decline (low risk), 2 for the tertile associated with greater eGFR decline (high risk), and 1 for the intermediate tertile (intermediate risk). A cumulative score was calculated as the sum of the factor-specific scores and used as the main independent variable. RESULTS: The cumulative score ranged from 0 to 10, that is, from low risk for all factors to high risk for all factors (skewness = 0.032, mean ± SD = 5 ± 2). To avoid the bias of low-n analyses, score 0 was re-coded as 1 and score 10 was recoded as 9; after re-coding, the cumulative score ranged from 1 to 9 (skewness = 0.016, mean ± SD = 5 ± 2). The cumulative score related to annualized eGFR change in multi-variable linear regression (slope = -0.027, 95%CI = -0.039/-0.014, p < 0.001); findings were consistent in apparently healthy examinees and other subgroups. De novo incidence of eGFR < 60 mL/min × 1.73 m2 was higher along the cumulative score (p < 0.001). Compared to score 1 (n examinees = 35, adjusted incidence = 2.0%), incidence of low kidney function was 4.5 times higher in score 5 (n examinees = 624, adjusted incidence = 8.9%) and 6.5 times higher in score 9 (n examinees = 86, adjusted incidence = 12.9%). The cumulative score related to incidence of low kidney function in multi-variable logistic regression (odds ratio = 1.19, 95%CI = 1.08/1.32, p < 0.001). CONCLUSIONS: The combination of five modifiable factors predicted large differences in long-term incidence of low kidney function.

Relation of Alcohol Intake to Kidney Function and Mortality Observational, Population-Based, Cohort Study.

Data are conflicting about the effects of alcohol intake on kidney function. This population-based study investigated associations of alcohol intake with kidney function and mortality. The study cohort included adult participants in Exam-1, Exam-2 (6-year follow-up), and Exam-3 (20-year follow-up) of the Gubbio study. Kidney function was evaluated as estimated glomerular filtration rate (eGFR, CKD-Epi equation, mL/min × 1.73 m2). Daily habitual alcohol intake was assessed by questionnaires. Wine intake accounted for >94% of total alcohol intake at all exams. Alcohol intake significantly tracked over time (R > 0.66, p < 0.001). Alcohol intake distribution was skewed at all exams (skewness > 2) and was divided into four strata for analyses (g/day = 0, 1−24, 25−48, and >48). Strata of alcohol intake differed substantially for lab markers of alcohol intake (p < 0.001). In multivariable regression, strata of alcohol intake related cross-sectionally to eGFR at all exams (Exam-1: B = 1.70, p < 0.001; Exam-2: B = 1.03, p < 0.001; Exam-3: B = 0.55, p = 0.010) and related longitudinally to less negative eGFR change from Exam-1 to Exam-2 (B = 0.133, p = 0.002) and from Exam-2 to Exam-3 (B = 0.065, p = 0.004). In multivariable Cox models, compared to no intake, intakes > 24 g/day were not associated with different mortality while an intake of 1−24 g/day was associated with lower mortality in the whole cohort (HR = 0.77, p = 0.003) and in the subgroup with eGFR < 60 mL/min × 1.73 m2 (HR = 0.69, p = 0.033). These data indicate a positive independent association of alcohol intake with kidney function not due to a mortality-related selection.

Vitamin C Acutely Affects Brain Perfusion and Mastication-Induced Perfusion Asymmetry in the Principal Trigeminal Nucleus.

Prolonged mastication may induce an asymmetric modification of the local perfusion of the trigeminal principal nucleus. The aim of the present study was to evaluate the possible influence of vitamin C (vit. C) on such effect. Four groups of healthy volunteers underwent arterial spin labeling magnetic resonance imaging (ASL-MRI) to evaluate the local perfusion of the trigeminal nuclei after a vit. C-enriched lunch or a control lunch. Two ASL-MRI scans were acquired, respectively, before and after a 1 h-long masticating exercise or a 1 h long resting period. The results showed (i) an increased global perfusion of the brain in the vit. C-enriched lunch groups, (ii) an increased local perfusion of the right principal trigeminal nucleus (Vp) due to mastication, and (iii) a reduction of the rightward asymmetry of the Vp perfusion, due to mastication, after the vit C-enriched meal compared to the control meal. These results confirmed a long-lasting effect of prolonged mastication on Vp perfusion and also suggest a possible effect of vit. C on cerebral vascular tone regulation. Moreover, the data strongly draw attention on the side-to-side relation in Vp perfusion as a possible physiological parameter to be considered to understand the origin of pathological conditions like migraine.

Skin Architecture, Kidney Transplantation, and Their Relationship to Basal and Squamous Cell Carcinomas.

BACKGROUND/AIM: Squamous cell carcinoma (SCC) is highly prevalent in kidney transplant patients (KT). It is characterized by the presence of an inflammatory infiltrate. In this study, we examined the presence of similar infiltrates in intact skin, which could be regarded as a precancerous step. PATIENTS AND METHODS: We retrospectively analyzed skin biopsies of 19 non-transplanted patients with a diagnosis of SCC or basal cell carcinoma (BCC) and 17 KT with either SCC or BCC. RESULTS: KT showed increased inflammatory infiltrate in the subepithelial region, compared to non-transplanted patients. The density of basal cell nuclei was also different among the four groups with an interaction effect between tumor type and transplantation. The extent of inflammatory infiltrates did not correlate with the eGFR and proteinuria. CONCLUSION: KT with a non-melanoma skin cancer show increased intact skin inflammatory infiltrate and alterations in the density of the basal cell layer compared to non-transplanted patients.

A Calorie-Restricted Ketogenic Diet Reduces Cerebral Cortex Vascularization in Prepubertal Rats.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD.

Auricular Acupressure Can Modulate Pain Threshold.

The objective of our study was to investigate if auriculotherapy (AT) can modulate pain threshold. In our experiments, AT consisted of placing Vaccaria seeds over the "fingers point" of one ear. Two groups of healthy volunteers were enrolled for the study. Each subject was asked to perform an autoalgometric test developed by our group on three occasions: before, 1 hour after, AT and 24 hours after AT. Participants of the first group received a 2-minute long session of AT, while participants of the second group received a 2-minute long session of sham treatment, consisting of a puncture/massage above the skin of the neck. The autoalgometric test consisted of applying an increasing pressure with the finger-tips and finger-backs of four fingers by the subjects themselves (i.e., eight sites were evaluated) against a round-shaped needle for two times: until a minimum pain sensation (first time, minimal test) or a maximally tolerable pain sensation (second time, maximal test). Our results showed a significant higher pain threshold in the maximal test at 24 hours after AT compared to sham treatment. This result indicates for the first time that AT can increase pain tolerability, rather than affecting the minimal pain threshold.