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.

Correlates of Calcidiol Deficiency in Adults-Cross-Sectional, Observational, Population-Based Study.

The prevalence, determinants, and clinical significance of vitamin D deficiency in the population are debated. The population-based study investigated the cross-sectional associations of several variables with serum 25-hydroxyvitamin D (calcidiol) measured using standardized calibrators. The study cohort consisted of 979 persons of the Moli-sani study, both sexes, ages ≥35 years. The correlates in the analyses were sex, age, education, local solar irradiance in the month preceding the visit, physical activity, anthropometry, diabetes, kidney function, albuminuria, blood pressure, serum cholesterol, smoking, alcohol intake, calorie intake, dietary vitamin D intake, and vitamin D supplement. The serum calcidiol was log transformed for linear regression because it was positively skewed (skewness = 1.16). The prevalence of calcidiol deficiency defined as serum calcidiol ≤12 ng/mL was 24.5%. In multi-variable regression, older age, lower solar irradiance, lower leisure physical activity, higher waist/hip ratio, higher systolic pressure, higher serum cholesterol, smoking, lower alcohol intake, and no vitamin D supplement were independent correlates of lower serum calcidiol (95% confidence interval of standardized regression coefficient ≠ 0) and of calcidiol deficiency (95% confidence interval of odds ratio > 1). The data indicate that low serum calcidiol in the population could reflect not only sun exposure, age, and vitamin D supplementation but also leisure physical activity, abdominal obesity, systolic hypertension, hypercholesterolemia, smoking, and alcohol intake.

Urinary Potassium and Kidney Function Decline in the Population-Observational Study.

Background-Some data suggest favorable effects of a high potassium intake on kidney function. The present population-based study investigated cross-sectional and longitudinal relations of urinary potassium with kidney function. Methods-Study cohort included 2027 Gubbio Study examinees (56.9% women) with age ≥ 18 years at exam-1 and with complete data on selected variables at exam-1 (1983-1985), exam-2 (1989-1992), and exam-3 (2001-2007). Urinary potassium as urinary potassium/creatinine ratio was measured in daytime spot samples at exam-1 and in overnight timed collections at exam-2. Estimated glomerular filtration rate (eGFR) was measured at all exams. Covariates in analyses included demographics, anthropometry, blood pressure, drug treatments, diabetes, smoking, alcohol intake, and urinary markers of dietary sodium and protein. Results-In multivariable regression, urinary potassium/creatinine ratio cross-sectionally related to eGFR neither at exam-1 (standardized coefficient and 95%CI = 0.020 and -0.059/0.019) nor at exam-2 (0.024 and -0.013/0.056). Exam-1 urinary potassium/creatinine ratio related to eGFR change from exam-1 to exam-2 (0.051 and 0.018/0.084). Exam-2 urinary potassium/creatinine ratio related to eGFR change from exam-2 to exam-3 (0.048 and 0.005/0.091). Mean of urinary potassium/creatinine ratio at exam-1 and exam-2 related to eGFR change from exam-1 to exam-3 (0.056 and 0.027/0.087) and to incidence of eGFR < 60 mL/min per 1.73 m2 from exam-1 to exam-3 (odds ratio and 95%CI = 0.78 and 0.61/0.98). Conclusion-In the population, urinary potassium did not relate cross-sectionally to eGFR but related to eGFR decline over time. Data support the existence of favorable effects of potassium intake on ageing-associated decline in kidney function.

The Psychosocial Burden of HCV Infection and the Impact of Antiviral Therapy on the Quality of Life in Liver and Kidney Transplant Recipients: A Pilot Study.

BACKGROUND: Therapy with direct-acting antivirals (DAA) for HCV is safe and effective in the liver (LT) and kidney transplant (KT) recipients; however, data on the quality of life (QoL) of patients are scanty. This pilot study is aimed at prospectively evaluating the QoL in LT and KT recipients before and after DAA treatment. METHODS: We prospectively enrolled 17 LT and 11 KT recipients with HCV infection starting a sofosbuvir-based antiviral therapy for 12 weeks. All participants before (T0), 12 (T12), and 24 (T24) weeks after the end of the therapy completed the Short Form Health Survey (SF-36) questionnaire, the Zung Self-rating Depression Scale, and State-Trait Anxiety Inventory (STAI-Y1-Y2). RESULTS: At T0, LT and KT patients were similar for gender, age, BMI, smoking habits, marital status, mean liver stiffness values at Fibroscan, and HCV genotype distribution (p > 0.05). There were no significant differences between the 2 groups in STAI-Y1, STAI-Y2, Zung, and SF-36 scores (p > 0.05). At T12, all the participants showed a sustained virological response (SVR). All items of the SF-36 questionnaire improved from the pretreatment to posttreatment period within the LT group, and the 4 domains role-physical, bodily pain, social function, role-emotional, and mental health reached statistical significance (p < 0.05 in all cases). On the contrary, in KT patients, there was no significant improvement in SF-36 mean scores compared to at baseline at T12 and T24. CONCLUSIONS: This pilot study suggested that DAA therapy is associated with a significant improvement of the QoL only in LT recipients. Probably, KT recipients did not consider HCV a "central player" in the course of their disease, and HCV eradication did not significantly impact on their QoL.

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.

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.

Low Protein Intake in the Population: Low Risk of Kidney Function Decline but High Risk of Mortality.

OBJECTIVE: This population-based study investigated low protein intake, mortality, and kidney function decline. DESIGN: Observational longitudinal cohort study. SUBJECTS: Target cohort consisted of 4,679 adults participating in 1988-1992 and 2001-2007 examinations of the Gubbio Study (baseline and follow-up). Data collection included overnight urine urea nitrogen (UUN) and other variables at baseline, serum creatinine at baseline and follow-up, and mortality from baseline to follow-up. Three hundred seventy-two persons were excluded for missing data. UUN in the lowest 20% of the distribution was defined as low and used as index of low protein intake. Estimated glomerular filtration rate (eGFR, mL/minute × 1.73 m2) was used as kidney function index. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Mortality and eGFR decline are the main outcome measures, and eGFR decline was defined as eGFR change from baseline to follow-up ≤ mean-1 standard deviation (Z-score ≤ -1). RESULTS: Eight hundred seventy-one deaths occurred over 15.9 ± 4.0 years of observation (417 from cardiovascular disease and 276 from neoplastic disease). Low UUN associated with mortality (hazard ratio, HR = 1.31, 95% confidence interval, CI = 1.12/1.53) due to association with mortality from neoplastic disease (HR = 1.33, 95% CI = 1.02/1.76). Mortality-corrected follow-up response rate was 79.9% (n = 2845). Baseline to follow-up eGFR change was -9.9 ± 10.1, and eGFR decline was found in 454 examinees. Low UUN associated with eGFR decline only in subgroup with baseline eGFR <90 (n = 1441, odds ratio = 0.44, 95% CI = 0.22/0.85). Low baseline eGFR interacted with the association between low UUN and eGFR decline (P = .024). CONCLUSION: Low protein intake predicted higher mortality in the whole population and lower incidence of eGFR decline only in subgroup with reduced kidney function.

Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power.

Background: Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population. Methods: Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988-92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001-07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR). Results: Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and -0.74 ± 0.76 mL/min × 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was ≤0.91, 95% confidence interval was ≤0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P ≥ 0.4). Conclusions: Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time.

Serum uric acid and eGFR_CKDEPI differently predict long-term cardiovascular events and all causes of deaths in a residential cohort.

OBJECTIVES: Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort. MATERIAL AND METHODS: Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2). RESULTS: Significant (p<0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05>p<0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC>0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04). CONCLUSION: SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

The high prevalence of alexithymia in hemodialyzed patients with secondary hyperparathyroidism unsuppressed by medical therapy is cured by parathyroidectomy.

There are scanty data available on alexithymia in patients with end-stage renal disease, which point to an independent association with depression and social support. This study was devised to investigate the prevalence of alexithymia and sleep disorders in patients maintenance hemodialysis with insuppressible secondary hyperparathyroidism, who need parathyroidectomy (PTX), because previous data from our laboratories as well as those of others showed that this patient-group are the worst sleepers among hemodialysis patients with end-stage renal disease. A total of 40 patients needing PTX were enrolled and studied before the surgery. As for the control group, 80 patients on maintenance hemodialysis not needing PTX were enrolled. We measured alexithymia with the Toronto Alexithymia Score (TAS-20), sleep disorders with the Pittsburgh Sleep Quality Index (PSQI), and depression with Beck Depression Inventory (BDI), intact parathyroid hormone (iPTH), calcium, phosphate, use of antihypertensives, systolic and diastolic blood pressure, hemoglobin concentration, and albumin concentration. Patients needing PTX in comparison with those not needing PTX had significantly higher iPTH, calcium, and phosphate; they also had significantly higher systolic and diastolic blood pressure. They were more significantly alexithymic (P < .001), had more severe sleep disorders (P < .001), and were more depressed (P < .043). In multivariate analysis, BDI correlated significantly with iPTH concentration (r = 0.505, P < .001). A reduction of TAS-20 occurred after PTX which correlated with the number of patients on antihypertensive drugs, PSQI, BDI, hemoglobin concentration in the univariate and multivariate analysis. When TAS-20 and PSQI were adjusted for BDI (using analysis of variance) there was still a significant difference of TAS-20 and PSQI between patients needing PTX and not needing PTX (P < .001). This study confirms the high prevalence of sleep disorders in patients with unsuppressed secondary hyperparathyroidism and discloses a high prevalence of Alexithymia which is ameliorated by PTX. However, the correlation of Alexithymia with sleep disorders does not depend on depression.

Parathyroidectomy improves the quality of sleep in maintenance hemodialysis patients with severe hyperparathyroidism.

Sleeping disorders are very common in patients with chronic kidney disease on dialysis (CKD5D) and are an emerging risk factor able to predict mortality. Parathyroid hormone (PTH) although considered a pivotal uremic toxin has rarely been associated with sleep disorders in uremia. In a study from our laboratory PTH concentrations failed to distinguish patients with sleep disorders from those without. In a study performed by Chou et al a 97% prevalence of insomnia was found in patients undergoing hemodialysis requiring parathyroidectomy. Surgery reduced PTH and increased sleeping hours within 3 months. The aim of this study was to study the effects of parathyroidectomy on the sleep disorders of insomniacs on maintenance hemodialysis. The study was performed in 16 insomniac patients on maintenance hemodialysis who successfully underwent surgery with autotransplantation of autologous parathyroid tissue (40 mg) under the skin of the forearm. Patients (5 F and 11 M) were studied from 1 month before surgery to 1 year after. Sleep disorders were assessed by means of a 27-item questionnaire--Sleep Disorder questionnaire (SDQ)--that identified sleeping disorders according to Diagnostic and Statistical Manual of Mental Disorders - IV Edition (DSM-IV) criteria. The Charlson Comorbidity Index (CCI) was also measured along with systolic and diastolic blood pressure, Hb, PTH, Ca, P. A 95.5% prevalence of sleep disorders was found pre operatively. Patients slept 4.90+/-1.2 hours, Ca averaged 10.09+/-0.54 mg/dL, Phosphate 5.5+/-1.93, CCI 9.8+/-1.1, PTH 1498+/-498 ng/mL. After 1 year follow-up 2 out 16 patients had normal sleep, 6 out 16 patients had subclinical sleep disorders and 8 remained insomniacs (p=0.008, Mc Nemar Test for paired data, insomniacs vs. no disturbance + subclinical disorders). Sleeping hours increased up to 6.0+/-1.24 (p<0.05), PTH was normalized, the Charlson Comorbidity Index was reduced (p<0.05) as were plasma calcium and phosphate (p<0.01). The study indicates that insomnia in patients with severe hyperparathyroidism on maintenance hemodialysis is ameliorated by parathyroidectomy.

Urinary albumin and cardiovascular profile in the middle-aged population.

The moderate increase in urinary albumin excretion defined as microalbuminuria is not rare and is associated with cardiovascular risk factors. Microalbuminuria prevalence is low in the absence of cardiovascular risk factors and progressively increases with the number cardiovascular risk factors. The main correlate of microalbuminuria is blood pressure, either systolic or diastolic pressure. The relation between blood pressure and microalbuminuria is continuous and graded because the microalbuminuria prevalence increases with the severity of hypertension. Among hypertensive patients on drug treatment, blood pressure control is associated with a low prevalence of microalbuminuria. Thus, blood pressure appears as a determinant of microalbuminuria rather than a mere correlate. For hypercholesterolemia, smoking, and diabetes, data are less strong but point to an independent positive association with microalbuminuria. Altogether, data indicate that microalbuminuria in the population reflects the presence of cardiovascular risk factors. Data on microalbuminuria and coronary heart disease support this idea. There is a continuous and graded relation between urinary albumin excretion and coronary heart disease prevalence. High urinary albumin excretion is likely a sign of vascular damage existing both at the renal and cardiac levels and induced by 1 or more uncontrolled cardiovascular risk factors.