Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

Humoral response after the fourth dose of the SARS-CoV-2 vaccine in the CKD spectrum: a prespecified analysis of the SENCOVAC study.

BACKGROUND: There is scarce evidence on the fourth dose of severe acute respiratory syndrome coronavirus 2 vaccines in chronic kidney disease (CKD) patients. We evaluated the humoral response and effectivity of the fourth dose in the CKD spectrum: non-dialysis CKD (ND-CKD), haemodialysis (HD), peritoneal dialysis (PD) and kidney transplant (KT) recipients. METHODS: This is a prespecified analysis of the prospective, observational, multicentric SENCOVAC study. In patients with CKD who had received a complete initial vaccination and one or two boosters and had anti-Spike antibody determinations 6 and 12 months after the initial vaccination, we analysed factors associated with persistent negative humoral response and higher anti-Spike antibody titres as well as the efficacy of vaccination on coronavirus disease 2019 (COVID-19) severity. RESULTS: Of 2186 patients (18% KT, 8% PD, 69% HD and 5% ND-CKD), 30% had received a fourth dose. The fourth dose increased anti-Spike antibody titres in HD (P = .001) and ND-CKD (P = .014) patients and seroconverted 72% of previously negative patients. Higher anti-Spike antibody titres at 12 months were independently associated with repeated exposure to antigen (fourth dose, previous breakthrough infections), previous anti-Spike antibody titres and not being a KT recipient. Breakthrough COVID-19 was registered in 137 (6%) patients, 5% of whom required admission. Admitted patients had prior titres <620 UI/ml and median values were lower (P = .020) than in non-admitted patients. CONCLUSIONS: A fourth vaccine dose increased anti-Spike antibody titres or seroconverted many CKD patients, but those with the highest need for a vaccine booster (i.e. those with lower pre-booster antibody titres or KT recipients) derived the least benefit in terms of antibody titres. Admission for breakthrough COVID-19 was associated with low anti-Spike antibody titres.

Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.

BACKGROUND: Growth Differentiation Factor-15 (GDF15) is a member of the TGF-ß superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD. METHODS: We measured serum and urinary GDF15 in a prospective cohort of 84 patients who underwent kidney biopsy and assessed their association with outcomes (survival, kidney replacement therapy) during a follow-up of 29 ± 17 months. RESULTS: There was a statistically significant correlation between serum and urine GDF15 values. However, while serum GDF15 values increased with decreasing glomerular filtration rate, urinary GDF15 did not. Immunohistochemistry located kidney GDF15 expression mainly in tubular cells, and kidney GDF15 staining correlated with urinary GDF15 values. Urine GDF15 was significantly higher in patients with a histologic diagnosis of diabetic nephropathy than in diabetic patients without diabetic nephropathy. This was not the case for serum GDF15. Both serum and urine GDF15 were negatively associated with patient survival in multivariate models. However, when both urine and serum GDF15 were present in the model, lower urine GDF15 predicted patient survival [B coefficient (SEM) - 0.395 (0.182) p 0.03], and higher urine GDF15 predicted a composite of mortality or kidney replacement therapy [0.191 (0.06) p 0.002], while serum GDF15 was not predictive. Decision tree analysis yielded similar results. The area under the curve (AUC) of the receiver operating curve (ROC) for urine GDF15 as a predictor of mortality was 0.95 (95% CI 0.89-1.00, p < 0.001). CONCLUSIONS: In conclusion, urinary GDF15 is associated with kidney histology patterns, mortality and the need for renal replacement therapy (RRT) in CKD patients who underwent a kidney biopsy.

Gender, Albuminuria and Chronic Kidney Disease Progression in Treated Diabetic Kidney Disease.

BACKGROUND: Women are reported to have a lower incidence of renal replacement therapy, despite a higher prevalence of chronic kidney disease (CKD). AIM: To analyze diabetic kidney disease (DKD) progression in men and women. METHODS: Prospective cohort: n = 261, 35% women, new consecutive nephrology DKD referrals. RESULTS: Women smoked less and better complied with the dietary phosphate and sodium restrictions. Despite a less frequent nephrology referral, women had lower baseline albuminuria. Over a 30 ± 10-month follow-up, albuminuria decreased in women and the estimated glomerular filtration rate (eGFR) loss was slower than in men. However, the percentage of rapid progressors was similar in both sexes. The best multivariate model predicting rapid progression in men (area under curve (AUC) = 0.92) and women differed. Albuminuria and fractional excretion of phosphate (FEphosphate) were part of the men multivariable model, but not of women. The AUC for the prediction of rapid progression by albuminuria was higher in men than in women, and the albuminuria cut-off points also differed. In women, there was a higher percentage of rapid progressors who had baseline physiological albuminuria. CONCLUSIONS: Female DKD differs from male DKD: albuminuria was milder and better responsive to therapy, the loss of eGFR was slower and the predictors of rapid progression differed from men: albuminuria was a better predictor in men than in women. Lifestyle factors may contribute to the differences.

Anti-smoking legislation and its effects on urinary cotinine and cadmium levels.

Anti-smoking legislation has been associated with an improvement in health indicators. Since the cadmium (Cd) body burden in the general population is markedly increased by smoke exposure, we analyzed the impact of the more restrictive legislation that came into force in Spain in 2011 by measuring Cd and cotinine in first morning urine samples from 83 adults in Madrid (Spain) before (2010) and after (2011) introduction of this law. Individual pair-wise comparisons showed a reduction of creatinine corrected Cotinine and Cd levels for non-active smokers, i. e. those which urinary cotinine levels are below 50 µg/L. After the application of the stricter law, cotinine levels in urine only decreased in non-active smokers who self-reported not to be exposed to second-hand smoke. The reduction in second hand smoke exposure was significantly higher in weekends (Friday to Sunday) than in working days (Monday to Thursday). The decrease in U-Cd was highly significant in non-active smokers and, in general, correlated with lower creatinine excretion. Therefore correction by creatinine could bias urinary Cd results, at least for cotinine levels higher than 500 µg/L. The biochemical/toxicological benefits detected herein support the stricter application of anti-smoking legislation and emphasize the need to raise the awareness of the population as regards exposure at home.

Mercury, lead and cadmium levels in the urine of 170 Spanish adults: a pilot human biomonitoring study.

Human biomonitoring is a well-recognized tool for estimating the exposure of human populations to environmental pollutants. However, information regarding biomarker concentrations of many environmental chemicals in the general population is limited for many countries. The Spanish Environment Ministry has recently funded a human biomonitoring study on the Spanish general population. This study aims to determine reference levels for several biomarkers, especially heavy metals, persistent organic pollutants (POPs) and cotinine, in urine, whole blood, serum and hair, and will involve 2000 volunteers throughout Spain. Samples were taken during 2009-2010 and analyses are currently underway. The results presented herein were obtained in a pilot study carried out in the Madrid region. The study group comprised 170 volunteers, of which 79% were female and 21% male (age: 23-66 years). All participants were asked to complete a questionnaire regarding diet and living habits and provides a morning urine sample. The geometric means for total mercury (Hg), lead (Pb) and cadmium (Cd) were 1.23, 1.11 and 0.25 µg/g creatinine, respectively. Levels of Pb and Hg were higher than those reported for the general population in the USA and Germany, whereas Cd was in the same range (CDC, 2009; Becker et al., 2003). The values reported here are similar to those reported in other Spanish studies.

The spot 14 protein inhibits growth and induces differentiation and cell death of human MCF-7 breast cancer cells.

The S14 (spot 14) gene encodes a protein that is predominantly expressed in lipogenic tissues, such as the liver, white and brown adipose tissues and the lactating mammary glands. Accumulated evidence suggests that S14 could play an important role in the induction of lipogenic enzymes. In humans, the S14 locus resides in the chromosome region 11q13, which is frequently amplified in breast tumours, and as a result, it has been suggested that this protein could play a role in the metabolism and growth of these kinds of tumours. In the present study, we have examined the effects of S14 overexpression in MCF-7 human breast cancer cells. We found that S14 causes (i) an inhibition of cell proliferation and of anchorage-independent growth, (ii) a marked reduction in the number of viable cells and (iii) the induction of differentiation and cell death of these cells. The inhibition of cell growth was associated with a decrease in the expression of cyclin D1 and a reduction of cyclin D1 promoter activity. Increased expression of S14 also caused the accumulation of cytochrome c in the cytosol and loss of mitochondrial membrane potential. These findings suggest that S14 may function as an important modulator of tumorigenesis in human breast by decreasing cell growth and inducing cell death and differentiation.

15-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism.

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been found to induce cell death in a variety of cells. In this regard, we reported recently that 15-deoxy-Delta-(12,14)-prostaglandin J2 (15dPG-J2), a specific ligand of the nuclear receptor PPARgamma, inhibits proliferation and induces cellular differentiation and apoptosis in the breast cancer cell line MCF-7. In addition to PPARgamma activation other proteins, such as NF-kappaB and AP1, have been shown to be targets of 15dPG-J2. However, the mechanism by which 15dPG-J2 triggers cell death is still elusive. Our results demonstrate that 15dPG-J2 initiates breast cancer cell death via a very rapid and severe impairment of mitochondrial function, as revealed by a drop in mitochondrial membrane potential (DeltaPsi(m)), generation of reactive oxygen species (ROS) and a decrease in oxygen consumption. In addition, 15dPG-J2 can also activate an intrinsic apoptotic pathway involving phosphatidyl serine externalization, caspase activation and cytochrome c release. Bcl-2 over-expression and zVADfmk, albeit preventing caspase activation, have no effect on 15dPG-J2-mediated mytochondrial dysfunction and loss of cell viability. In contrast, the addition of radical scavengers or rotenone, which prevent 15dPG-J2-induced ROS production, block the loss of cell viability induced by this prostaglandin. Finally, 15dPG-J2-induced cell death appears to involve disruption of the microtubule cytoskeletal network. Together, these results suggest that PG-J2-induced mitochondrial dysfunction and ROS production inevitably leads to death, with or without caspases.