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1.
Investigational new drugs for the treatment of chronic renal failure: an overview of the literature.
Terzo, C, Gembillo, G, Cernaro, V, Longhitano, E, Calabrese, V, Casuscelli, C, Peritore, L, Santoro, D
Expert opinion on investigational drugs. 2024;(4):319-334
Abstract
INTRODUCTION Chronic kidney disease (CKD) is widespread throughout the world, with a high social and health impact. It is considered a 'silent killer' for its sudden onset without symptoms in the early stages of the disease. The main goal of nephrologists is to slow the progression of kidney disease and treat the associated symptoms with a range of new medications. AREAS COVERED The aim of this systematic review is to analyze the new investigational drugs for the treatment of chronic renal failure. Data were obtained from the available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION Among the drugs currently being researched, SGLT2 inhibitors appear to be the most promising drugs for the treatment of CKD, has they have slower progression of CKD and protection of cardiorenal function. An important role in the future of CKD treatment is played by autologous cell-therapy, which appears to be a new frontier in the treatment of CKD. Other therapeutic strategies are currently being investigated and have been shown to slow the progression of CKD. However, further studies are needed to determine whether these approaches may offer benefits in slowing the progression of CKD in the near future.
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2.
Lung Dysfunction and Chronic Kidney Disease: A Complex Network of Multiple Interactions.
Gembillo, G, Calimeri, S, Tranchida, V, Silipigni, S, Vella, D, Ferrara, D, Spinella, C, Santoro, D, Visconti, L
Journal of personalized medicine. 2023;(2)
Abstract
Chronic kidney disease (CKD) is a progressive disease that affects > 10% of the total population worldwide or >800 million people. CKD poses a particularly heavy burden in low- and middle-income countries, which are least able to cope with its consequences. It has become one of the leading causes of death worldwide and is one of the few non-communicable diseases where the number of related deaths has increased over the last two decades. The high number of people affected, and the significant negative impact of CKD should be a reason to increase efforts to improve prevention and treatment. The interaction of lung and kidney leads to highly complex and difficult clinical scenarios. CKD significantly affects the physiology of the lung by altering fluid homeostasis, acid-base balance and vascular tone. In the lung, haemodynamic disturbances lead to the development of alterations in ventilatory control, pulmonary congestion, capillary stress failure and pulmonary vascular disease. In the kidney, haemodynamic disturbances lead to sodium and water retention and the deterioration of renal function. In this article, we would like to draw attention to the importance of harmonising the definitions of clinical events in pneumology and renal medicine. We would also like to highlight the need for pulmonary function tests in routine clinical practise for the management of patients with CKD, in order to find new concepts for pathophysiological based disease-specific management strategies.
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3.
Progress in pharmacotherapy for the treatment of hyperphosphatemia in renal failure.
Cernaro, V, Longhitano, E, Calabrese, V, Casuscelli, C, Di Carlo, S, Spinella, C, Gembillo, G, Santoro, D
Expert opinion on pharmacotherapy. 2023;(15):1737-1746
Abstract
INTRODUCTION Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease. AREAS COVERED We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients. EXPERT OPINION A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.
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4.
Review and Practical Excursus of the Propensity Score: Low Protein Diet Compared to Mediterranean Diet in Patients With Chronic Kidney Disease.
Calabrese, V, Gembillo, G, Buda, M, Cernaro, V, Longhitano, E, Pontoriero, A, Polizzi, M, Metro, D, Santoro, D
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2023;(6)
Abstract
Although Randomized clinical trials (RCT) represent the gold standard to compare two or more treatments, the impact of observational studies cannot be ignored. Obviously, these latter are performed on unbalanced sample, and differences among the compared groups could be detected. These differences could have an impact on the estimated association between our allocation and our outcome. To avoid it, some methods should be applied in the analysis of observational cohort. Propensity score (PS) can be considered as a value which sums up and balances the known variables. It aims to adjust or balance the probability of receiving a specific allocation group, and could be used to match, stratify, weight, and perform a covariate adjustment. PS is calculated with a logistic regression, using allocation groups as the outcome. Thanks to PS, we compute the probability of being allocated to one group and we can match patients obtaining two balanced groups. It avoids computing analysis in unbalanced groups. We compared low protein diet (LPD) and the Mediterranean diet in CKD patients and analysed them using the PS methods. Nutritional therapy is fundamental for the prevention, progression and treatment of Chronic Kidney Disease (CKD) and its complications. An individualized, stepwise approach is essential to guarantee high adherence to nutritional patterns and to reach therapeutic goals. The best dietary regimen is still a matter of discussion. In our example, unbalanced analysis showed a significant renal function preservation in LPD, but this correlation was denied after the PS analysis. In conclusion, although unmatched analysis showed differences between the two diets, after propensity analysis no differences were detected. If RCT cannot be performed, balancing the PS score allows to balance the sample and avoids biased results.
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5.
Phosphate Control in Peritoneal Dialysis Patients: Issues, Solutions, and Open Questions.
Cernaro, V, Calderone, M, Gembillo, G, Calabrese, V, Casuscelli, C, Lo Re, C, Longhitano, E, Santoro, D
Nutrients. 2023;(14)
Abstract
Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.
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6.
Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.
Barry, A, McNulty, MT, Jia, X, Gupta, Y, Debiec, H, Luo, Y, Nagano, C, Horinouchi, T, Jung, S, Colucci, M, et al
Nature communications. 2023;(1):2481
Abstract
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
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7.
Trabecular bone score and phalangeal quantitative ultrasound are associated with muscle strength and fracture risk in hemodialysis patients.
Catalano, A, Gaudio, A, Bellone, F, La Fauci, MM, Xourafa, A, Gembillo, G, Basile, G, Natale, G, Squadrito, G, Corica, F, et al
Frontiers in endocrinology. 2022;:940040
Abstract
There is growing interest in the relationship between chronic kidney disease (CKD) and fragility fracture risk. Bone mineral density (BMD) is a major determinant of bone strength, although its role as a predictor of fracture in advanced CKD and hemodialysis is still under debate. We aimed to further investigate surrogates of bone quality and their associations with muscle strength and fracture risk in hemodialysis. Multiple clinical risk factors for fracture and an estimated 10-year probability of fracture, BMD at lumbar spine and femur, trabecular bone score (TBS), X-ray vertebral morphometry, phalangeal bone quantitative ultrasonography (QUS), tibial pulse-echo ultrasonography (PEUS), and handgrip strength were evaluated in a setting of hemodialysis patients in treatment with acetate-free biofiltration (AFB) or bicarbonate hemodialysis. The bone ultrasound measurements, both at phalangeal and tibial sites, were significantly associated with lumbar and femoral DXA values. Handgrip strength was significantly associated with the 10-year probability of fracture (r = -0.57, p < 0.001 for major fractures and r = -0.53, p < 0.001 for hip fracture, respectively), with femur neck, total femur, and L1-L4 BMD values (r = 0.47, p = 0.04; r = 0.48, p = 0.02; r = 0.58, p = 0.007, respectively), with TBS at the lumbar spine (r = 0.71, p < 0.001) and with the phalangeal QUS measure of AD-SoS (r = 0.369, p = 0.023). In the hemodialysis group, 10 participants (24.3%) reported at least one morphometric vertebral fracture (Vfx); conversely, only six participants (15%) showed Vfx in the control group. In the hemodialysis group, participants with Vfx compared with participants without Vfx reported significantly different TBS, bone transmission time (BTT), cortical thickness, and handgrip strength (p < 0.05). At multiple regression analysis, by identifying as dependent variable the 10-year fracture risk for major fracture, after correcting for age, BMI, time since dialysis, AD-SoS, cortical bone thickness, and handgrip strength, only BTT (β = -15.21, SE = 5.91, p = 0.02) and TBS (β = -54.69, SE = 21.88, p = 0.02) turned out as independently associated with fracture risk. In conclusion, hemodialysis patients showed a higher fracture risk and lower surrogate indices of bone strength as TBS and QUS parameters. In this cohort of patients, handgrip strength measurements appeared to be a useful instrument to identify high-fracture-risk subjects.
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8.
Evidence for charge-based mimicry in anti dsDNA antibody generation.
Bruschi, M, Angeletti, A, Kajana, X, Moroni, G, Sinico, RA, Fredi, M, Vaglio, A, Cavagna, L, Pratesi, F, Migliorini, P, et al
Journal of autoimmunity. 2022;:102900
Abstract
Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.
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9.
Indole-3-acetic acid correlates with monocyte-to-high-density lipoprotein (HDL) ratio (MHR) in chronic kidney disease patients.
Cernaro, V, Calabrese, V, Loddo, S, Corsaro, R, Macaione, V, Ferlazzo, VT, Cigala, RM, Crea, F, De Stefano, C, Gembillo, G, et al
International urology and nephrology. 2022;(9):2355-2364
Abstract
PURPOSE Indole-3-acetic acid is a protein-bound indolic uremic toxin deriving from tryptophan metabolism. Increased levels are associated with higher thrombotic risk and both cardiovascular and all-cause mortality. An emerging biomarker of cardiovascular disease is the monocyte-to-high-density lipoprotein ratio (MHR). The main purpose of this study was to investigate the association of indole-3-acetic acid with MHR and other markers of cardiovascular risk in patients with chronic kidney disease (CKD). METHODS We enrolled 61 non-dialysis CKD patients and 6 dialysis patients. Indole-3-acetic acid levels were measured with ELISA technique. RESULTS In the whole cohort of 67 patients, indole-3-acetic acid was directly related to Ca × P (ρ = 0.256; P = 0.0365) and MHR (ρ = 0.321; P = 0.0082). In the 40 patients with previous cardiovascular events, indole-3-acetic acid correlated with uric acid (r = 0.3952; P = 0.0116) and MHR (ρ = 0.380; P = 0.0157). MHR was related with fibrinogen (ρ = 0.426; P = 0.0010), arterial hypertension (ρ = 0.274; P = 0.0251), C-reactive protein (ρ = 0.332; P = 0.0061), gender (ρ = - 0.375; P = 0.0017; 0 = male, 1 = female), and CKD stage (ρ = 0.260; P = 0.0337). A multiple regression analysis suggested that indole-3-acetic acid might be an independent predictor of MHR. CONCLUSION This study shows a significant association between indole-3-acetic acid and MHR. Prospective studies are required to evaluate if decreasing indole-3-acetic acid concentrations may reduce MHR levels and cardiovascular events and improve clinical outcomes.
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10.
Impact of hyperkalemia in length of hospital stay in dialysis-dependent patients.
Calabrese, V, Tripepi, GL, Santoro, D
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2022;(5):1050-1051