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PURPOSE OF REVIEW: The integration of risk prediction in managing chronic kidney disease (CKD) is universally considered a key point of routine clinical practice to guide time-sensitive choices, such as dialysis access planning or counseling on kidney transplant options. Several prognostic models have been developed and validated to provide individualized evaluation of kidney failure risk in CKD patients. This review aims to analyze the current evidence on existing predictive models and evaluate the different advantages and disadvantages of these tools. RECENT FINDINGS: Since Tangri et al. introduced the Kidney Failure Risk Equation in 2011, the nephrological scientific community focused its interest in enhancing available algorithms and finding new prognostic equations. Although current models can predict kidney failure with high discrimination, different questions remain unsolved. Thus, this field is open to new possibilities and discoveries. SUMMARY: Accurately informing patients of their prognoses can result in tailored therapy with important clinical and psychological implications. Over the last 5âyears, the number of disease-modifying therapeutic options has considerably increased, providing possibilities to not only prevent the kidney failure onset in patients with advanced CKD but also delay progression from early stages in at-risk individuals.
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Falência Renal Crônica , Insuficiência Renal Crônica , Insuficiência Renal , Humanos , Progressão da Doença , Diálise Renal , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , PrognósticoRESUMO
Data on the effectiveness of denosumab on osteoporosis after kidney transplantation are limited. We investigated the long-term bone mineral density (BMD) changes in kidney transplant recipients (KTRs) treated with denosumab compared to untreated KTRs. We enrolled KTRs treated with denosumab 60 mg/6 months for 4 years. An untreated group of sex and age-matched KTRs with a 1:1 ratio was included. The primary outcome was BMD changes assessed by Dual-energy X-ray Absorptiometry over 4 years. Data on serum creatinine, alkaline phosphatase (ALP), parathyroid hormone, and 25-hydroxyvitamin D were collected. All patients received oral cholecalciferol and calcium supplementation. 23 denosumab-treated KTRs were enrolled, and 23 untreated KTRs. The median time from transplant to the start of denosumab was 4 years (range 0:24). The denosumab group showed a significant increase from baseline in BMD at the lumbar spine (LS) (9.0 ± 10.7%, p < 0.001), and total hip (TH) (3.8 ± 7.9%, p = 0.041). The untreated group showed a significant decrease at all sites (- 3.0 ± 7%, p = 0.041 at the LS; - 6.3 ± 9.2%, p = 0.003 at the TH; - 6.7 ± 9.3%, p = 0.003 at the FN). The between-group differences in percent BMD changes were statistically significant at all sites. Similar results were found for the respective Z-scores. The ALP serum levels significantly decreased from baseline only in the denosumab group, with a significant between-group difference (p = 0.032). No significant differences in serum creatinine, hypocalcaemic events or acute graft rejection rates were observed. Four years of denosumab therapy were associated with increased BMD in KTRs, while untreated KTRs showed significant BMD losses at all sites.
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Conservadores da Densidade Óssea , Densidade Óssea , Denosumab , Transplante de Rim , Humanos , Denosumab/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Conservadores da Densidade Óssea/uso terapêutico , Adulto , Idoso , Osteoporose/tratamento farmacológico , Absorciometria de FótonRESUMO
BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is a growing global health concern. Recent research has indicated sex disparities in CKD-related complications, yet the impact of sex differences on critical kidney function levels that trigger these complications and mortality remains inadequately documented. METHODS: We investigated sex-specific disparities in CKD-related complications and mortality according to eGFR levels. We analyzed NHANES data spanning from 1999 to 2018, including adult participants with an eGFR of 15-150 ml/min per 1.73m². The outcomes were CKD-related complications (hypertension, anaemia, CV diseases, acidosis, hyperphosphatemia, hyperparathyroidism) and all-cause and cause-specific mortality (CV mortality and non-CV mortality). Sex-stratified multivariable logistic and Cox regression models yielded odds ratios (ORs) and hazard ratios (HRs) for the relationship between eGFR categories and outcomes. Sex-stratified natural splines were used to explore the relationship between continuous eGFR and outcomes and identified eGFR thresholds of statistical significance. RESULTS: The study included 49 558 participants (50.3% women, 49.7% men). Multivariable logistic regression demonstrated a significant eGFR association with all CKD-related complications, exhibiting a linear trend across eGFR categories. Modelling eGFR as a natural spline revealed varied significance thresholds between sexes for anaemia and hyperparathyroidism. Additionally, the eGFR-hyperphosphatemia association was more pronounced in men. We observed substantial but not statistically significant differences between men and women in the thresholds of statistical significance for CV (significance appeared at a higher eGFR in men) and non-CV mortality (significance appeared at a higher eGFR in women). CONCLUSIONS: Research shows sex disparities in most CKD-related complications. Men develop anaemia and hyperparathyroidism earlier, women show steeper anaemia increase. Men have higher CV mortality risk. As eGFR decreased, men faced a higher risk of CV mortality at a higher eGFR threshold than women.
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OBJECTIVE: To develop a follow-up algorithm for urinary stone patients after definitive treatment. MATERIALS AND METHODS: The panel performed a systematic review on follow-up of urinary stone patients after treatment (PROSPERO: CRD42020205739). Given the lack of comparative studies we critically evaluated the literature and reached a consensus on the follow-up scheme. RESULTS: A total of 76 studies were included in the analysis, including 17 RCTs. In the stone-free general population group, 71-100% of patients are stone-free at 12 months while 29-94% remain stone-free at 36 months. We propose counselling these patients on imaging versus discharge after the first year. The stone-free rate in high-risk patients not receiving targeted medical therapy is < 40% at 36 months, a fact that supports imaging, metabolic, and treatment monitoring follow-up once a year. Patients with residual fragments ≤ 4 mm have a spontaneous expulsion rate of 18-47% and a growth rate of 10-41% at 12 months, supporting annual imaging follow-up. Patients with residual fragments > 4 mm should be considered for surgical re-intervention based on the low spontaneous expulsion rate (13% at 1 year) and high risk of recurrence. Plain film KUB and/or kidney ultrasonography based on clinicians' preference and stone characteristics is the preferred imaging follow-up. Computed tomography should be considered if patient is symptomatic or intervention is planned. CONCLUSIONS: Based on evidence from the systematic review we propose, for the first time, a follow-up algorithm for patients after surgical stone treatment balancing the risks of stone recurrence against the burden of radiation from imaging studies.
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Algoritmos , Urolitíase , Humanos , Urolitíase/terapia , Seguimentos , Assistência ao Convalescente/métodosRESUMO
Renal amyloidosis is a rare condition caused by the progressive accumulation of misfolded proteins within glomeruli, vessels, and interstitium, causing functional decline and requiring prompt treatment due to its significant morbidity and mortality. Congo red (CR) stain on renal biopsy samples is the gold standard for diagnosis, but the need for polarized light is limiting the digitization of this nephropathology field. This study explores the feasibility and reliability of CR fluorescence on virtual slides (CRFvs) in evaluating the diagnostic accuracy and proposing an automated digital pipeline for its assessment. Whole-slide images from 154 renal biopsies with CR were scanned through a Texas red fluorescence filter (NanoZoomer S60, Hamamatsu) at the digital Nephropathology Center of the Istituto di Ricovero e Cura a Carattere Scientifico San Gerardo, Monza, Italy, and evaluated double-blinded for the detection and quantification through the amyloid score and a custom ImageJ pipeline was built to automatically detect amyloid-containing regions. Interobserver agreement for CRFvs was optimal (k = 0.90; 95% CI, 0.81-0.98), with even better concordance when consensus-based CRFvs evaluation was compared to the standard CR birefringence (BR) (k = 0.98; 95% CI, 0.93-1). Excellent performance was achieved in the assessment of amyloid score overall by CRFvs (weighted k = 0.70; 95% CI, 0.08-1), especially within the interstitium (weighted k = 0.60; 95% CI, 0.35-0.84), overcoming the misinterpretation of interstitial and capsular collagen BR. The application of an automated digital pathology pipeline (Streamlined Pipeline for Amyloid detection through CR fluorescence Digital Analysis, SPADA) further increased the performance of pathologists, leading to a complete concordance with the standard BR. This study represents an initial step in the validation of CRFvs, demonstrating its general reliability in a digital nephropathology center. The computational method used in this study has the potential to facilitate the integration of spatial omics and artificial intelligence tools for the diagnosis of amyloidosis, streamlining its detection process.
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Amiloidose , Vermelho Congo , Humanos , Reprodutibilidade dos Testes , Inteligência Artificial , Amiloide/metabolismo , Coloração e Rotulagem , Amiloidose/diagnóstico por imagem , Amiloidose/metabolismoRESUMO
PURPOSE: We sought to determine which treatment between flexible ureteroscopy and shock wave lithotripsy has a better stone-free rate in pediatric patients (<18 years) with renal or proximal ureteric stones (<2 cm). Subanalysis for all outcomes for randomized controlled trials only. MATERIALS AND METHODS: Using PubMed, Web of Science, and the Cochrane database, we identified studies (randomized clinical trials and prospective comparative nonrandomized studies) published until August 2022 reporting surgical outcomes of pediatrics patients undergoing flexible ureteroscopy and shock wave lithotripsy with renal or proximal ureteric stones <2 cm (PROSPERO ID: CRD42022378790). Only randomized controlled trials were considered for meta-analysis. Stone-free rate, operative time, and complications were analyzed. Analysis was performed in R. RESULTS: A total of 6 studies identified, of which 3 were randomized clinical trials and 4 had data on renal stones. A total of 669 patients were analyzed. Mean age ranged from 4.4 to 12.4 years. The shock wave lithotripsy group presented a range of stone-free rate between 21 and 90% while the flexible ureteroscopy group presented a range of stone-free rates between 37% and 97%. Meta-analysis of randomized controlled trials only (n=302) demonstrated significantly higher stone-free rate in flexible ureteroscopy vs shock wave lithotripsy (RR = 1.17, 95% CI: 1.04-1.33, P = 0.01), operative time (mean difference = +16.4 minutes, 95% CI: 7.3-25.5, P < 0.01) and hospital stay (mean difference = +0.25 days, 95% CI: 0.14-0.36, P < 0.001). But no difference in fluoroscopy exposure time (mean difference = -21.0 seconds, 95% CI: -42.6 to 0.56, P = 0.07), Clavien I-II (RR = 1.23, 95% CI: 0.71-2.12, P = 0.45) or Clavien III-V complications (RR = 1.04, 95% CI: 0.32-3.42, P = 0.95). CONCLUSIONS: Flexible ureteroscopy has a significantly higher stone-free rate than shock wave lithotripsy, with no difference in complication rate or fluoroscopy exposure time, and significantly higher operative times and hospital stay. However, the current evidence base for this is weak and further randomized trials are needed.
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Cálculos Renais , Litotripsia , Cálculos Ureterais , Cálculos Urinários , Criança , Pré-Escolar , Humanos , Cálculos Renais/terapia , Cálculos Renais/etiologia , Estudos Prospectivos , Resultado do Tratamento , Cálculos Ureterais/terapia , Ureteroscopia , Cálculos Urinários/etiologia , Urologia , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: The aim of this real-life cross-sectional explorative study was to compare radiofrequency echographic multi-spectrometry (REMS) with dual-energy X-rays absorptiometry (DXA) in the BMD assessment of patients receiving peritoneal dialysis (PD). Furthermore, we investigated the relationship between lumbar aortic calcifications (AOCs) and the DXA lumbar measurements. METHODS: Consecutive patients referring to the PD clinic of our hospital were included. Lumbar spine and femur scans were acquired with both techniques (including lumbar laterolateral DXA scans). The risk assessment of two fracture risk algorithms (FRAX® and DeFRA®) were compared. Cohen's k coefficients were used to assess the inter-technique agreement in the classification of patients as osteoporotic. Lumbar AOCs were estimated semi-quantitatively on laterolateral DXA scans. RESULTS: 41 patients were enrolled. No significant differences were documented between the BMD T-scores measured through DXA or REMS at the femur. At the lumbar spine, the DXA anteroposterior mean T-score (- 0.49 ± 1.98) was significantly higher than both the laterolateral DXA (- 1.66 ± 0.99) and the REMS (- 2.00 ± 1.94) measurements (p < 0.01 vs both). No significant differences were found between the DXA and REMS fracture risk estimates with both algorithms. The inter-technique Cohen's k coefficient (for the worst T-score, any site) was 0.421, p < 0.001. The discrepancy between the DXA laterolateral and anteroposterior lumbar T-score was positively associated with the AOCs extent and severity (r = 0.402, p < 0.01). CONCLUSIONS: Our data showed a promising agreement, in a real-life PD setting, between DXA and REMS BMD assessment and in the consequent fracture risk estimation and confirm the AOCs interference on the diagnostic accuracy of lumbar DXA.
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Fraturas Ósseas , Diálise Peritoneal , Humanos , Densidade Óssea , Absorciometria de Fóton/métodos , Estudos Transversais , Vértebras Lombares/diagnóstico por imagem , Diálise Peritoneal/efeitos adversos , Análise EspectralRESUMO
BACKGROUND: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. METHODS: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. RESULTS: Variants at the CTRC (p = 1.22 × 10-21) and SPINK1 (p = 6.59 × 10-47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. CONCLUSIONS: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.
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Estudo de Associação Genômica Ampla , Pancreatite Alcoólica , Teorema de Bayes , Predisposição Genética para Doença , Humanos , Proteínas Nucleares , Pâncreas , Pancreatite Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Inibidor da Tripsina Pancreática de Kazal/genéticaRESUMO
BACKGROUND: Few studies have examined that the role of serum potassium concentration [K+] variability on clinical outcomes is still poorly investigated. The aim of our study was to analyse the association between serum ([K+]) disorders, with focus on [K+] variability and mortality in a large, unselected cohort of hospitalized patients. METHODS: We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between 1 January 2010 and 31 December 2014 with inclusion of adult patients with ≥2 [K+] measurements. The outcome of interest was in-hospital mortality. The exposures of interest were [K+] fluctuations, hypohyperkalaemia and mixed dyskalaemia during hospital stay. [K+] variability was evaluated using the coefficient of variation (CV). Logistic regression models were fitted to obtain odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the exposures of interest and in-hospital death. RESULTS: Overall, 64 507 patients met our inclusion criteria. During a median follow-up of 8 days, 965 patients (1.5%) died. Multivariable adjusted logistic models suggested a higher risk for death in patients in the third (OR = 1.45, 95% CI 1.13-1.88; P = 0.003) and fourth (OR = 3.30, 95% CI 2.64-4.16; P < 0.001) highest quartiles of [K+] CV compared with those in the lowest quartile with a significant linear trend across quartiles (P-trend <0.001). Results did not change after restricting the analyses to patients with normokalaemia (NK). All [K+] disorders were independently associated with an increased risk of in-hospital death compared with NK. CONCLUSIONS: High [K+] variability is an independent risk factor of in-hospital mortality, even within the normal [K+] range.
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Hospitalização , Potássio , Adulto , Estudos de Coortes , Mortalidade Hospitalar , Humanos , Estudos RetrospectivosRESUMO
Hypertension and chronic kidney disease (CKD) are closely linked pathological processes. Combating high blood pressure (BP) is an essential part of preventing CKD progression and reducing cardiovascular (CV) risk. Data from recent randomized controlled trials on patients at high CV risk showed the beneficial effects of intensive action to meet BP targets on mortality related to CV disease. The impact of meeting such targets on renal function is still unclear, however, particularly for patients with CKD. This issue has been the object of several post hoc analyses because lowering BP definitely has a nephroprotective role, but the early decline in glomerular filtration rate (GFR) associated with antihypertensive therapies and strict BP targets is still a concern in nephrology clinical practice. The present review discusses the results of studies on this topic, focusing specifically on the clinical significance of early GFR decline in response to treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or to different BP targets, in terms of renal and CV outcomes, and how this tips the balance towards continuing or discontinuing antihypertensive therapy.
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Hipertensão , Falência Renal Crônica , Insuficiência Renal Crônica , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
INTRODUCTION: Electrolyte disorders are common findings in kidney diseases and might represent a useful biomarker preceding kidney injury. Serum potassium [K+] imbalance is still poorly investigated for association with acute kidney injury (AKI), and most evidence came from intensive care units. The aim of our study was to comprehensively investigate this association in a large, unselected cohort of hospitalized patients. METHODS: We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 1, 2010 and December 31, 2014, with inclusion of adult patients with at least 2 [K+] and 3 serum creatinine measurements who did not develop AKI during an initial 10-day window. The outcome of interest was in-hospital AKI. The exposures of interest were [K+] fluctuations and hypo (HoK) and hyperkalemia (HerK). [K+] variability was evaluated using the coefficient of variation. Cox proportional hazards regression models were used to obtain hazard ratios and 95% confidence intervals of the association between the exposures of interest and development of AKI. RESULTS: About 21,830 hospital admissions from 18,836 patients were included in our study. During a median follow-up of 5 (interquartile range [IQR] 7) days, AKI was observed in 555 hospital admissions (2.9%); median time for AKI development was 5 (IQR 7) days. Higher [K+] variability was independently associated with increased risk of AKI with a statistically significant linear trend across groups (p value = 0.012). A significantly higher incidence of AKI was documented in patients with HerK compared with normokalemia. No statistically significant difference was observed between HoK and HerK (p value = 0.92). CONCLUSION: [K+] abnormalities including fluctuations even within the normal range are associated with development of AKI.
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Injúria Renal Aguda , Hiperpotassemia , Desequilíbrio Hidroeletrolítico , Injúria Renal Aguda/epidemiologia , Adulto , Estudos de Coortes , Humanos , Hiperpotassemia/complicações , Rim , Potássio , Estudos Retrospectivos , Fatores de Risco , Desequilíbrio Hidroeletrolítico/complicaçõesRESUMO
Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.
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Cistinúria , Cálculos Renais , Adolescente , Sistemas de Transporte de Aminoácidos Básicos/genética , Criança , Cistina/metabolismo , Cistinúria/diagnóstico , Cistinúria/genética , Cistinúria/terapia , Humanos , Rim/metabolismo , Cálculos Renais/etiologia , Cálculos Renais/genética , Qualidade de VidaRESUMO
Peritoneal dialysis (PD) is an efficient renal replacement therapy for patients with end-stage renal disease. Even if it ensures an outcome equivalent to hemodialysis and a better quality of life, in the long-term, PD is associated with the development of peritoneal fibrosis and the consequents patient morbidity and PD technique failure. This unfavorable effect is mostly due to the bio-incompatibility of PD solution (mainly based on high glucose concentration). In the present review, we described the mechanisms and the signaling pathway that governs peritoneal fibrosis, epithelial to mesenchymal transition of mesothelial cells, and angiogenesis. Lastly, we summarize the present and future strategies for developing more biocompatible PD solutions.
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Diálise Peritoneal , Fibrose Peritoneal , Soluções para Diálise/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/terapia , Peritônio/patologia , Qualidade de VidaRESUMO
RUNX2 and SOX9 are two pivotal transcriptional regulators of chondrogenesis. It has been demonstrated that RUNX2 and SOX9 physically interact; RUNX2 transactivation may be inhibited by SOX9. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. Epigenetic control of gene expression plays a major role in the alternative differentiation fates of stem cells; in particular, it has been reported that SOX9 can promote the expression of miRNA (miR)-204. Our aim was therefore to investigate the miR-204-5p role during chondrogenesis and to identify the relationship between this miR and the transcription factors plus downstream genes involved in chondrogenic commitment and differentiation. To evaluate the role of miR-204 in chondrogenesis, we performed in vitro transfection experiments by using Mesenchymal Stem Cells (MSCs). We also evaluated miR-204-5p expression in zebrafish models (adults and larvae). By silencing miR-204 during the early differentiation phase, we observed the upregulation of SOX9 and chondrogenic related genes compared to controls. In addition, we observed the upregulation of COL1A1 (a RUNX2 downstream gene), whereas RUNX2 expression of RUNX2 was slightly affected compared to controls. However, RUNX2 protein levels increased in miR-204-silenced cells. The positive effects of miR204 silencing on osteogenic differentiation were also observed in the intermediate phase of osteogenic differentiation. On the contrary, chondrocytes' maturation was considerably affected by miR-204 downregulation. In conclusion, our results suggest that miR-204 negatively regulates the osteochondrogenic commitment of MSCs, while it positively regulates chondrocytes' maturation.
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Condrogênese/genética , MicroRNAs/genética , Animais , Diferenciação Celular/genética , Células Cultivadas , Condrócitos/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Regulação para Baixo/genética , Humanos , Células-Tronco Mesenquimais/fisiologia , Osteogênese/genética , Fatores de Transcrição SOX9/genética , Células-Tronco/fisiologia , Ativação Transcricional/genética , Regulação para Cima/genética , Peixe-ZebraRESUMO
Heparanase (HPSE) is an endoglycosidase that catalyses the cutting of the side chains of heparan-sulphate proteoglycans (HS), thus determining the remodelling of the extracellular matrix and basement membranes, as well as promoting the release of different HS-related molecules as growth factors, cytokines and enzymes. Ever since the HPSE was identified in the late 1980s, several experimental studies have shown that its overexpression was instrumental in increasing tumor growth, metastatic dissemination, angiogenesis and inflammation. More recently, HPSE involvment has also been demonstrated in mediating tumor-host crosstalk, in inducing gene transcription, in the activation of signaling pathways and in the formation of exosomes and in autophagy. All of these activities (enzymatic and non-enzymatic) together make heparanase a multifunctional molecule that increases the aggressiveness and chemo-resistance of tumor cells. Conversely, heparanase gene-silencing or tumor treatment with compounds that inhibit heparanase activity have been shown to significantly attenuate tumor progression in different animal models of tumorigenesis, further emphasizing the therapeutic potential of anti-heparanase therapy for several types of neoplasms. This review focuses on present knowledge and recent development in the study of heparanase in cancer progression as well as on novel mechanisms by which heparanase regulates tumor metastasis and chemo-resistance. Moreover, recent advances in strategies for its inhibition as a potential therapeutic option will be discussed.
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Glucuronidase/genética , Glucuronidase/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Animais , Autofagia , Coagulação Sanguínea , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Matriz Extracelular/metabolismo , Glucuronidase/antagonistas & inibidores , Humanos , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Espaço Intracelular/metabolismo , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. METHODS: In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72. RESULTS: Two unrelated individuals were found to have two different variants in SLC4A1 that had never been described before. CONCLUSIONS: Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.
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Acidose Tubular Renal/genética , Nefrolitíase/genética , Acidose Tubular Renal/complicações , Adulto , Estudos Transversais , Feminino , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Nefrolitíase/etiologiaRESUMO
BACKGROUND: The aim of our study was to describe seasonal trends of acute kidney injury (AKI) and its relationship with weather conditions in a hospitalized population. METHODS: We retrospectively collected demographic (age, sex), clinical (ICD-9-CM codes of diagnosis discharge) and laboratory data (creatinine values) from the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 2010 and December 2014 with inclusion of all patients ≥18 years with at least two values available for creatinine. The outcome of interest was AKI development, defined according to creatinine kinetics criteria. The exposures of interest were the months and seasons of the year; air temperature and humidity level were also evaluated. Log-binomial regression models adjusted for age, sex, eGFR, comorbidities, Charlson/Deyo index score, year of hospitalization were used to estimate risk ratios (RR) and 95% confidential intervals (CI). RESULTS: A total of 64,610 patients met the inclusion criteria. AKI occurred in 2864 (4.4%) hospital admissions. After full adjustment, winter period was associated with increased risk of AKI (RR 1.16, 95% CI 1.05, 1.29, p=0.003). Lower air temperature and higher humidity level were associated with risk of AKI, however in multivariable-adjusted models only higher humidity level showed a significant and independent association. CONCLUSIONS: AKI is one of the most common complications of hospitalized populations with a defined seasonal pattern and a significant increase in incidence during wintertime; weather conditions, particularly higher humidity level, are independent predictors of AKI and could partially justify the observed seasonal variations.
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Injúria Renal Aguda/epidemiologia , Hospitalização/estatística & dados numéricos , Estações do Ano , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
The endothelial glycocalyx, the gel layer covering the endothelium, is composed of glycosaminoglycans, proteoglycans, and adsorbed plasma proteins. This structure modulates vessels' mechanotransduction, vascular permeability, and leukocyte adhesion. Thus, it regulates several physiological and pathological events. In the present review, we described the mechanisms that disturb glycocalyx stability such as reactive oxygen species, matrix metalloproteinases, and heparanase. We then focused our attention on the role of glycocalyx degradation in the induction of profibrotic events and on the possible pharmacological strategies to preserve this delicate structure.
Assuntos
Endotélio/química , Fibrose/genética , Glicocálix/química , Mecanotransdução Celular/genética , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Permeabilidade Capilar/genética , Endotélio/ultraestrutura , Fibrose/patologia , Glucuronidase/efeitos adversos , Glicocálix/genética , Glicocálix/ultraestrutura , Glicosaminoglicanos/química , Glicosaminoglicanos/genética , Humanos , Metaloproteinases da Matriz/efeitos adversos , Proteoglicanas/química , Proteoglicanas/genética , Espécies Reativas de Oxigênio/efeitos adversosRESUMO
Peritoneal dialysis (PD) is an important, if underprescribed, modality for the treatment of patients with end-stage kidney disease. Among the barriers to its wider use are the deleterious effects of currently commercially available glucose-based PD solutions on the morphological integrity and function of the peritoneal membrane due to fibrosis. This is primarily driven by hyperglycaemia due to its effects, through multiple cytokine and transcription factor signalling-and their metabolic sequelae-on the synthesis of collagen and other extracellular membrane components. In this review, we outline these interactions and explore how novel PD solution formulations are aimed at utilizing this knowledge to minimise the complications associated with fibrosis, while maintaining adequate rates of ultrafiltration across the peritoneal membrane and preservation of patient urinary volumes. We discuss the development of a new generation of reduced-glucose PD solutions that employ a variety of osmotically active constituents and highlight the biochemical rationale underlying optimization of oxidative metabolism within the peritoneal membrane. They are aimed at achieving optimal clinical outcomes and improving the whole-body metabolic profile of patients, particularly those who are glucose-intolerant, insulin-resistant, or diabetic, and for whom daily exposure to high doses of glucose is contraindicated.
Assuntos
Diabetes Mellitus/terapia , Soluções para Diálise/uso terapêutico , Intolerância à Glucose/terapia , Resistência à Insulina , Falência Renal Crônica/terapia , Diálise Peritoneal , Soluções para Diálise/efeitos adversos , Glucose/efeitos adversos , Glucose/uso terapêutico , Humanos , PeritônioRESUMO
BACKGROUND: Little is known about the underlying aetiology of fatigue in haemodialysis (HD) patients apart from a significant association and overlapping symptomatology with depressive symptoms. Growing evidence exists for the involvement of the immune system, by pro-inflammatory cytokines, in the development of fatigue in other inflammatory diseases. In HD patients, increased exposure to bacterial endotoxins may contribute to an inflammatory response and may potentially lead to fatigue. We therefore aimed (i) to assess the interrelationship between serum endotoxin (EA) levels, interleukin-6 (IL-6) levels and fatigue in HD patients; (ii) to evaluate whether there is a relationship between depressive symptoms and inflammation as well and (iii) to what extent depressive symptoms and fatigue are related to each other. METHODS: Fatigue and depressive symptoms in daily life were assessed in 59 individuals using the SF-36 vitality subscale and the Geriatric Depression Scale. Blood samples were collected on a mid-week dialysis session to determine EA levels, through the Endotoxin Activity Assay (EAA™), and IL-6 concentrations, through the commercially available Abcam ELISA (Enzyme-Linked Immunosorbent Assay) kit. RESULTS: EA, IL-6 levels and depressive symptoms were significantly correlated with fatigue. EA levels and depressive symptoms were significant predictors of fatigue, explaining 31% of its variance. However, EA and IL-6 were not significantly associated with depression. CONCLUSIONS: Fatigue in HD patients may be related to endotoxemia and inflammation through IL-6. Furthermore, fatigue is significantly associated with depressive symptoms. Future research into the causal interrelationship of inflammation, fatigue and depression in HD patients might lead to potential targets for therapeutic strategies.