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INTRODUCTION: Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD). It begins as an adaptive increase in parathyroid hormone levels to prevent calcium and phosphate derangements. Over time, this condition becomes maladaptive and is associated with increased morbidity and mortality. Current therapies encompass phosphate-lowering strategies, vitamin D analogues, calcimimetics and parathyroidectomy. These approaches harbor inherent limitations, stimulating interest in the development of new drugs for SHPT to overcome these limitations and improve survival and quality of life among CKD patients. AREAS COVERED: This review delves into the main pathophysiological mechanisms involved in SHPT, alongside the treatment options that are currently available and under active investigation. Data presented herein stem from a comprehensive search conducted across PubMed, Web of Science, ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) spanning from 2000 onwards. EXPERT OPINION: The advancements in investigational drugs for SHPT hold significant promise for enhancing treatment efficacy while minimizing side effects associated with conventional therapies. Although several challenges still hinder their adoption in clinical practice, ongoing research will likely continue to expand the available therapeutic options, refine treatment strategies, and tailor them to individual patient profiles.
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Desarrollo de Medicamentos , Drogas en Investigación , Hiperparatiroidismo Secundario , Calidad de Vida , Insuficiencia Renal Crónica , Humanos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/fisiopatología , Hiperparatiroidismo Secundario/etiología , Drogas en Investigación/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Animales , Calcimiméticos/farmacología , Calcimiméticos/administración & dosificación , Calcimiméticos/uso terapéutico , Hormona Paratiroidea , Paratiroidectomía , Vitamina D/farmacología , Calcio/metabolismo , Fosfatos/metabolismoRESUMEN
INTRODUCTION: Renal injury is among the leading causes of morbidity and mortality; however, there are no reliable indicators for determining the likelihood of developing chronic kidney disease (CKD), CKD progression, or AKI events. Vascular growth factors called angiopoietins have a role in endothelial function, vascular remodeling, tissue stabilization, and inflammation and have been implicated as prognostic and predictive markers in AKI. METHODS: Although the exact mechanism of the relationship between kidney injury and angiopoietins is unknown, this review demonstrates that AKI patients have higher angiopoietin-2 levels and that higher angiopoietin-1 to angiopoietin-2 ratio may potentially be linked with a reduced risk of the CKD progression. RESULTS: This review therefore emphasizes the importance of angiopoietin-2 and proposes that it could be an important predictor of AKI in clinical settings. CONCLUSION: There is a need for further large-scale randomized clinical trials in order to have a better understanding of the significance of angiopoietin-2 and for the determination of its potential clinical implications.
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Angiopoyetina 1 , Angiopoyetina 2 , Biomarcadores , Insuficiencia Renal Crónica , Humanos , Biomarcadores/sangre , Angiopoyetina 2/sangre , Pronóstico , Angiopoyetina 1/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/sangre , Progresión de la EnfermedadRESUMEN
Fibroblast growth factor 23 (FGF-23) has been associated with increased cardiovascular risk and poor survival in dialysis patients. It is well established that FGF-23 synthesis is directly induced by positive phosphate (P) balance. On the other hand, P-lowering treatments such as nutritional P restriction, P binders and dialysis are capable of reducing FGF-23 levels. However, there are many uncertainties regarding the possibility of adopting FGF-23 to guide the clinical decision-making process in the context of chronic kidney disease-mineral bone disorder (CKD-MBD). Furthermore, the best assay to adopt for measurement of FGF-23 levels (namely the intact vs the C-terminal one) remains to be determined, especially in conditions capable of altering the synthesis as well as the cleavage of the intact and biologically active molecule, as occurs in the presence of CKD and its complications. This Editorial discusses the main insights provided by the post hoc analysis of the NOPHOS trial, with particular attention given to evidence-based peculiarities of the intact and the C-terminal assays available for measuring FGF-23 levels, especially in patients receiving additive P-lowering therapy in the presence of inflammation, anemia and iron deficiency.
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INTRODUCTION: Cardiovascular disease (CVD) is one of the global leading causes of morbidity and mortality in chronic kidney disease (CKD) patients. Vascular calcification (VC) is a major cause of CVD in this population and is the consequence of complex interactions between inhibitor and promoter factors leading to pathological deposition of calcium and phosphate in soft tissues. Different pathological landscapes are associated with the development of VC, such as endothelial dysfunction, oxidative stress, chronic inflammation, loss of mineralization inhibitors, release of calcifying extracellular vesicles (cEVs) and circulating calcifying cells. AREAS COVERED: In this review, we examined the literature and summarized the pathophysiology, biomarkers and focused on the treatments of VC. EXPERT OPINION: Even though there is no consensus regarding specific treatment options, we provide the currently available treatment strategies that focus on phosphate balance, correction of vitamin D and vitamin K deficiencies, avoidance of both extremes of bone turnover, normalizing calcium levels and reduction of inflammatory response and the potential and promising therapeutic approaches liketargeting cellular mechanisms of calcification (e.g. SNF472, TNAP inhibitors).Creating novel scores to detect in advance VC and implementing targeted therapies is crucial to treat them and improve the future management of these patients.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Calcificación Vascular , Humanos , Calcio , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Calcificación Vascular/etiología , Calcificación Vascular/complicaciones , Enfermedades Cardiovasculares/complicaciones , FosfatosRESUMEN
Multiple risk factors for chronic kidney disease (CKD), one of the major causes of morbidity and mortality in the adult population globally, have been identified, including older age, male gender, family history, smoking, diabetes mellitus, hypertension, ischaemic heart diseases and various medications. Preterm delivery, affecting >10% of the newborns in the USA, is a global concern with increasing incidence in recent decades. Preterm birth has been linked to multiple medical comorbidities such as diabetes mellitus, hypertension and cardiovascular diseases, while its association with CKD has recently been investigated. Prematurity and intrauterine growth restriction (IUGR) have been associated with an increased risk for CKD, specific histopathological examination findings and CKD-associated risk factors such as diabetes mellitus, hypertension and dyslipidaemia. In this narrative review, our aim is to evaluate and summarize the association between the risk for CKD and prematurity, low birthweight and IUGR along with potential underlying pathophysiological mechanisms.
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Diabetes Mellitus , Hipertensión , Nacimiento Prematuro , Insuficiencia Renal Crónica , Adulto , Femenino , Recién Nacido , Masculino , Humanos , Nacimiento Prematuro/etiología , Factores de Riesgo , Retardo del Crecimiento Fetal/etiología , Hipertensión/complicaciones , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/diagnósticoRESUMEN
Chronic kidney disease and the need for kidney replacement therapy have increased dramatically in recent decades. Forecasts for the coming years predict an even greater increase, especially in low- and middle-income countries, due to the rise in metabolic and cardiovascular diseases and the aging population. Access to kidney replacement treatments may not be available to all patients, making it especially strategic to set up therapy programs that can ensure the best possible treatment for the greatest number of patients. The choice of the "ideal" kidney replacement therapy often conflicts with medical availability and the patient's tolerance. This paper discusses the pros and cons of various kidney replacement therapy options and their real-world applicability limits.
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BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. METHODS: We used data from the European Quality study, which includes patients aged ≥65 years with estimated glomerular filtration rate ≤20 mL/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. RESULTS: In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. CONCLUSIONS: CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Insuficiencia Renal Crónica , Humanos , Anciano , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Calcio , Hormona Paratiroidea , Fosfatos , Calcio de la Dieta , Biomarcadores , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Diálisis RenalAsunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Anciano , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Transportador 2 de Sodio-Glucosa , Hipoglucemiantes , Readmisión del Paciente , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
INTRODUCTION: In chronic kidney disease (CKD), the high morbidity and mortality risk for cardiovascular disease (CVD) are not easily explained only on the basis of traditional factors. Among nontraditional ones involved in CKD, malnutrition, inflammation, and atherosclerosis/calcification have been described as the "MIA syndrome." METHODS: In this pilot study, we evaluated the association between the variation in serum levels of 27 uremic retention solutes plus 6 indexes related to the MIA syndrome processes in a population of dialysis patients. RESULTS: As expected, we found a direct correlation between serum albumin and both phosphate and total cholesterol (r = 0.54 and 0.37, respectively; p < 0.05). Moreover, total cholesterol and phosphate directly correlate (r = 0.40, p < 0.05). The relationship between malnutrition and inflammation is highlighted by the correlation of serum cholesterol levels with serum alpha-1 acid glycoprotein and IL-6 levels (r = -0.56, r = -0.39, respectively; p < 0.05). Moreover, the relation between inflammation and atherosclerosis/calcification is supported by the correlation of IL-6 with VEGF levels and vascular smooth muscle cell high-Pi in vitro calcification (r = 0.81, r = 0.66, respectively; p < 0.01). CONCLUSION: We found significant correlations between several uremic retention solutes and malnutrition, inflammation, and atherosclerosis/calcification. Our findings support the hypothesis of a central role of the uremic milieu in the MIA syndrome and ultimately in the pathogenesis of CKD-specific CVD risk factors.
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Aterosclerosis , Enfermedades Cardiovasculares , Desnutrición , Insuficiencia Renal Crónica , Uremia , Humanos , Diálisis Renal/efectos adversos , Tóxinas Urémicas , Interleucina-6 , Proyectos Piloto , Factor A de Crecimiento Endotelial Vascular , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Inflamación , Desnutrición/etiología , Enfermedades Cardiovasculares/etiología , Colesterol , Fosfatos , Uremia/complicaciones , Uremia/terapiaRESUMEN
A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients' characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53−3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34−4.79 versus HR 1.99, CI 1.17−3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD.
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Chronic kidney disease (CKD) patients are more susceptible to infections compared to the general population. SARS-CoV-2 virus pathology is characterized by a cytokine storm responsible for the systemic inflammation typical of the COVID-19 disease. Since CKD patients have a reduced renal clearance, we decided to investigate whether they accumulate harmful mediators during the COVID-19 disease. We conducted a retrospective study on 77 COVID-19 hospitalized subjects in the acute phase of the illness. Thirteen different cytokines were assessed in plasma collected upon hospitalization. The patients were divided into three groups according to their estimated glomerular filtration rate, eGFR < 30 (n = 23), 30 < eGFR < 60 (n = 33), eGFR > 60 mL/min (n = 21). We found that Tumor Necrosis Factor α and its receptors I and II, Interleukin-7, Leukemia Inhibitory Factor, FAS receptor, Chitinase 3-like I, and the Vascular Endothelial Growth Factor showed an increased accumulation that negatively correlate with eGFR. Moreover, non-survivor patients with an impaired kidney function have significantly more elevated levels of the same mediators. In conclusion, there is a tendency in COVID-19 ESRD patients to accumulate harmful cytokines. The accumulation seems to associate with mortality outcomes and may be due to reduced clearance but also to increased biosynthesis in most severe cases.
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COVID-19 , Quitinasas , Insuficiencia Renal Crónica , Insuficiencia Renal , Humanos , Quimiocinas , Receptor fas , Tasa de Filtración Glomerular/fisiología , Interleucina-7 , Factor Inhibidor de Leucemia , Estudios Retrospectivos , SARS-CoV-2 , Factor de Necrosis Tumoral alfa , Factor A de Crecimiento Endotelial Vascular , Citocinas/inmunologíaRESUMEN
BACKGROUND: The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the symptoms typical in uraemic patients. These molecules are defined as uraemic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put towards developing dialysis membranes that allow the removal of large middle molecules without clinically relevant albumin loss. These membranes are the medium cut-off (MCO) membranes that allow the removal of middle molecules up to â¼50 000 Da. METHODS: We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded haemodialysis (HDx) (novel MCO membrane Theranova 400) and conventional haemodialysis (HD) in 20 prevalent HD patients. Ten patients used conventional HD high-flux dialyser and 10 patients used HDx for 3 months; later the patients switched and received the other treatment for a further 3 months. We then analysed the pro-calcifying effect of uraemic serum in a model of high phosphate(Pi)-induced calcification in vascular smooth muscle cells (VSMCs). RESULTS: In this study, every patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential from HDx-treated patients' serum compared with HD. Studying pathogenetic processes involved in high Pi-induced calcium deposition, we found that uraemic serum of HDx-treated patients induced less VSMC necrosis compared with uraemic serum of HD patients. Nevertheless, no differences were found between the different dialytic treatments in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC simil-osteoblastic differentiation such as bone morphogenetic protein 2, runt-related transcription factor 2, osteocalcin, matrix Gla protein, osteopontin, elastin and collagen I α1. In an effort to characterize the difference in uraemic toxin profile during the two different dialytic treatments, we measured a panel of 10 uraemic toxins and 3 precursors, finding a significant increased removal during HDx of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, tryptophane and some of its metabolites, such as 3-indoxyl sulphate, indole 3-acetic acid and kynurenine. CONCLUSIONS: These preliminary data are promising, although larger patients' groups are needed to better understand the effects of HDx on vascular calcification.
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Introduction: Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation).Areas covered: The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients.Expert opinion: Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.
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Hiperparatiroidismo Secundario/terapia , Insuficiencia Renal Crónica/complicaciones , Deficiencia de Vitamina D/complicaciones , Suplementos Dietéticos , Progresión de la Enfermedad , Humanos , Hiperparatiroidismo Secundario/etiología , Receptores de Calcitriol/efectos de los fármacos , Receptores de Calcitriol/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Vitamina D/administración & dosificación , Vitamina D/efectos adversos , Deficiencia de Vitamina D/terapiaRESUMEN
Monitoring venous congestion by ultrasound assessment of hepatic venogram allowed individualized fluid management in severe cardiorenal syndrome type 5 due to light chain myeloma, preserving residual renal function and avoiding heart failure.
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BACKGROUND: Despite significant advances in haemodialysis (HD) in recent decades, current dialysis techniques are limited by inadequate removal of uraemic solutes such as middle molecules and protein-bound uraemic toxins. Novel medium cut-off (MCO) membrane or 'expanded haemodialysis' (HDx) provides diffusive removal of conventional and large middle molecular weight uraemic toxins, with marginal albumin leak. METHODS: This prospective, open-label, controlled, cross-over pilot study compared HDx (novel MCO membrane Theranova® 400) and conventional HD in 20 prevalent HD patients. Biochemical, dialysis adequacy and safety measures (adverse events, infections and hospitalization frequency) were recorded. Ten patients underwent conventional HD high-flux dialyser and 10 patients underwent HDx for 3 months, and the patients then switched and received the other treatment for a further 3 months. RESULTS: Treatment with HDx was associated with a significant reduction in serum albumin concentration [median (interquartile range) reduction -0.45 g/dL (-0.575 to -0.05); P = 0.025]. However, median albumin levels were ≥3.5 g/dL and no patients had clinical symptoms of hypoalbuminaemia or needed intravenous albumin administration. The number of infections was lower in patients treated with HDx (n = 7/19) compared with patients treated with HD (n = 14/20; P = 0.03). Patients treated with HDx had reduced levels of interleukin (IL)-1ß (from 0.06 ± 0.02 pg/mL versus 0.28 ± 0.18 pg/mL with HD) and IL-6 (6.45 ± 1.57 pg/mL versus 9.48 ± 2.15 pg/mL), while tumour necrosis factor-α levels remain unchanged. CONCLUSIONS: This study demonstrates that the chronic use of the novel MCO dialyser Theranova® appears to be safe and well-tolerated, without serious side effects or hypoalbuminaemia, as well as fewer infections. These results need to be confirmed in larger randomized clinical trials.
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Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti-inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID-19.