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Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.
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Antibody-mediated rejection (ABMR) is a major cause of kidney allograft failure. Biopsy-based surrogate endpoints reflecting ABMR progression on sequential biopsies that predict long-term outcome offer the potential to make treatment trials for ABMR feasible. However, the Banff transplant glomerulopathy (TG) scoring system (chronic glomerular injury score [cg]) relies on relatively crude and arbitrary ordinal grades and has low inter-observer concordance that currently limits its usefulness as a surrogate endpoint for ABMR progression in clinical drug trials. Here, we describe and validate a novel quantitative method for quantifying progression of TG in ABMR. Using digital pathology in sequential biopsies from 75 patients at various stages of ABMR, we scored all capillaries in the most affected glomeruli for basement membrane duplication that were correlated with allograft function, outcome, Banff lesion scores, and gene expression. Our digital scoring reflected TG progression better than the categorical Banff cg score and correlated with Banff ABMR and chronicity lesions, but not transcript changes. In multivariate analysis, the delta change between biopsies with serum creatinine and mean percent duplicated glomerular basement membranes was significantly associated with graft loss. Neither the delta in any Banff lesion scores (including cg) nor in gene expression was associated with outcome. Receiver operating characteristic curve analysis showed that the digital pathology approach was superior to the conventional score for predicting graft failure. Thus, our digital pathology-based approach for scoring TG accurately assessed progression in TG. However, further validation as a potential surrogate endpoint in clinical trials for the treatment of ABMR is warranted.
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Enfermedades Renales , Insuficiencia Renal , Humanos , Anticuerpos , Biopsia , Membrana Basal Glomerular , Rechazo de Injerto/genéticaRESUMEN
BACKGROUND: Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro. METHODS: This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays. RESULTS: In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {-62% [95% confidence interval (CI) -76 to -44], P < .0001 and -38% [-62 to -0.14], P < .001, respectively} compared with washout. Nine of 14 plasma cytokines/chemokines significantly decreased with high-dose SO, with consistent reductions in interleukin-6 (IL-6) and IL-8. Exposure of HASMC and HCAEC cultures to serum of SO-treated patients reduced calcification and markers of activation (IL-6, IL-8 and vascular cell adhesion protein 1) compared with washout. Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. Effects of CPP removal were confirmed in an independent cohort of chronic kidney disease patients. CONCLUSIONS: High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.
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Diálisis Renal , Calcificación Vascular , Humanos , Masculino , Femenino , Diálisis Renal/efectos adversos , Interleucina-6 , Estudios Cruzados , Interleucina-8 , Inflamación/tratamiento farmacológico , Inflamación/etiología , Citocinas/metabolismo , Calcificación Vascular/etiología , Calcificación Vascular/prevención & control , FosfatosRESUMEN
DEFINITION AND EPIDEMIOLOGY: Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density Tscore isâ¯≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured Tscore (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C). DIAGNOSIS AND RISK STRATIFICATION OF OSTEOPOROSIS IN CKD: Densitometry (using dual Xray absorptiometry, DXA): low Tscore correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the Tscore by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-scoreâ¯≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFRâ¯< 15â¯ml/min/1.73â¯m2) or CKD 5D (dialysis). SPECIFIC TREATMENT OF OSTEOPOROSIS IN PATIENTS WITH CKD: Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFRâ¯≥ 60â¯ml/min/1.73â¯m2): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFRâ¯< 60â¯ml/min/1.73â¯m2 to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59â¯ml/min/1.73â¯m2) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFRâ¯< 30â¯ml/min/1.73â¯m2) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFRâ¯< 30â¯ml/min/1.73â¯m2) and high fracture risk (e.g. FRAX scoreâ¯> 20% for a major osteoporotic fracture orâ¯> 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFRâ¯< 30â¯ml/min/1.73â¯m2 to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C). PHYSICAL MEDICINE AND REHABILITATION: Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40â¯min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica , Nefrología , Osteoporosis , Fracturas Osteoporóticas , Medicina Física y Rehabilitación , Insuficiencia Renal Crónica , Humanos , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/epidemiología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Calcio , Fracturas Osteoporóticas/diagnóstico , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Austria , Osteoporosis/diagnóstico , Osteoporosis/epidemiología , Osteoporosis/etiología , Insuficiencia Renal Crónica/complicaciones , Densidad Ósea , Vitamina D , Minerales , Fósforo , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Active malignancy is an absolute contraindication to kidney transplantation. As for chronic myeloid leukemia (CML), a Philadelphia chromosome-positive myeloproliferative neoplasm, the introduction of tyrosine kinase inhibitors has transformed CML from a lethal into a manageable chronic disease with a close-to-normal life expectancy. To date it is unknown whether kidney transplantation can be safely performed in patients with pre-existing CML. We describe the clinical course of a 57-year-old male patient with chronic kidney disease caused by reflux nephropathy. This patient had undergone first kidney transplantation 20 years earlier and had again been on chronic hemodialysis for 6 years when CML was diagnosed. First-line therapy with 400 mg imatinib daily was well tolerated and induced an optimal cytogenetic and molecular response 3 months after initiation. One and a half years after CML diagnosis, a second kidney transplantation from a deceased donor was performed. Immunosuppression included basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids. Currently, 2 years posttransplant, renal allograft function is stable (serum creatinine 1.09 mg/dL, estimated glomerular filtration rate 75 mL/min per 1.73 m2 ), and CML remains in deep molecular remission with imatinib. Imatinib-treated CML in deep molecular remission could be regarded as inactive malignancy and may therefore not be viewed as an absolute contraindication to kidney transplantation.
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Antineoplásicos , Trasplante de Riñón , Leucemia Mielógena Crónica BCR-ABL Positiva , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Enfermedad Crónica , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Chronic kidney disease (CKD) facilitates a unique environment to strongly accelerate vascular calcification - the pathological deposition of calcium-phosphate in the vasculature. These calcifications are associated with the excessive cardiovascular mortality of CKD patients. RECENT FINDINGS: Vascular calcification is a multifaceted active process, mediated, at least partly, by vascular smooth muscle cells. These cells are able to transdifferentiate into cells with osteo/chondrogenic properties, which exert multiple effects to facilitate vascular tissue mineralization. As the understanding of the underlying pathophysiology increases, first therapeutic concepts begin to emerge. SUMMARY: This brief review provides an overview on the so far known mechanisms involved in the initiation and progression of vascular calcification in CKD.
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Insuficiencia Renal Crónica/complicaciones , Calcificación Vascular/etiología , Condrogénesis , Humanos , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/fisiologíaRESUMEN
BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T50 calcification inhibition test (T50-test) is a global functional test analyzing the overall propensity of calcification in serum, and low T50-time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T50-time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T50-time in CKD patients. MATERIAL AND METHODS: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO3- ≤21 mmol/L), in which patients are randomized to either achieve serum HCO3- levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T50-time was assessed. RESULTS: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T50-time was 275 (± 64) min. After 4 weeks, the mean change of T50-time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (ß = -25; 95% CI: -71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T50-time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T50-time (ß = -145; 95% CI: -237 to -52). CONCLUSION: Oral sodium bicarbonate supplementation showed no effect on T50-time in acidotic CKD patients.
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Acidosis/tratamiento farmacológico , Calcinosis/prevención & control , Insuficiencia Renal Crónica/tratamiento farmacológico , Bicarbonato de Sodio/administración & dosificación , Adulto , Anciano , Calcinosis/sangre , Calcinosis/tratamiento farmacológico , Suplementos Dietéticos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bicarbonato de Sodio/farmacología , Bicarbonato de Sodio/uso terapéutico , Rigidez Vascular/efectos de los fármacosRESUMEN
Renal osteodystrophy affects the majority of patients with advanced chronic kidney disease (CKD) and is characterized by progressive bone loss. This study evaluated the effects of sclerostin knockout on bone in a murine model of severe, surgically induced CKD in both sclerostin knockout and wild-type mice. Mice of both genotypes with normal kidney function served as controls. Tibiae were analyzed using micro-computed tomography, and lumbar vertebrae were analyzed by histomorphometry. Results were tested for statistical significance by 2-way ANOVA to investigate whether bone of the knockout mice reacted differently to CKD compared with bone of wild-type mice. In the tibiae, there was no difference after creation of CKD between wild-type and knockout animals for cortical thickness or cross-sectional moment of inertia. Increases in cortical porosity induced by CKD differed significantly between genotypes in the tibial metaphysis but not in the diaphysis. In the trabecular compartment, no difference in reaction to CKD between genotypes was found for bone volume, trabecular number, trabecular thickness, and trabecular separation. In the lumbar vertebrae, significant differences in response to CKD between wild-type and knockout mice were seen for both bone volume and trabecular thickness. Osteoblast parameters did not differ significantly, whereas osteoclast numbers significantly increased in the wild-type but significantly decreased in knockout mice with CKD. No differences in response to CKD between genotypes were found for bone formation rate or mineral apposition rate. Thus, complete absence of sclerostin has only minor effects on CKD-induced bone loss in mice.
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Densidad Ósea , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Glicoproteínas/genética , Osteogénesis , Insuficiencia Renal Crónica/complicaciones , Proteínas Adaptadoras Transductoras de Señales , Animales , Huesos/citología , Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/genética , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/metabolismo , Modelos Animales de Enfermedad , Femenino , Genotipo , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/patología , Insuficiencia Renal Crónica/metabolismo , Tibia , Microtomografía por Rayos XRESUMEN
BACKGROUND/AIMS: Sclerostin, a soluble inhibitor of Wnt-signaling, inhibits bone formation. We assessed the impact of dialysis on serum sclerostin and whether sclerostin is detectable in effluent dialysates. METHODS: In a prospective study of 54 prevalent hemodialysis patients, parameters of bone and mineral metabolism were assessed at the beginning and at the end of dialysis. In a subset of patients (n = 19) sclerostin was measured in serum at start, 1, 2, and 3 h of dialysis and in the effluent dialysate at several points in time. RESULTS: Sclerostin serum levels decreased from median 71.4 pmol/l to 43.5 pmol/l during dialysis (p < 0.0001). In patients with high pre-dialysis sclerostin serum levels, sclerostin was detected in the dialysate. Higher Kt/V correlated with greater relative decrease of sclerostin (r = 0.467; p = 0.001). CONCLUSION: Sclerostin is dialysable. Furthermore, sclerostin serum levels decrease during dialysis. Whether targeting lower sclerostin levels by means of improved dialysis adequacy has direct relevance to bone disease remains to be shown.
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Proteínas Morfogenéticas Óseas/sangre , Soluciones para Diálisis/química , Fallo Renal Crónico/sangre , Diálisis Renal , Proteínas Adaptadoras Transductoras de Señales , Anciano , Femenino , Marcadores Genéticos , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores SexualesRESUMEN
Background: This study investigated whether parathyroid hormone (PTH) lowering with etelcalcetide, and the consequent effects on mineral and bone metabolism, could improve serum calcification propensity (T50 time) and decrease calciprotein particle (CPP) load in hemodialysis patients with secondary hyperparathyroidism. Methods: In this single-arm, prospective, dose-escalation proof-of-principle study, hemodialysis patients received etelcalcetide at 2.5 mg/dialysis session with increments of 2.5 mg every 4 weeks to a maximum dose of 15 mg three times a week or until a pre-specified safety endpoint was reached, followed by an 8-week wash-out phase. Results: Out of 36 patients recruited (81% male, 62 ± 13 years), 16 patients completed the study per protocol with a mean maximum tolerated dose of etelcalcetide of 9.5 ± 2.9 mg/dialysis session. With escalating doses of etelcalcetide, PTH and serum calcium levels significantly decreased (P < 0.0001). While there was no significant change in T50 times or serum phosphate levels, etelcalcetide did yield significant and consistent reductions in serum levels of endogenous calciprotein monomers [-35.4 (-44.4 to -26.5)%, P < 0.0001], primary [-22.4 (-34.5 to -10.3)%, P < 0.01] and secondary CPP [-29.1 (-45.7 to -12.4)%, P < 0.01], an effect that was reversed after therapy withdrawal. Serum levels of osteoclastic markers significantly decreased with escalating doses of etelcalcetide, while levels of the osteoblastic marker remained stable. Conclusions: Lowering of PTH with etelcalcetide did not result in statistically significant changes in T50. By contrast, homogenous reductions in serum levels of calciprotein monomers, primary and secondary CPP were observed.
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Klotho, a multifunctional protein, acts as a co-receptor in fibroblast growth factor 23 and exerts its impact through various molecular pathways, including Wnt, hypoxia-inducible factor and insulin-like growth factor 1 pathways. The physiological significance of Klotho is the regulation of vitamin D and phosphate metabolism as well as serving as a vital component in aging and neurodegeneration. The role of Klotho in aging and neurodegeneration in particular has gained considerable attention. In this narrative review we highlight several key insights into the molecular basis and physiological function of Klotho and synthesize current research on the role of Klotho in neurodegeneration and aging. Klotho deficiency was associated with cognitive impairment, reduced growth, diminished longevity and the development of age-related diseases in vivo. Serum Klotho levels showed a decline in individuals with advanced age and those affected by chronic kidney disease, establishing its potential diagnostic significance. Additionally, multiple medications have been demonstrated to influence Klotho levels. Therefore, this comprehensive review suggests that Klotho could open the door to novel interventions aimed at addressing the challenges of aging and neurodegenerative disorders.
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Introduction: Serum calcification propensity (T50 time) is associated with mortality in patients on dialysis. Several solitary interventions improve T50. However, whether a combination of interventions yields further increases in T50 is unknown. We hypothesized that a combination of 2 interventions, namely increasing magnesium concentration while simultaneously substituting acetate for citrate in the dialysis fluid, leads to increases in T50 values. Methods: In a randomized controlled trial, 60 patients on chronic hemodialysis were allocated to either continue on standard (S) dialysate (3 mmol/l acetate, 0.5 mmol/l magnesium) or a sequence of magnesium-enriched (Mg0.75) dialysate (3 mmol/l acetate, 0.75 mmol/l magnesium) for 2 weeks followed by combination treatment using citrate-buffered, magnesium-enriched (Cit+Mg0.75) dialysate (1 mmol/l citrate, 0.75 mmol/l magnesium) for 3 weeks. The primary end point was the difference in T50 times between the S group and the Cit+Mg0.75 group. Results: There was no significant difference in T50 time between the S group and the Cit+Mg0.75 group (236 ± 77 vs. 265 ± 97 min, P = 0.23). The size (hydrodynamic radius) of secondary calciprotein particles did not differ between the S group and the Cit+Mg0.75 group (294 ± 95 vs. 309 ± 91 nm, P = 0.56). In longitudinal analyses, serum magnesium concentrations increased from 1.07 ± 0.17 to 1.24 ± 0.17 mmol/l with the Mg0.75 dialysate (P < 0.0001) but decreased again to 1.19 ± 0.16 mmol/l with the Cit+Mg0.75 dialysate (P < 0.0001). Conclusion: The combination of citrate buffer with increased magnesium concentration in dialysate does not improve T50.
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The incidence of renal osteodystrophy (ROD) increases with deteriorating kidney function, affecting virtually every patient on chronic dialysis treatment. ROD can persist after kidney transplantation and may be aggravated by immunosuppressants, mainly glucocorticoids. Fracture risk, including hip fractures, is markedly elevated in patients with renal disease compared to the general population. Depending on the type of ROD, high or low bone turnover can be found. Because of poor positive and negative predictive values of serological markers of bone turnover and limited technical capabilities of various bone imaging modalities, the only reliable method to correctly classify ROD is the transiliac bone biopsy. Elevated bone turnover can be successfully treated with active vitamin D, cinacalcet, or parathyreoidectomy, but all of these therapies may lead to oversuppression of bone metabolism. Currently, no specific therapy is available for low turnover bone disease. Bisphosphonates can be a therapeutic option for selected patients after renal transplantation.
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Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/diagnóstico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/terapia , Hiperparatiroidismo Secundario/diagnóstico , Hiperparatiroidismo Secundario/terapia , Biomarcadores/sangre , Biopsia , Remodelación Ósea/fisiología , Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/patología , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Pruebas de Función Renal , Trasplante de Riñón , Hormona Paratiroidea/sangre , Diálisis Renal , Tomografía Computarizada de Haz Cónico EspiralRESUMEN
Chronic kidney disease (CKD) drastically increases the risk for cardiovascular morbidity and mortality and its worldwide prevalence is still rising. Effective treatment slows CKD progression, prevents development of end-stage kidney disease and cardiovascular disease thereby prolonging survival of patients. Recently, several large-scale studies with sodium-glucose cotransport2 inhibitors (SGLT-2i) have demonstrated profound nephroprotective and cardioprotective properties in patients with type 2 diabetes mellitus with both CKD and heart failure. Recently, the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial demonstrated that the selective SGLT-2i dapagliflozin reduced the hazard ratio for a composite renal and cardiovascular death endpoint in patients with CKD with or without type 2 diabetes. Furthermore, dapagliflozin exerted strong nephroprotection in CKD patients with diverse etiologies like IgA nephropathy. Furthermore, other promising CKD trials such as with empagliflozin are underway. Hence, individualized treatment with SGLT2i represents a promising therapeutic option for patients with both diabetic and non-diabetic CKD. Here we summarize the current knowledge on the treatment with SGLT-2i in CKD patients underscoring a strong rationale for SGLT2 inhibition to be incorporated into standard of care for most CKD patients also with non-diabetic kidney disease. Finally, we aim to translate the current evidence into recommendations for the clinical practice in the management of patients with CKD.
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Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , RiñónRESUMEN
BACKGROUND AND AIMS: Secondary calciprotein particles (CPP-II) induce inflammation and contribute to vascular calcification. CPP-II size is associated with vascular calcification in patients with chronic kidney disease (CKD) and all-cause mortality in hemodialysis patients. Here, we investigate for the first time a possible role of CPP-II size in patients with peripheral artery disease (PAD) without severe CKD. METHODS: We measured the hydrodynamic radius (Rh) of CPP-II by using dynamic light scattering in a cohort of 281 PAD patients. Mortality was evaluated over a period of ten years by central death registry queries. 35% of patients died during the observation period (median of 8.8 (6.2-9.0) years). Cox-regression analyses were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) and to allow for multivariable adjustment. RESULTS: The mean CPP-II size was 188 (162-218) nm. Older patients, patients with reduced kidney function, and those with media sclerosis had larger CPP-II (p < 0.001, p = 0.008, and p = 0.043, retrospectively). There was no association between CPP-II size and overall atherosclerotic disease burden (p = 0.551). CPP-II size was independently significantly associated with all-cause (HR 1.33 (CI 1.01-1.74), p = 0.039) and cardiovascular mortality (HR 1.52 (CI 1.05-2.20), p = 0.026) in multivariable regression analyses. CONCLUSIONS: Large CPP-II size is associated with mortality in PAD patients and might be a new feasible biomarker for the presence of media sclerosis in this patient population.
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Enfermedad Arterial Periférica , Insuficiencia Renal Crónica , Calcificación Vascular , Humanos , Tamaño de la Partícula , Estudios Retrospectivos , Esclerosis/complicaciones , Calcificación Vascular/etiología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/complicaciones , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/complicacionesRESUMEN
Due to immunosuppressive therapy, transplant patients are more susceptible to viral and bacterial infections. A potentially deadly new virus haunted us in 2020: SARS-CoV2, causing coronavirus disease 19 (COVID-19). We analyzed the consequences of this previously unknown risk for our living-donor transplant program in the first year of the pandemic. After the complete lockdown in spring 2020, our transplant center in Linz resumed the living-donor kidney transplantation program from June to September 2020, between the first and second waves of COVID-19 in Austria. We compared the outcomes of these living-donor kidney transplantations with the transplant outcomes of the corresponding periods of the three previous years. From June 4 to September 9, 2020, five living-donor kidney transplantations were performed. All donors and recipients were screened for COVID 19 infection by PCR testing the day before surgery. Kidney transplant recipients remained isolated in single rooms until discharge from hospital. All recipients and donors remained SARS-CoV2 negative during the follow-up of 10 months and have been fully vaccinated to date. The number of living transplants in the studied period of 2020 was constant compared to the same months of 2017, 2018, and 2019. Living-donor kidney transplantation can be continued using testing for SARS-CoV2 and meticulous hygienic precautions in epidemiologically favorable phases of the SARS-CoV2 pandemic. Donors and recipients should be carefully selected and informed about risks and benefits.
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Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. The identification and management of fracture risk in these patients remains challenging. This manuscript explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated areal bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (FRAX) in these patients. It further reviews the impact of diabetes drugs on bone tissue as well as the efficacy of osteoporosis treatments in this population. An algorithm for the identification and management of diabetic patients at increased fracture risk is proposed.
Asunto(s)
Diabetes Mellitus Tipo 2 , Osteoporosis , Fracturas Osteoporóticas , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Fracturas Osteoporóticas/diagnóstico , Fracturas Osteoporóticas/prevención & control , Austria , Factores de Riesgo , Osteoporosis/complicaciones , Osteoporosis/diagnóstico , Osteoporosis/terapia , Densidad Ósea , Huesos , Minerales , Medición de RiesgoRESUMEN
The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.