Biochemical Clusters as Substitutes of Bone Biopsies in Kidney Transplant Patients.

Bone and mineral metabolism abnormalities are frequent in kidney transplant recipients and have been associated with cardiovascular morbidity. The primary aim of this study was to analyse the association between routine clinically available biochemical evaluation, non-routine histomorphometric bone evaluation, and vascular disease in kidney transplanted patients. A cross-sectional analysis was performed on 69 patients, 1-year after kidney transplantation. Laboratory analysis, radiography of hands and pelvis, bone biopsy, bone densitometry, and coronary CT were performed. One-year post-transplantation, nearly one-third of the patients presented with hypercalcemia, 16% had hypophosphatemia, 39.3% had iPTH levels > 150 pg/mL, 20.3% had BALP levels > 40 U/L, and 26.1% had hypovitaminosis D. Evaluation of extraosseous calcifications revealed low Adragão and Agatston scores. We divided patients into three clusters, according to laboratory results routinely used in clinical practice: hypercalcemia and hyperparathyroidism (Cluster1); hypercalcemia and high BALP levels (Cluster2); hypophosphatemia and vitamin D deficiency (Cluster 3). Patients in clusters 1 and 2 had higher cortical porosity (p = 0.001) and osteoid measurements, although there was no difference in the presence of abnormal mineralization, or low volume. Patients in cluster 2 had a higher BFR/BS (half of the patients in cluster 2 had high bone turnover), and most patients in cluster 1 had low or normal bone turnover. Cluster 3 has no differences in volume, or turnover, but 60% of the patients presented with pre-osteomalacia. All three clusters were associated with high vascular calcifications scores. Vascular calcifications scores were not related to higher bone mineral density. Instead, an association was found between a higher Adragão score and the presence of osteoporosis at the femoral neck (p = 0.008). In conclusion, inferring bone TMV by daily clinical biochemical analysis can be misleading, and bone biopsy is important for assessing both bone turnover and mineralization after kidney transplantation, although hypophosphatemia combined with vitamin D deficiency is associated with abnormal mineralization. The presence of hypercalcemia with high levels of PTH or high levels of BALP, or hypophosphatemia and vitamin D deficiency should remind us to screen vascular calcification status of patients.Clinical Research: ClinicalTrials.gov ID NCT02751099.

Hyperparathyroidism, Serum Phosphorus and Dietary Intake in Hemodialysis Patients: Is There a Novel Relationship?

The management of hyperparathyroidism (intact parathyroid hormone (iPTH) serum levels > 585 pg/mL), frequently focuses on the appropriate control of mineral and bone markers, with the decrease in serum and dietary phosphorus as two of the targets. We aimed to investigate the association between iPTH, serum phosphorus levels and dietary intake. This was a cross-sectional, multicenter, observational study with 561 patients on hemodialysis treatment. Clinical parameters, body composition and dietary intake were assessed. For the analysis, patients were divided into three groups: (a) iPTH < 130, (b) iPTH between 130 and 585 and (c) iPTH > 585 pg/mL. The association between PTH, serum phosphorus and dietary intake was analyzed using linear regression models. In the whole sample, 23.2% of patients presented an iPTH > 585 pg/mL. Patients with higher iPTH levels were those with longer HD vintage and lower ages, higher serum phosphorus, serum calcium, Ca/P product, albumin and caffeine intake, and a lower dietary intake of phosphorus, fiber, riboflavin and folate. Higher serum phosphorus predicted higher iPTH levels, even in the adjusted model. However, lower dietary phosphorus and fiber intake were predictors of higher iPTH levels, including in the adjusted model. Our results bring new data to the relationship between dietary intake and iPTH values. Despite higher serum phosphorus being observed in patients with HPTH, an opposite association was noted regarding dietary phosphate and fiber.

Predicting Cellular Rejection of Renal Allograft Based on the Serum Proteomic Fingerprint.

Kidney transplantation is an essential medical procedure that significantly enhances the survival rates and quality of life for patients with end-stage kidney disease. However, despite advancements in immunosuppressive therapies, allograft rejection remains a leading cause of organ loss. Notably, predictions of cellular rejection processes primarily rely on biopsy analysis, which is not routinely performed due to its invasive nature. The present work evaluates if the serum proteomic fingerprint, as acquired by Fourier Transform Infrared (FTIR) spectroscopy, can predict cellular rejection processes. We analyzed 28 serum samples, corresponding to 17 without cellular rejection processes and 11 associated with cellular rejection processes, as based on biopsy analyses. The leave-one-out-cross validation procedure of a Naïve Bayes model enabled the prediction of cellular rejection processes with high sensitivity and specificity (AUC > 0.984). The serum proteomic profile was obtained in a high-throughput mode and based on a simple, rapid, and economical procedure, making it suitable for routine analyses and large-scale studies. Consequently, the current method presents a high potential to predict cellular rejection processes translatable to clinical scenarios, and that should continue to be explored.

Recurrent obstruction of biliary stent-in-stent: a heated solution.

Intraductal radiofrequency ablation (RFA) has been used in the management of malignant biliary obstruction and ampullary neoplasms. Some small studies refer to its role in managing benign biliary strictures with some promising results. The complications are not neglectable, namely cholangitis, pancreatitis, bleeding, and perforation, although most of them can be managed conservatively. There are two catheters available. Only the ERLA (EndoLumunal Radiofrequency Ablation, Taewoong Medical) catheter can control temperature and impedance, allowing it to reduce the risk of complications.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

Long-term cholecalciferol supplementation in hemodialysis patients: Effects on mineral metabolism, inflammation, and cardiac parameters.

BACKGROUND: Low levels of 25-hydroxyvitamin D [25(OH)D] are frequent in chronic kidney disease and are associated with adverse outcomes. The aim of this 5-year prospective study was to evaluate the effects of cholecalciferol supplementation on mineral metabolism, inflammation and cardiac parameters in hemodialysis (HD) patients. METHODS: The study included 97 patients. Cholecalciferol was given after HD according to 25(OH)D baseline levels measured twice (end of winter and of summer). The 25(OH)D levels, circulating bone metabolism, inflammation parameters, brain natriuretic peptide (BNP), pulse pressure (PP), and left ventricular mass index (LVMI) were evaluated before and after supplementation. RESULTS: There was a significant increase in 25(OH)D levels after supplementation (p < 0.001); however, serum calcium (p = 0.02), phosphorus (p = 0.018), and iPTH (p = 0.03) were decreased. Magnesium levels increased during the study (p = 0.03). A reduction in the number of patients under active vitamin D (p < 0.001) and in the dose and number of patients treated with darbepoetin (p = 0.02) was observed. Serum albumin increased (p < 0.001), and C-reactive protein decreased (p = 0.01). BNP (p < 0.001), PP (p = 0.007), and LVMI (p = 0.02) were significantly reduced after supplementation. CONCLUSIONS: Long-term cholecalciferol supplementation allowed correction of 25(OH)D deficiency, improved mineral metabolism with less use of active vitamin D, attenuated inflammation, reduced the dose of the erythropoiesis-stimulating agent, and improved cardiac dysfunction.

Penile and digital calciphylaxis: A case report and literature review.

Calcific uremic arteriolopathy (CUA) represents a rare but severe disease with high morbimortality. The authors present the case of a 58-year-old male patient with chronic kidney disease due to obstructive uropathy, on hemodialysis (HD). He started HD due to uremic syndrome with a severe renal dysfunction, dysregulation of calcium and phosphate metabolism, and he presented with distal penile ischemia, which was treated with surgical debridement and hyperbaric oxygen therapy. Four months later, painful distal digital necrosis of both hands was observed. Extensive arterial calcification was observed on X-ray. A skin biopsy confirmed the presence of CUA. Sodium thiosulfate was administered for 3 months, HD was intensified, and hyperphosphatemia control was achieved, with progressive improvement of the lesions. This case illustrates an uncommon presentation of CUA in a patient on HD for a few months, non-diabetic and not anticoagulated, but with a severe dysregulation of calcium and phosphate metabolism.

Mediterranean Diet: A Dietary Pattern Related to Nutritional Benefits for Hemodialysis Patients.

OBJECTIVES: In adults with chronic kidney disease, not on dialysis, there is a recent recommendation suggesting the prescription of a Mediterranean diet pattern but there is still no evidence to suggest a specific dietary pattern for hemodialysis (HD) patients. The aim of this study was to identify dietary patterns in HD patients and analyze their relationship with nutritional status, physical activity, and survival. DESIGN AND METHODS: This was a longitudinal prospective multicenter study with 12 months of follow-up that included 582 HD patients from 37 dialysis centers. Clinical parameters, dietary intake, and physical activity were assessed. Dietary patterns were derived from principal component analysis. A p-value lower than 0.05 was considered statistically significant. RESULTS: Three different dietary patterns were identified: "Mediterranean," "Western," and "low animal protein." Patients in the Mediterranean pattern group showed higher intakes of protein (P = .040), omega 3 fatty acids (P < .001), vitamins B12 (P < .001), B6 (P < .001), C (P < .001), D (P < .001), folic acid (P < .001) and presented a higher practice of moderate physical activity (P = .010). Despite the lower number of deaths that occurred in the Mediterranean dietary pattern group, we did not observe a statistically significant lower mortality risk (P = .096). CONCLUSIONS: The Mediterranean style pattern was associated with a better nutritional intake profile and lifestyle related factors such as a higher practice of moderate physical activity in HD patients.

The Potential Modulatory Effects of Exercise on Skeletal Muscle Redox Status in Chronic Kidney Disease.

Chronic Kidney Disease (CKD) is a global health burden with high mortality and health costs. CKD patients exhibit lower cardiorespiratory and muscular fitness, strongly associated with morbidity/mortality, which is exacerbated when they reach the need for renal replacement therapies (RRT). Muscle wasting in CKD has been associated with an inflammatory/oxidative status affecting the resident cells' microenvironment, decreasing repair capacity and leading to atrophy. Exercise may help counteracting such effects; however, the molecular mechanisms remain uncertain. Thus, trying to pinpoint and understand these mechanisms is of particular interest. This review will start with a general background about myogenesis, followed by an overview of the impact of redox imbalance as a mechanism of muscle wasting in CKD, with focus on the modulatory effect of exercise on the skeletal muscle microenvironment.

Endoscopic ampullectomy of a giant pedunculated ampullary adenoma.

The authors present a case of a 72-year-old woman with a personal history of arterial hypertension, dyslipidemia and gallstones. For suspected choledocholithiasis, a MR-Cholangiopancreatography was performed, which revealed the presence of an endoluminal polypoid structure in the third duodenal portion.

Gastric mixed neuroendocrine/non neuroendocrine neoplasia: a rare entity.

Gastric neoplasms have different histological subtypes. Mixed neuroendocrine/non neuroendocrine neoplasms (MiNEN), as defined by the World Health Organization (WHO) 2019 Classification of Tumours of the Digestive System, are rare composite tumours bearing morphological characteristics of more than one histological type. Historically, the diagnosis requires that each component accounts for at least 30% of the total tumour burden. We present the case of a 70-year-old male, who was referred to our endoscopy unit for resection of a depressed lesion (Paris classification type 0 IIc) of 40mm in largest diameter, located on the lesser curvature of the gastric body. The lesion was submitted to en bloc resection by endoscopic submucosal dissection. Histological examination revealed a poorly differentiated intramucosal adenocarcinoma and a grade G3 well differentiated neuroendocrine tumour (NET), on a background of chronic atrophic gastritis. Unfortunately, examination of the NET component revealed intercepted margins. The patient is currently undergoing tumour staging and will be discussed by a multidisciplinary team to determine subsequent management.

The Role of Bone Volume, FGF23 and Sclerostin in Calcifications and Mortality; a Cohort Study in CKD Stage 5 Patients.

Chronic kidney disease-mineral and bone disorder has been associated with increasing morbid-mortality. The aim of this study was to determine the prevalence and phenotype of bone disease before transplantation and to correlate FGF23 and sclerostin levels with bone histomorphometry, and study possible associations between FGF23, sclerostin, and bone histomorphometry with cardiovascular disease and mortality. We performed a cross-sectional cohort study of a sample of 84 patients submitted to renal transplant, which were prospectively followed for 12 months. Demographic, clinical, and echocardiographic data were collected, laboratory evaluation, bone biopsy, and X-ray of the pelvis and hands were performed. Patient and graft survival were recorded. We diagnosed low bone turnover in 16 patients (19.5%); high bone turnover in 22 patients (26.8%); osteomalacia in 1 patient (1.2%), and mixed renal osteodystrophy in 3 patients (3.7%). At the end of 12 months, 5 patients had graft failure (5.9%), 4 had a cardiovascular event (4.8%), and 4 died. Age was associated with low remodeling disease, whereas high BALP and phosphorus and low sclerostin with high turnover disease. Sclerostin was a risk factor for isolated low bone volume. High BALP, low phosphorus, and low FGF23 were risk factors for abnormal mineralization. FGF23 appears as an independent factor for severity of vascular calcifications and for cardiovascular events, whereas the presence of valve calcifications was associated with low volume and with turnover deviations. Sclerostin was associated a higher HR for death. Sclerostin and FGF23 seemed to provide higher cardiovascular risk, as well as low bone volume, which associated with extra-osseous calcifications.

Zinc Deficient Intake in Hemodialysis Patients: A Path to a High Mortality Risk.

BACKGROUND: Zinc is essential for human nutrition and plays an important role in hemodialysis (HD) patients. The aim of this study is to analyze the relationship between zinc intake and mortality in HD patients. METHODS: This is a longitudinal, prospective, multicenter study with 582 HD patients from 37 dialysis centers. We recorded clinical and body composition parameters. Dietary intake and physical activity data were obtained using the Food Frequency Questionnaire and International Physical Activity Questionnaire. All statistical tests were performed using SPSS 24.0 software. A P value lower than 0.05 was considered statistically significant. RESULTS: Patients' mean age was 67.8 ± 17.7 years and median HD vintage was 65 (43-104) months. About 53.6% of the patients presented a deficient daily intake of zinc. Patients with the highest zinc intake were those who had a higher lean tissue index (P = .022), energy (P < .001), and protein (p = .022) intakes. Zinc intake was positively correlated with energy (r = 0.709) and protein intake (r = 0.805) and negatively correlated with the malnutrition screening tool score (r = -0.087). A higher energy, protein, and lower carbohydrates intake, as well as lower HD vintage and higher lean tissue index were predictors of zinc intake. A higher mortality risk was observed in patients with zinc intake below the recommended values, even after the adjustment for age, presence of diabetes, gender, dialysis vintage, albumin, lean tissue index, energy intake/kilogram, and level of physical activity (P = .021). CONCLUSION: There is a high prevalence of HD patients with an inadequate zinc intake, which is related to worse nutritional and body composition parameters and with a higher mortality risk.

Management of RAASi-associated hyperkalemia in patients with cardiovascular disease.

Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis.

Bone Mineral Disease After Kidney Transplantation.

Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations. The final consequences are reflected fundamentally as abnormal mineral metabolism (hypercalcemia, hypophosphatemia) and bone alterations [high or low bone turnover disease (as fibrous osteitis or adynamic bone disease), an eventual compromise of bone mineralization, decrease bone mineral density and bone fractures]. The major cause of post-transplantation hypercalcemia is the persistence of severe secondary hyperparathyroidism, and treatment options include calcimimetics or parathyroidectomy. On turn, hypophosphatemia is caused by both the persistence of high blood levels of PTH and/or high blood levels of FGF23, with its correction being very difficult to achieve. The most frequent bone morphology alteration is low bone turnover disease, while high-turnover osteopathy decreases in frequency after transplantation. Although the pathogenic mechanisms of these abnormalities have not been fully clarified, the available evidence suggests that there are a number of factors that play a very important role, such as immunosuppressive treatment, persistently high levels of PTH, vitamin D deficiency and hypophosphatemia. Fracture risk is four-fold higher in transplanted patients compared to general population. The most relevant risk factors for fracture in the kidney transplant population are diabetes mellitus, female sex, advanced age (especially > 65 years), dialysis vintage, high PTH levels and low phosphate levels, osteoporosis, pre-transplant stress fracture and high doses or prolonged steroids therapy. Treatment alternatives for CKD-MBD after transplantation include minimization of corticosteroids, use of calcium and vitamin D supplements, antiresorptives (bisphosphonates or Denosumab) and osteoformers (synthetic parathyroid hormone). As both mineral metabolism and bone disorders lead to increased morbidity and mortality, the presence of these changes after transplantation has to be prevented (if possible), minimized, diagnosed, and treated as soon as possible.

The Role of Bone Biopsy in the Management of CKD-MBD.

A bone biopsy is still considered the gold standard for diagnosis of renal osteodystrophy. It allows to measure both static and dynamic parameters of bone remodeling and is the only method able to evaluate mineralization and allows analysis of both cortical and trabecular bone. Although bone volume can be measured indirectly by dual-energy X-ray absorptiometry, mineralization defects, bone metal deposits, cellular number/activity, and even turnover abnormalities are difficult to determine by techniques other than qualitative bone histomorphometry. In this review, we evaluate the role of bone biopsy in the clinical practice.

Muscle-Bone Crosstalk in Chronic Kidney Disease: The Potential Modulatory Effects of Exercise.

Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.

Bone densitometry versus bone histomorphometry in renal transplanted patients: a cross-sectional study.

Bone loss leads to increase risk of fractures in renal transplantation. The aim of this study was to analyse the relationship between bone densitometry (DXA) findings, bone histomorphometry and bone-related molecules 1-year after renal transplantation. We performed a cross-sectional study of de novo renal transplanted patients that agreed to perform a bone biopsy and a DXA examination 1 year after transplantation. All patients underwent a laboratory evaluation, bone biopsy, DXA examination and cardiac CT 1 year after transplantation. 67 patients were included, 16 had a normal examination, and 18 patients were classified as having osteoporosis by DXA. Correlations between bone mineral density and T-scores of total femur and femoral neck were the ones that best correlated with bone volume assessed by a bone biopsy. The sensitivity of DXA for osteoporosis diagnosis was 47.0%, and the specificity was 81.2%. The positive predictive value was 50.0%, and the negative predictive value (NPV) was 80.0%. DXA parameters also correlated with klotho and sclerostin serum levels. In this population, a normal examination excluded the presence of osteoporosis, helping in identifying patients that would not benefit from therapy. Overall, densitometry in total femur and femoral neck correlated well with bone volume measured by bone biopsy.

Association between physical activity and mortality in end-stage kidney disease: a systematic review of observational studies.

BACKGROUND: End-stage Kidney Disease patients have a high mortality and hospitalization risk. The association of these outcomes with physical activity is described in the general population and in other chronic diseases. However, few studies examining this association have been completed in end-stage Kidney Disease patients, raising the need to systematically review the evidence on the association of physical activity with mortality and hospitalization in this population. METHODS: Electronic databases (EBSCO, Scopus and Web of Science) and hand search were performed until March 2020 for observational studies reporting the association of physical activity with mortality or hospitalization in adult end-stage Kidney Disease patients on renal replacement therapy (hemodialysis, peritoneal dialysis and kidney transplant). Methodological quality of the included studies was assessed using the Quality in Prognosis Studies tool. The review protocol was registered in PROSPERO (CRD42020155591). RESULTS: Eleven studies were included: six in hemodialysis, three in kidney transplant, and two in hemodialysis and peritoneal dialysis patients. Physical activity was self-reported, except in one study that used accelerometers. All-cause mortality was addressed in all studies and cardiovascular mortality in three studies. Nine studies reported a significant reduction in all-cause mortality with increased levels of physical activity. Evidence of a dose-response relationship was found. For cardiovascular mortality, a significant reduction was observed in two of the three studies. Only one study investigated the association of physical activity with hospitalization. CONCLUSIONS: Higher physical activity was associated with reduced mortality in end-stage Kidney Disease patients. Future studies using objective physical activity measures could strengthen these findings. The association of physical activity with hospitalization should be explored in future investigations.

Endoscopic resolution of a duodenal perforation due to a pancreatic stent.

We read with interest the article by Roa Esparza I et al. reporting the endoscopic management of a duodenal perforation. In fact, we have dealt with a similar case using a different technique.