Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Documento de consenso sobre el abordaje de la hiperpotasemia / Consensus document on the management of hyperkalaemia

La hiperpotasemia es una alteración electrolítica frecuente con consecuencias potencialmente graves a corto, medio y largo plazo, tanto en términos de morbilidad y mortalidad como de consumo de recursos del Sistema Nacional de Salud. El abordaje de la hiperpotasemia por diversas especialidades médicas y la reciente disponibilidad de nuevos tratamientos farmacológicos específicos hace necesaria una acción unificada y actualizada. El presente documento de consenso entre las sociedades científicas más directamente implicadas en el abordaje de la hiperpotasemia (Sociedad Española de Cardiología, Sociedad Española de Endocrinología y Nutrición, Sociedad Española de Medicina Interna, Sociedad Española de Medicina de Urgencias y Emergencias y Sociedad Española de Nefrología) repasa, en primer lugar, aspectos básicos del balance de potasio y de la potasemia, centrándose posteriormente en el concepto, epidemiología, fisiopatología, y abordaje diagnóstico y terapéutico de la hiperpotasemia. Se han revisado las evidencias y los principales estudios publicados con el objetivo de que sea una herramienta útil en el abordaje multidisciplinar del paciente con hiperpotasemia (AU)

Hyperkalaemia is a common electrolyte imbalance with potentially serious short-, medium- and long-term consequences on morbidity and mortality rates and the use of national health service resources. The fact that different medical specialities can manage hyperkalaemia makes it important to have a unified approach, and the recent availability of new specific drug treatments means that the approach needs to be updated. This consensus document from the scientific societies most directly involved in the management of hyperkalaemia (Sociedad Española de Cardiología [Spanish Society of Cardiology], Sociedad Española de Endocrinología y Nutrición [Spanish Society of Endocrinology and Nutrition], Sociedad Española de Medicina Interna [Spanish Society of Internal Medicine], Sociedad Española de Medicina de Urgencias y Emergencias [Spanish Society of Emergency Medicine and Emergencies] and Sociedad Española de Nefrología [Spanish Society of Nephrology]) first of all reviews basic aspects of potassium balance and blood potassium. Then it goes on to focus on the concept, epidemiology, pathophysiology and diagnostic and therapeutic approaches to hyperkalaemia. The available evidence and the main published studies have been reviewed with the aim of providing a useful tool in the multidisciplinary approach to patients with hyperkalaemia (AU)

Association of Klotho with Coronary Artery Disease in Subjects with Type 2 Diabetes Mellitus and Preserved Kidney Function: A Case-Control Study.

Circulating Klotho levels are significantly reduced in subjects with type 2 diabetes mellitus (T2DM) and in kidney disease patients. In this work, the relationship between Klotho levels and the coronary artery disease (CAD) burden in subjects with T2DM and preserved kidney function was analyzed. For this, we performed a cross-sectional case-control study involving 133 subjects with T2DM and 200 age-, sex- and CAD-incidence-matched, non-diabetic patients undergoing non-emergency diagnostic coronary angiography. All of them were non-albuminuric and with normal glomerular filtration rates. The concentrations of serum Klotho, fibroblast growth factor 23, and inflammatory markers were also measured. As expected, the serum Klotho concentration was lower in the T2DM group (12.3% lower, p = 0.04). However, within the group of patients with T2DM, those subjects with CAD presented significantly higher Klotho levels than those without significant coronary stenosis (314.5 (6.15-562.81) vs. 458.97 (275.2-667.2) pg/mL; p = 0.02). Multiple regression analysis revealed that serum Klotho was positively related with stenosis values exclusively in subjects with T2DM (adjusted R2 = 0.153, p < 0.01). Moreover, logistic regression analysis showed that Klotho was positively associated with the presence of significant CAD in the group of T2DM patients (OR: 1.001; p = 0.041). Our data suggest that higher levels of circulating Klotho in subjects with T2DM and preserved kidney function are associated with the presence of significant CAD.

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction-a substudy of the DAPA-VO2 study.

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m2 (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.

Associations between Inflammation, Hemoglobin Levels, and Coronary Artery Disease in Non-Albuminuric Subjects with and without Type 2 Diabetes Mellitus.

In this cross-sectional study, we evaluated the associations of inflammation and hemoglobin with coronary artery disease (CAD) in subjects with type 2 diabetes mellitus (T2DM) and preserved kidney function. We recruited 638 participants-254 with T2DM-subjected to coronary angiography with no known cardiovascular disease, normal glomerular filtration rates, and without albuminuria. The hemoglobin and serum levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), were measured. Multivariable analyses showed that inflammatory markers were not related to the severity of the stenosis in the group of subjects with diabetes. Conversely, inflammatory cytokines and albuminuria were directly related to the percentage of stenosis in subjects without T2DM (R2 = 0.038, p < 0.001). Patients with diabetes presented lower hemoglobin levels, particularly in those who also had significant CAD (14.4 [13.6-15.1] vs. 13.6 [12.2-14.8] g/dL, p = 0.03). Similarly, hemoglobin levels and albuminuria were inversely related to the severity of stenosis exclusively in subjects with diabetes, even after adjusting for multiple confounding factors (R2 = 0.081, p < 0.001). We conclude that reductions in hemoglobin levels in subjects with T2DM and normoalbuminuria may constitute a more relevant risk factor for CAD than inflammation.

Klotho inversely relates with carotid intima- media thickness in atherosclerotic patients with normal renal function (eGFR ≥60 mL/min/1.73m2): a proof-of-concept study.

Introduction: Klotho protein is predominantly expressed in the kidneys and has also been detected in vascular tissue and peripheral blood circulating cells to a lesser extent. Carotid artery intima-media thickness (CIMT) burden, a marker of subclinical atherosclerosis, has been associated with reductions in circulating Klotho levels in chronic kidney disease patients, who show reduced levels of this protein at all stages of the disease. However, the contribution of serum Klotho and its expression levels in peripheral blood circulating cells and in the carotid artery wall on the CIMT in the absence of kidney impairment has not yet been evaluated. Methods: We conducted a single-center study in 35 atherosclerotic patients with preserved kidney function (eGFR≥60 mL/min/1.73m2) subjected to elective carotid surgery. Serum levels of Klotho and cytokines TNFa, IL6 and IL10 were determined by ELISA and transcripts encoding for Klotho (KL), TNF, IL6 and IL10 from vascular segments were measured by qRT-PCR. Klotho protein expression in the intima-media and adventitia areas was analyzed using immunohistochemistry. Results: APatients with higher values of CIMT showed reduced Klotho levels in serum (430.8 [357.7-592.9] vs. 667.8 [632.5-712.9] pg/mL; p<0.001), mRNA expression in blood circulating cells and carotid artery wall (2.92 [2.06-4.8] vs. 3.69 [2.42-7.13] log.a.u., p=0.015; 0.41 [0.16-0.59] vs. 0.79 [0.37-1.4] log.a.u., p=0.013, respectively) and immunoreactivity in the intimal-medial area of the carotids (4.23 [4.15-4.27] vs. 4.49 [4.28-4.63] log µm2 p=0.008). CIMT was inversely related with Klotho levels in serum (r= -0.717, p<0.001), blood mRNA expression (r=-0.426, p=0.011), and with carotid artery mRNA and immunoreactivity levels (r= -0.45, p=0.07; r= -0.455, p= 0.006, respectively). Multivariate analysis showed that serum Klotho, together with the gene expression levels of tumor necrosis factor TNFa in blood circulating cells, were independent determinants of CIMT values (adjusted R2 = 0.593, p<0.001). Discussion: The results of this study in subjects with eGFR≥60mL/min/1.73m2 show that patients with carotid artery atherosclerosis and higher values of CIMT present reduced soluble Klotho levels, as well as decreased KL mRNA expression in peripheral blood circulating cells and Klotho protein levels in the intima-media of the carotid artery wall.

Experimental Models to Study Diabetes Mellitus and Its Complications: Limitations and New Opportunities.

Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-iddm, as representative models of type 1 DM (DM-1); the Zucker diabetic fatty (ZDF) and Goto-kakizaki (GK) rats, as representative models of type 2 DM (DM-2); and other models induced by surgical, dietary and pharmacological-alloxan and streptozotocin-procedures. Given the variety of DM models in rats, as well as the non-uniformity in the protocols and the absence of all the manifestation of the long-term multifactorial complications of DM in humans, the researchers must choose the one that best suits the final objectives of the study. These circumstances, added to the fact that most of the experimental research in the literature is focused on the study of the early phase of DM, makes it necessary to develop long-term studies closer to DM in humans. In this review, a recently published rat DM model induced by streptozotocin injection with chronic exogenous administration of insulin to reduce hyperglycaemia has also been included in an attempt to mimic the chronic phase of DM in humans.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Mineral and bone metabolism markers and mortality in diabetic patients on haemodialysis.

BACKGROUND: Diabetic patients on haemodialysis have a higher risk of mortality than non-diabetic patients. The aim of this COSMOS (Current management of secondary hyperparathyroidism: a multicentre observational study) analysis was to assess whether bone and mineral laboratory values [calcium, phosphorus and parathyroid hormone (PTH)] contribute to this risk. METHODS: COSMOS is a multicentre, open-cohort, 3-year prospective study, which includes 6797 patients from 227 randomly selected dialysis centres in 20 European countries. The association between mortality and calcium, phosphate or PTH was assessed using Cox proportional hazard regression models using both penalized splines smoothing and categorization according to KDIGO guidelines. The effect modification of the association between the relative risk of mortality and serum calcium, phosphate or PTH by diabetes was assessed. RESULTS: There was a statistically significant effect modification of the association between the relative risk of mortality and serum PTH by diabetes (P = .011). The slope of the curve of the association between increasing values of PTH and relative risk of mortality was steeper for diabetic compared with non-diabetic patients, mainly for high levels of PTH. In addition, high serum PTH (>9 times the normal values) was significantly associated with a higher relative risk of mortality in diabetic patients but not in non-diabetic patients [1.53 (95% confidence interval 1.07-2.19) and 1.17 (95% confidence interval 0.91-1.52)]. No significant effect modification of the association between the relative risk of mortality and serum calcium or phosphate by diabetes was found (P = .2 and P = .059, respectively). CONCLUSION: The results show a different association of PTH with the relative risk of mortality in diabetic and non-diabetic patients. These findings could have relevant implications for the diagnosis and treatment of chronic kidney disease-mineral and bone disorders.

Serum and Urinary Soluble α-Klotho as Markers of Kidney and Vascular Impairment.

This study was designed to investigate the controversy on the potential role of sKlotho as an early biomarker in Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), to assess whether sKlotho is a reliable marker of kidney α-Klotho, to deepen the effects of sKlotho on vascular smooth muscle cells (VSMCs) osteogenic differentiation and to evaluate the role of autophagy in this process. Experimental studies were conducted in CKD mice fed a normal phosphorus (CKD+NP) or high phosphorus (CKD+HP) diet for 14 weeks. The patients' study was performed in CKD stages 2-5 and in vitro studies which used VSMCs exposed to non-calcifying medium or calcifying medium with or without sKlotho. The CKD experimental model showed that the CKD+HP group reached the highest serum PTH, P and FGF23 levels, but the lowest serum and urinary sKlotho levels. In addition, a positive correlation between serum sKlotho and kidney α-Klotho was found. CKD mice showed aortic osteogenic differentiation, together with increased autophagy. The human CKD study showed that the decline in serum sKlotho is previous to the rise in FGF23. In addition, both serum sKlotho and FGF23 levels correlated with kidney function. Finally, in VSMCs, the addition of sKlotho prevented osteogenic differentiation and induced autophagy. It can be concluded that serum sKlotho was the earliest CKD-MBD biomarker, a reliable indicator of kidney α-Klotho and that might protect against osteogenic differentiation by increasing autophagy. Nevertheless, further studies are needed to investigate the mechanisms of this possible protective effect.

Role of Klotho and AGE/RAGE-Wnt/ß-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes.

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/ß-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-ß1, and Wnt/ß-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats.

From cardiorenal syndromes to cardionephrology: a reflection by nephrologists on renocardiac syndromes.

Cardiorenal syndromes (CRS) are broadly defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS are currently classified into five categories, mostly based on disease-initiating events and their acuity or chronicity. CRS types 3 and 4 (also called renocardiac syndromes) refer to acute and chronic kidney dysfunction resulting in acute and chronic heart dysfunction, respectively. The notion of renocardiac syndromes has broadened interest in kidney-heart interactions but uncertainty remains in the nephrological community's understanding of the clinical diversity, pathophysiological mechanisms and optimal management approaches of these syndromes. This triple challenge that renocardiac syndromes (and likely other cardiorenal syndromes) pose to the nephrologist can only be faced through a specific and demanding training plan to enhance his/her cardiological scientific knowledge and through an appropriate clinical environment to develop his/her cardiological clinical skills. The first must be the objective of the subspecialty of cardionephrology (or nephrocardiology) and the second must be the result of collaboration with cardiologists (and other specialists) in cardiorenal care units. This review will first consider various aspects of the challenges that renocardiac syndromes pose to nephrologists and, then, will discuss those aspects of cardionephrology and cardiorenal units that can facilitate an effective response to the challenges.

Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease.

Reducing oxidative stress stands at the center of a prevention and control strategy for mitigating cellular senescence and aging. Kidney disease is characterized by a premature aging syndrome, and to find a modulator targeting against oxidative stress, mitochondrial dysfunction, and cellular senescence in kidney cells could be of great significance to prevent and control the progression of this disease. This review focuses on the pathogenic mechanisms related to the appearance of oxidative stress damage and mitochondrial dysfunction in kidney disease. In this scenario, the anti-aging Klotho protein plays a crucial role by modulating signaling pathways involving the manganese-containing superoxide dismutase (Mn-SOD) and the transcription factors FoxO and Nrf2, known antioxidant systems, and other known mitochondrial function regulators, such as mitochondrial uncoupling protein 1 (UCP1), B-cell lymphoma-2 (BCL-2), Wnt/ß-catenin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), transcription factor EB, (TFEB), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Therefore, Klotho is postulated as a very promising new target for future therapeutic strategies against oxidative stress, mitochondria abnormalities, and cellular senescence in kidney disease patients.

The Value of Klotho in Kidney Transplantation.

Kidney transplant recipients have better survival rates and improved quality of life than long-term dialysis patients. However, delayed graft function, immunosuppressive therapy nephrotoxicity, and rejection episodes may compromise graft and patient survival. The KL gene is highly expressed in kidney tubular cells and encodes the antiaging and kidney-protective protein Klotho, which has membrane-anchored and soluble forms and regulates mineral metabolism. Klotho expression decreases during acute kidney injury or chronic kidney disease, and human chronic kidney disease shares features of accelerated aging with murine Klotho deficiency. In this work, we review clinical studies on the relationship between Klotho and kidney transplantation. Specifically, we address the dynamics of serum and kidney Klotho levels in donors and kidney transplant recipients, the role of Klotho as a marker of current graft function and graft outcomes, and the potential impact of Klotho on kidney protection in the transplantation context. A better understanding of the potential biomarker and therapeutic utility of Klotho in kidney transplant recipients may provide new insights into the control of graft function and new therapeutic strategies to preserve allograft function.

Targeting inflammation to treat diabetic kidney disease: the road to 2030.

Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016. Given the contribution of inflammation to the pathogenesis of DKD, we review the impact on kidney inflammation of the current standard of care, therapies undergoing clinical trials, or repositioned drugs for DKD. Moreover, we review recent advances in the molecular regulation of inflammation in DKD and discuss potential novel therapeutic strategies with clinical relevance. Finally, we provide a road map for future research aimed at integrating the growing knowledge on inflammation and DKD into clinical practice to foster improvement of patient outcomes.

Consensus document on the management of hyperkalemia.

Hyperkalaemia is a common electrolyte imbalance with potentially serious short-, medium- and long-term consequences on morbidity and mortality rates and the use of national health service resources. The fact that different medical specialities can manage hyperkalaemia makes it important to have a unified approach, and the recent availability of new specific drug treatments means that the approach needs to be updated. This consensus document from the scientific societies most directly involved in the management of hyperkalaemia (Sociedad Española de Cardiología [Spanish Society of Cardiology], Sociedad Española de Endocrinología y Nutrición [Spanish Society of Endocrinology and Nutrition], Sociedad Española de Medicina Interna [Spanish Society of Internal Medicine], Sociedad Española de Medicina de Urgencias y Emergencias [Spanish Society of Accident and Emergency Medicine] and Sociedad Española de Nefrología [Spanish Society of Nephrology]) first of all reviews basic aspects of potassium balance and blood potassium. Then it goes on to focus on the concept, epidemiology, pathophysiology and diagnostic and therapeutic approaches to hyperkalaemia. The available evidence and the main published studies have been reviewed with the aim of providing a useful tool in the multidisciplinary approach to patients with hyperkalaemia.

Serum Phosphate Levels Modify the Impact of FGF23 Levels on Hemoglobin in Chronic Kidney Disease.

Anemia is a complication of chronic kidney disease (CKD). Phosphate and fibroblast growth factor-23 (FGF23) have a close relationship, as both are related to the pathogenesis of anemia. However, the possible interplay between them regarding their effect on anemia has not been evaluated. This was a cross-sectional study of 896 participants from the NEFRONA study (273 CKD3, 246 CKD4-5, 282 dialysis and 95 controls). The levels of 25(OH) and 1,25(OH)2 vitamin D, intact FGF23 (iFGF23) and soluble Klotho were measured, together with standard blood biochemistries. Anemia was defined as hemoglobin levels < 13 g/dL in men and <12 g/dL in women. Patients with anemia (407, 45.4%) were younger, mostly men and diabetic; were in advanced CKD stages; had lower calcium, 1,25(OH)2 vitamin D and albumin levels; and had higher ferritin, phosphate, intact PTH, and iFGF23. An inverse correlation was observed between hemoglobin and both iFGF23 and phosphate. The multivariate logistic regression analyses showed that the adjusted risk of anemia was independently associated with higher serum phosphate and LogiFGF23 levels (ORs (95% CIs) of 4.33 (2.11−8.90) and 8.75 (3.17−24.2), respectively (p < 0.001)). A significant interaction between phosphate and iFGF23 (OR of 0.66 (0.53−0.83), p < 0.001) showed that the rise in the adjusted predicted risk of anemia with the increase in iFGF23 was steeper when phosphate levels were low. Phosphate levels acted as modifiers of the effect of iFGF23 concentration on anemia. Thus, the effect of the increase in iFGF23 levels was stronger when phosphate levels were low.

Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease.

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease.