Effect of SGLT2 inhibitors on anemia and their possible clinical implications.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was early appearent that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.

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.

Differences in Malnutrition Inflammation Score of Hemodialysis Patients Associated With Hemodialysis Factors. A Spanish Multicenter Epidemiologic Study.

OBJECTIVES: The aims of this study are to analyze the prevalence of malnutrition in hemodialysis (HD) patients in Spain, and to assess the association of malnutrition in these patients with sociodemographic characteristics, comorbidity, and parameters related to HD. DESIGN AND METHODS: A multicenter, retrospective, cross-sectional study in HD patients from centers all over Spain was conducted. Nutritional status of patients was assessed using Malnutrition Inflammation Score (MIS), and was stratified according to MIS values into 5 categories: ≤2, normal nutrition; >2 to ≤5, mild malnutrition or risk of malnutrition; >5 to ≤7, moderate malnutrition; >7 to ≤10, severe malnutrition, and >10, extreme malnutrition. RESULTS: A total of 52 Spanish HD Units participated in the study enrolling 2,748 patients. Mean age of patients was 68.20 ± 14.24 years, 1,811 (65.9%) were men. Mean time on HD was 55.63 ± 63.25 months. Using an MIS cut-off point of 2 for malnutrition, 89% of patients were malnourished (MIS > 2). However, with a cut-off point of 5, more commonly described in the literature, the percentage of patients with malnutrition was reduced to 51.7%. Using this cut-off, we observed significant differences between patients with malnutrition and normo-nourished patients in biochemical parameters, age, Charlson Index, HD residual renal function, scheme, and vascular access (permanent catheter vs arteriovenous fistula). A multivariate regression analysis showed that age, sex, HD scheme, vascular access, residual renal function, and comorbidity index were predictive factors for malnutrition. We found that a high percentage of HD patients with malnutrition did not receive oral supplementation. CONCLUSIONS: The prevalence of malnutrition in HD patients in Spain, assessed using the MIS scale, was high. Higher malnutrition was associated with the use of catheter versus fistula, and standard HD versus online hemodiafiltration, and with the absence of residual renal function, older age, greater comorbidity, and male sex. Malnourished patients had a low rate of oral supplementation.

Experience in Spain with the first patients in home hemodialysis treated with low-flow dialysate monitors.

Home hemodialysis (HHD) with low-flow dialysate devices has gained popularity in recent years due to its simple design, portability, and ability to provide greater freedom of movement for our patients. However, there are doubts about the adequacy that this technology offers, since it uses monitors with low-flow bath and lactate. The aim of this study was to demonstrate the clinical benefits of low-flow HHD with the NxStage System One® recently introduced in Spain. We present the results of an observational, retrospective cohort study that included the first patients who started short daily HHD with this device in 12 Spanish centers. We analyzed the evolution of 86 patients at 0, 6 and 12 months, including data related to prescription, and evolution of biochemical parameters related to dialysis dose, anemia, mineral-bone metabolism; evolution of residual renal function, medication usage, and causes of withdrawal during the followup. We were able to demonstrate that this NxStage System One® monitor, in patients with HHD, have provided an adequate dialysis dose, with optimal ultrafiltration rate, with improvement of main biochemical markers of dialysis adequacy. The usage of this technique was associated to a decrease of antihypertensive drugs, phosphate binders and erythropoietin agents, with very good results both patient and technique survival. The simplicity of the technique, together with its good clinical outcomes, should facilitate the growth and utilization of HHD, both in incident and prevalent patients.

Experience in Spain with the first patients in home hemodialysis treated with low-flow dialysate monitors. / Experiencia en España con los primeros pacientes en hemodiálisis domiciliaria tratados con monitores de bajo flujo de líquido de diálisis.

Home hemodialysis (HHD) with low-flow dialysate devices has gained popularity in recent years due to its simple design, portability, and ability to provide greater freedom of movement for our patients. However, there are doubts about the adequacy that this technology offers, since it uses monitors with low-flow bath and lactate. The aim of this study was to demonstrate the clinical benefits of low-flow HHD with the NxStage System One® recently introduced in Spain. We present the results of an observational, retrospective cohort study that included the first patients who started short daily HHD with this device in 12 Spanish centers. We analyzed the evolution of 86 patients at 0, 6 and 12 months, including data related to prescription, and evolution of biochemical parameters related to dialysis dose, anemia, mineral-bone metabolism; evolution of residual renal function, medication usage, and causes of withdrawal during the followup. We were able to demonstrate that this NxStage System One® monitor, in patients with HHD, have provided an adequate dialysis dose, with optimal ultrafiltration rate, with improvement of main biochemical markers of dialysis adequacy. The usage of this technique was associated to a decrease of antihypertensive drugs, phosphate binders and erythropoietin agents, with very good results both patient and technique survival. The simplicity of the technique, together with its good clinical outcomes, should facilitate the growth and utilization of HHD, both in incident and prevalent patients.

Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events.

Abnormalities in Glucose Metabolism, Appetite-Related Peptide Release, and Pro-inflammatory Cytokines Play a Central Role in Appetite Disorders in Peritoneal Dialysis.

Background: Appetite disorders are frequent and scantly studied in peritoneal dialysis (PD) patients and are associated with malnutrition and cardiovascular complications. Objective: We investigated the relationship between uremic insulin resistance, pro-inflammatory cytokines, and appetite-related peptides release (ARPr) with eating-behavior disorders in PD patients. Methods: We included 42 PD patients (12 suffering anorexia, 12 obese with high food-intake, and 18 asymptomatic) and 10 controls. We measured blood levels of ARPr including orexigens [neuropeptide-Y (NPY), ghrelin, and nitric-oxide], anorexigens [cholecystokinin, insulin, corticotropin-releasing factor, leptin, and adiponectin (Ad)], and cytokines (TNF-α, sTNFα-R2, and IL-6) both at baseline and after administering a standard-food stimulus (SFS). We also measured the expression of TNF-α, leptin and Ad-encoding mRNAs in abdominal adipose tissue. We compared these markers with eating motivation measured by a Visual Analog Scale (VAS). Results: Anorexics showed both little appetite, measured by a VAS, and low levels of orexigens that remained constant after SFS, coupled with high levels of anorexigens at baseline and after SFS. Obeses showed higher appetite, increased baseline levels of orexigens, lower baseline levels of anorexigens and cytokines and two peaks of NPY after SFS. The different patterns of ARPr and cytokines pointed to a close relationship with uremic insulin resistance. In fact, the euglycemic-hyperglycemic clamp reproduced these disorders. In anorexics, TNF-α fat expression was increased. In obese patients, leptin expression in fat tissue was down-regulated and showed correlation with the appetite. Conclusion: In PD, appetite is governed by substances that are altered at baseline and abnormally released. Such modulators are controlled by insulin metabolism and cytokines and, while anorexics display inflammatory predominance, obese patients predominantly display insulin resistance.

Osteoporosis, bone mineral density and CKD-MBD (II): Therapeutic implications. / Osteoporosis, densidad mineral ósea y complejo CKD-MBD (II): implicaciones terapéuticas.

Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an ageing population, these observations are not only dependent on "renal osteodystrophy" but also on the associated OP. As BMD predicts incident fractures in CKD patients (partI), we now aim to analyse the potential therapeutic consequences. Post-hoc analyses of randomised studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly "healthy" women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualised.

Advanced glycation end products (AGEs) estimated by skin autofluorescence are related with cardiovascular risk in renal transplant.

BACKGROUND: Advanced glycation end products (AGEs) accumulation, a measure of cumulative metabolic stress, constitute a novel pathogenic mechanism involved in aging, diabetes, cardiovascular (CVD) and chronic kidney disease (CKD). Despite removal of uremic toxins and AGEs after a successful renal transplant (RT), CVD remains the leading cause of mortality. We hypothesized that AGEs measurement by Skin Autofluorescence (SAF) might be useful even after a successful RT and thus reflect the high cardiovascular risk burden of these patients. METHODS: 189 stable RT (61% men, aged 56±13.0 years), CKD stages 1-4 and >12 months since RT were enrolled. Variables collected comprised comorbid history, medication use, smoking habit, routine biochemistry, subclinical atheromatosis by ankle-brachial-index (ABI) and allograft resistivity index (RI), 24-h ABPM, anthropometry and handgrip strength. AGEs were measured by SAF and expressed in arbitrary units (AU). Vascular age was estimated by Koetsier´s formula (SAF-0.83/0.024) and expected 10-years cardiovascular death risk was calculated with the REGICOR score. RESULTS: Mean SAF was 3.00±0.83 AU and estimated vascular age 90±34.7 years (30 years above biological age). SAF was higher among men (3.10±0.91 vs 2.81±0.66), diabetic nephropathy (3.49±0.75 vs 2.96±0.83) and steroid users (3.14±0.86 vs 2.71±0.69). We observed a positive correlation of SAF with night-systolic blood pressure (r = 0.25, p = 0.001), parathormone (r = 0.20, p<0.01), phosphate (r = 0.28, p<0.001) and negative with hemoglobin (r = -0.29, p<0.001), CKD-EPI (r = -0.32, p<0.001), albumin (r = -0.17, p<0.05), and dynamometry (r = -0.20, p<0.01). Subclinical vascular atheromatosis (ABI and RI) as well as the REGICOR scale (r = 0.35 p<0.001) were also correlated with SAF. In multivariable analysis age, gender, steroid use, serum phosphate and handgrip strength remained independently associated with SAF. CONCLUSIONS: SAF levels are elevated in RT patients and correlate with CVD risk. Besides age and male sex, our results suggest that phosphate overload, steroid use and nutritional status are important factors linking to AGEs accumulation.

Osteoporosis, bone mineral density and CKD-MBD complex (I): Diagnostic considerations. / Osteoporosis, densidad mineral ósea y complejo CKD-MBD (I): consideraciones diagnósticas.

Osteoporosis (OP) and chronic kidney disease (CKD) independently influence bone and cardiovascular health. A considerable number of patients with CKD, especially those with stages 3a to 5D, have a significantly reduced bone mineral density leading to a high risk of fracture and a significant increase in associated morbidity and mortality. Independently of classic OP related to age and/or gender, the mechanical properties of bone are also affected by inherent risk factors for CKD ("uraemic OP"). In the first part of this review, we will analyse the general concepts regarding bone mineral density, OP and fractures, which have been largely undervalued until now by nephrologists due to the lack of evidence and diagnostic difficulties in the context of CKD. It has now been proven that a reduced bone mineral density is highly predictive of fracture risk in CKD patients, although it does not allow a distinction to be made between the causes which generate it (hyperparathyroidism, adynamic bone disease and/or senile osteoporosis, etc.). Therefore, in the second part, we will analyse the therapeutic indications in different CKD stages. In any case, the individual assessment of factors which represent a higher or lower risk of fracture, the quantification of this risk (i.e. using tools such as FRAX®) and the potential indications for densitometry in patients with CKD could represent an important first step pending new clinical guidelines based on randomised studies which do not exclude CKD patients, all the while avoiding therapeutic nihilism in an area of growing importance.

Restless Legs Syndrome: An Unresolved Uremic Disorder after Renal Transplantation.

BACKGROUND: Restless legs syndrome (RLS) is a common complication of uremia that may improve after transplantation. Its frequency might not be as low as expected, as some uremic disturbances may continue even after a successful graft. Our aim was to investigate the prevalence and related conditions for RLS in renal transplant patients. METHODS: We carried out a cross-sectional, observational study. A self-administered questionnaire following the International Restless Legs Syndrome Study Group diagnostic criteria was administered to 129 patients (82 men and 47 women) aged 57 ± 12.8 years followed up for at least 1 year, with stable renal function (Cr 1.5 ± 0.54 mg/dL). Patients with probable RLS according to the screening questionnaire underwent comprehensive neurological examination to exclude RLS mimics. RESULTS: The frequency of RLS according to questionnaires was 29.5% (18 men/20 women). After neurological exam, RLS was confirmed in 19 patients providing an overall frequency of 14.8% (higher than the prevalence in the general population). A definitive diagnosis of RLS was established for 6 men (7.3%) and 13 women (27.7%), indicating a positive predictive value for the screening questionnaire of 65% for women and 33% for men. There were fewer patients under renin-angiotensin aldosterone system (RAAS) blocking treatment in the RLS group (21.1 vs. 47.3%). Women with RLS had poorer renal function (52 ± 17.5 vs. 42 ± 13.9 mL/min) and phosphate-reabsorption rate (75 ± 10.5 vs. 65 ± 9.2). There was no difference in age, comorbidities, anticalcineurin therapy, renal function, anemia and time since transplantation between transplant patients with and without RLS. CONCLUSION: The prevalence of RLS after transplantation remains high (14.8%). This condition is twice more prevalent for females. Contribution of RAAS, graft function and phosphate overload requires further investigation.

Testosterone deficiency in dialysis patients: Difference between dialysis techniques. / Déficit de testosterona en los pacientes en diálisis: diferencias según la técnica de diálisis.

Testosterone deficiency is a prevalent condition in male patients with chronic kidney disease. However, it is not known whether the type of renal replacement therapy has an impact on testosterone deficiency that accompanies loss of renal function. METHODS: The cross-sectional study enrolled 79 prevalent male patients on dialysis; 43 on haemodialysis (HD) and 36 on peritoneal dialysis (PD). The median age was 69 years and 31.6% were diabetics. Endogenous testosterone levels were measured by immunoluminescence assay (normal range 3-10.5ng/ml), while nutritional/inflammatory markers, bone and mineral metabolism markers, anaemia, type of dialysis technique and time on dialysis were also assessed. Body composition was evaluated by bioimpedance vector analysis and bioimpedance spectroscopy. Testosterone deficiency was defined as levels below 3ng/ml. RESULTS: Mean testosterone levels were 8.81±6.61ng/ml. Testosterone deficiency affected 39.5% of HD patients and only 5.6% of PD patients. In the univariate analysis, testosterone levels were directly correlated with type of dialysis technique (HD) (Rho Spearman 0.366; P<.001) and time on dialysis (Rho -0.412; P=.036) and only with the HD technique in the multivariate analysis. No other significant correlations were found. CONCLUSIONS: Circulating testosterone levels in men on dialysis were independently associated with HD technique. It can be concluded that a new factor -namely the dialysis technique- may be associated with falling testosterone levels and the associated loss of muscle mass and inflammation. Further studies are needed to establish whether the dialysis technique itself triggers testosterone elimination.

What is the optimal level of vitamin D in non-dialysis chronic kidney disease population?

AIM: To evaluate thresholds for serum 25(OH)D concentrations in relation to death, kidney progression and hospitalization in non-dialysis chronic kidney disease (CKD) population. METHODS: Four hundred and seventy non-dialysis 3-5 stage CKD patients participating in OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into 3 groups according to 25(OH)D levels at enrollment (less than 20 ng/mL, between 20 and 29 ng/mL, and at or above 30 ng/mL), considering 25(OH)D between 20 and 29 ng/mL as reference group. Association between 25(OH)D levels and death (primary outcome), and time to first hospitalization and renal progression (secondary outcomes) over a 3-year follow-up, were assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. To identify 25(OH)D levels at highest risk for outcomes, receiver operating characteristic (ROC) curves were performed. RESULTS: Over 29 ± 12 mo of follow-up, 46 (10%) patients dead, 156 (33%) showed kidney progression, and 126 (27%) were hospitalized. After multivariate adjustment, 25(OH)D < 20 ng/mL was an independent predictor of all-cause mortality (HR = 2.33; 95%CI: 1.10-4.91; P = 0.027) and kidney progression (HR = 2.46; 95%CI: 1.63-3.71; P < 0.001), whereas the group with 25(OH)D at or above 30 ng/mL did not have a different hazard for outcomes from the reference group. Hospitalization outcomes were predicted by 25(OH) levels (HR = 0.98; 95%CI: 0.96-1.00; P = 0.027) in the unadjusted Cox proportional hazards model, but not after multivariate adjusting. ROC curves identified 25(OH)D levels at highest risk for death, kidney progression, and hospitalization, at 17.4 ng/mL [area under the curve (AUC) = 0.60; 95%CI: 0.52-0.69; P = 0.027], 18.6 ng/mL (AUC = 0.65; 95%CI: 0.60-0.71; P < 0.001), and 19.0 ng/mL (AUC = 0.56; 95%CI: 0.50-0.62; P = 0.048), respectively. CONCLUSION: 25(OH)D < 20 ng/mL was an independent predictor of death and progression in patients with stage 3-5 CKD, with no additional benefits when patients reached the levels at or above 30 ng/mL suggested as optimal by CKD guidelines.

Restless legs syndrome in non-dialysis renal patients: is it really that common?

BACKGROUND: Sleep disorders are frequent in chronic kidney disease (CKD). Among them, restless legs syndrome (RLS) may affect up to 60% of patients on dialysis, and it has been related to a poor quality of life and higher cardiovascular risk. Despite its high prevalence in advanced stages of renal disease, RLS frequency in non-dialysis CKD has not been clearly established. The aim of this study was to assess the frequency of RLS in non-dialysis CKD patients (stages 2 to 4) followed in a reference nephrology outpatient clinic. METHODS: A standardized questionnaire following the international RLS study group diagnostic criteria was self-administered by 110 patients regularly followed in the nephrology clinic. The series comprised 69 men and 41 women, aged 68 ± 13.2 years, with mean serum creatinine of 1.7 ± 0.8 mg/dL. Subsequently, patients classified as probable RLS according to the questionnaire underwent a systematic neurological examination. The presence of peripheral artery disease was evaluated by the ankle-brachial index (ABI). RESULTS: The frequency of probable RLS according to the questionnaire results was 21% (17% for men and 27% for women). However, after thorough neurological examination, the diagnosis of RLS was confirmed in only 5 patients. Therefore, the overall definitive RLS frequency was 4.5% (within the prevalence reported for the general population) and was higher among women (9.7% vs 0.2%). In the remaining cases symptoms were due to leg discomfort related with other disorders. Patients with probable and improbable RLS were not significantly different in age, ABI, diabetes, and other comorbid circumstances, except for tricyclic antidepressant prescription, which was more frequent in the probable RLS group (17% vs 2%). Renal function was better in definitive RLS patients than cases classified as probable RLS by the questionnaire but not confirmed after neurological exam. CONCLUSIONS: Although RLS can represent an early manifestation of CKD, its prevalence seems very close to that reported for the general population. Diagnostic confirmation of RLS dramatically falls after expert examination, raising the question whether, in the study of RLS cohorts, CKD has a potentially causal relationship or is a confounding factor associated with other causes of leg discomfort.