Chronic kidney disease (CKD) is a complex and multifactorial disease, and one of the most prevalent worldwide. Chronic kidney disease–mineral bone disorders (CKD–MBD) with biochemical and hormonal alterations are part of the complications associated with the progression of CKD. Pathophysiology of CKD–MBD focused on abnormalities in serum levels of several biomarkers  which are discussed in this review. We therefore examine the prognostic association between CKD–MBD and the increased risk for cardiovascular events, mortality, and CKD progression to end-stage kidney disease (ESKD). Lastly, we present specific treatments acting on CKD to prevent and treat the complications associated with secondary hyperparathyroidism (SHPT): control of hyperphosphatemia , the use of calcimimetic agents, vitamin D, and analogues, and the use of bisphosphonates or denosumab in patients with osteoporosis. Chronic kidney disease (CKD) has emerged as one of the most prevalent noncommunicable disease, affecting about 10% of the general population worldwide [Mineral bone disorders  are characterized by biochemical and hormonal alterations with a significant increased risk for bone fractures, CV events, mortality, and CKD progression . The maiAccording to the Kidney Disease: Improving Global Outcomes (KDIGO) 2006 guidelines, CKD–MBD is defined as ‘‘a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: (a) abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; (b) abnormalities in bone turn-over, mineralization, volume, linear growth, or strength; or (c) vascular or other soft tissue calcification’’ . Hence, 2 (based on the different methods to assess GFR) and it worsens with its progression (stage 3b–5) [Although CKD–MBD generally starts early in the course of the CKD, it becomes apparent with secondary hyperparathyroidism, hyperphosphatemia, and hypocalcemia only when GFR falls below 45–50 mL/min/1.73 mge 3b–5) , our undge 3b–5) ,9. This ge 3b–5)  due to age 3b–5) . The identification of FGF-23 and its coreceptor Klotho has resulted in a new perspective of the “trade-off” theory. FGF-23 has both short-term beneficial (reduction in serum phosphate level) and long-term adverse effects, as its circulating concentration progressively increases while GFR falls down, achieving levels that are several hundred times the normal range in late CKD stages . Thus, FFGF-23 is primarily synthesized by osteocytes and osteoblasts in response to oral phosphate loading and increased serum levels of 1,25-dihydroxyvitamin D3 2D3) and PTH. Additional factors that regulate FGF-23 production and secretion include ionized calcium, reduced levels of iron deposits, the RAAS, oxidative stress, and inflammation . The phyAfter a successful kidney transplant with stable graft function, FGF-23 levels decrease significantly within normal limits .Klotho is a type I membrane β-glycosidase-like protein that confers tissue specificity to FGF-23  and its Phosphate is pivotal for many cellular functions, as a constituent of DNA, cell membrane lipids, high-energy phosphate, second messengers, and protein phosphorylation . Phospha2, there is a dysregulation of the FGF23–Klotho axis: increased FGF-23 levels are no longer able to enhance the excretion of phosphate in the remaining functioning nephrons, eventually leading to the development of overt hyperphosphatemia, which stimulates further secretion of FGF-23 from the bone. At the same time, high levels of FGF-23 suppress 1,25(OH)2D3 production [In advanced CKD, when GFR declines below 30–40 mL/min/1.73 moduction , which coduction  and direoduction . With a oduction ,34. In toduction . It has oduction .Also known as calcitriol, 1α,25-dihydroxyvitamin D3 is the active form of vitamin D synthesized in renal proximal tubules by 1-α-hydroxylase (CYP27B1), which catalyzes the hydroxylation of 25-hydroxyvitamin D (25(OH)D). It is degraded by 24-hydroxylase (CYP24A1) that converts 1,25(OH)2D3 to inactive metabolites . EquilibSHPT is characterized by increased synthesis and secretion of PTH from parathyroid glands in progressive CKD in response to systemic alteration of mineral homeostasis, such as hyperphosphatemia, hypocalcemia, and reduced 1,25(OH)2D3 . In patients with advanced CKD, although FGF-23 binds to the FGFR–Klotho complex in the parathyroid glands to inhibit PTH production, the ability of FGF-23 to suppress PTH is lost due to decreased Klotho . The primary regulation of PTH secretion is mediated by calcium ions in the extracellular fluid that directly bind and activate calcium-sensing receptors (CaSR) expressed on parathyroid cells, leading to an increase in intracellular calcium that reduces PTH release . On the Renal osteodystrophy is a component of the mineral and bone disorders related to CKD (CKD–MBD) and it is the term used to describe the spectrum of abnormalities in bone morphology that develops in patients with CKD . SkeletaAlterations in bone quality in both high-turnover and low-turnover bone diseases may contribute to the diminished mechanical competence of bone in CKD. Low-turnover bone is manifested by changes in microstructural parameters , whereas bone with high-turnover is manifested by changes in material composition and nanomechanical properties  . BecausePatients with CKD are at increased risk of cardiovascular mortality as demonstrated in many studies and this risk increases progressively as renal function declines ,52.Cardiovascular mortality in patients affected by CKD is related to traditional risks factors  and non-traditional risks factors associated with CKD condition, such as chronic inflammation, anemia, and mineral metabolism disorders . CKD–MBDHyperphosphatemia is a crucial point for the management of CKD patients, especially in dialysis patients, because therapeutic strategies are often ineffective in maintaining phosphorus serum levels within target values. A recent study that collected data from 17,414 HD patients demonstrated that a scarce targeting of phosphate in the first weeks after baseline was strongly associated with CV fatal events. Moreover, a better survival was observed in these patients if phosphorus values were lower than 4.5 mg/dL . The resAccording to Bellasi et al., CKD patients with phosphate levels ≥4.3 mg/dL have an increased risk of progression to ESKD and mortality . Another2 were associated with greater risk of ESKD [2, Rebholz et al. demonstrated that higher baseline serum levels of FGF-23 are positively correlated with a higher risk of incident kidney disease [FGF23 is another important molecule involved in CKD–MBD and poor prognosis. FGF 23 actions on target tissues by stimulating FGF receptors (FGFR) and Klotho, which acts as a coreceptor. The myocardium was the first organ that was shown to respond to circulating FGF-23 in a Klotho-independent way . FGF-23  of ESKD . In a la disease .Other studies relating to PTH have shown a “U”-shaped association between PTH values and increased risk of mortality. Similarly, higher PTH levels forecast CKD progression and the increase in PTH over time is also associated with CKD progression, confirming the importance of repeated measures over this biomarker to better stratify the individual prognosis in CKD patients . According to KDIGO 2017, in patients with CKD G5D, are suggested PTH levels in the range of 2 to 9 times the upper normal limit . In factFor all these reasons, in the complex scenario of CKD–MBD, management of metabolic alterations correlated to hyperparathyroidism is crucial to minimize the adverse consequences such as CV risk and CKD progression associated with this condition. A detailed summary of the observational studies in MBD is reported in The management of CKD–MBD is largely based on several strategies to prevent the adverse complications associated with SHPT. The current KDIGO guideline recommends treatment of SHPT based on repeated measures of the biochemical markers of disordered mineral bone metabolism, which include serum phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D. PTH target in patients on dialysis is set on two to nine times the normal range, according to KDIGO , and 150In patients with CKD G3a-5, updated guidelines recommend that decisions about phosphate-lowering treatments should be based on progressive or persistent hyperphosphatemia. Early prevention of hyperphosphatemia is not currently supported by data derived from randomized studies, even if observational evidence suggests to maintain serum phosphorus levels as low as possible . PhosphaThe daily phosphate intake of a healthy person is approximately 1000–2000 mg. In adult patients with CKD undergoing dialysis with serum phosphate concentrations of 4–4.5 mg/dL, the daily dietary phosphate intake should be limited to approximately 800 mg . The dieTherefore, a strict limitation on the dietary phosphate intake can, however, lead to protein deficiency and malnutrition due to reduced protein intake. To reach the goal of dietary phosphate intake restriction while maintaining the high protein intake required in dialysis patients, it is recommended that patients select foods with a low phosphorus to protein (P–P) ratio, such as egg white or protein from vegetable-based sources, and prefer cooking procedures that induce food demineralization, such as boiling . Foods wPhosphate binders sequester dietary phosphate within the gastrointestinal tract forming a non-absorbable complex with phosphate, so they prevent its absorption and enhance its fecal excretion. The binding ability is limited to approximately 200–300 mg of phosphate daily, thus a controlled dietary phosphate load is still required. These drugs are generally well tolerated and can be taken during or after meals. The main classes of phosphate-lowering agents are calcium-based phosphate-binders (CBP), non-calcium-based phosphate-binders (NCBP), and aluminum-based phosphate-binders. The use of aluminum containing phosphate binders is nowadays avoided due to the risk of development of aluminum-related toxicity, including osteomalacia and encephalopathy .Calcium-containing phosphate binders  have a slightly lower phosphate-binding capacity than aluminum-based phosphate binders but have no risk of aluminum accumulation and they are more cost-effective. However, they may cause positive calcium balance and elevated calcium-phosphorus (Ca × P) product level, which is linked to hypercalcemia, and cardiac and vascular calcification . Block eCalcium acetate/magnesium carbonate (CaMg) is a combination phosphate binder, and it is an effective alternative to pure calcium salts to reduce calcium exposure, combined with the potential benefits associated with increased serum magnesium levels, such as reduced cardiovascular calcifications, hypertension, and mortality risk . In the Based on this evidence, KGIDO guidelines suggest restricting the dose of calcium-based phosphate binders . The resThe main calcium-free and aluminum-free phosphate-lowering agents are sevelamer and lanthanum carbonate. These drugs are much more used since they do not cause calcium overload and hypercalcemia. Sevelamer is a weakly basic anion-exchange resin available in the chloride form (sevelamer hydrochloride) and in the buffered form with bicarbonate (sevelamer carbonate). The safety and efficacy of these two compounds are equivalent, although some patients treated with sevelamer hydrochloride may develop more gastrointestinal side effects, such as vomiting and diarrhea, and metabolic acidosis due to the intestinal exchange of chloride for bicarbonate . Treatmep-value 0.37) [Lanthanum carbonate contains the trivalent cation lanthanum, and it forms a water-insoluble compound, lanthanum phosphate, in the gut . Accordiue 0.37) . The new generation of calcium-free and aluminum-free phosphate-lowering agents is represented by iron-based phosphate binders. Ferric citrate and sucroferric oxyhydroxide are the two iron-based phosphate binders clinically approved for safety and efficacy for the treatment of hyperphosphatemia . The useRemoval of phosphate through dialysis in CKD patient stage G5 is dependent on the type of dialysis, session length, and dialysate flow. For patients who perform peritoneal dialysis four times per day with 2 L exchanges, an estimated amount of 2.0–2.2 g of phosphate is removed per week. In patients on conventional three-times-a-week, 4 h per session hemodialysis schedule, the amount of phosphate removed is approximately 2.3–2.6 g, only half of the assumed dietary intake, if limited to 800 mg/day . Thence,As kidney function declines, incidence and severity of SHPT increases and leads to abnormalities in bone turnover and mineralization. For patients with CKD stage G5 with SHPT, the updated 2017 guidelines do not clarify which is the first-line therapy to administer but it recommends the use of calcimimetics, calcitriol, or vitamin D analogues in monotherapy, or a combination of calcimimetics with calcitriol or vitamin D analogues . MoreoveVitamin D is a group of fat-soluble secosteroids involved in the regulation of gene transcription in target tissues through the binding to its nuclear vitamin D receptor (VDR). Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend the correction of hypovitaminosis D through nutritional vitamin D replacement in CKD and dialysis patients to prevent SHPT ,72. The The major natural source of vitamin D is acquired from sunlight-induced cutaneous synthesis, and the rest derives from diet as ergocalciferol (D2) from vegetable sources and cholecalciferol (D3) from animal sources. Many vitamin D supplementation regimens use either ergocalciferol or cholecalciferol on a daily, weekly, or monthly basis. Vitamin D precursors are hydroxylated in the liver to calcifediol , the major circulating form of vitamin D. Calcifediol is therefore hydroxylated in the kidneys to calcitriol , the active form of vitamin D, which activates the vitamin D receptor in the cellular nucleus. Calcitriol deficiency results in a decreased intestinal absorption of calcium and may lead to hypocalcemia, which further stimulates PTH secretion. Calcitriol is available as capsules, an oral solution, and an intravenous solution. Synthetic activated vitamin D analogues, also known as vitamin D receptor activators (VDRAs), include paricalcitol, doxercalciferol, alfacalcidol, and others. Multiple RCTs reported significant reductions of PTH levels with calcitriol or vitamin analogues compared to placebo ,104,105.Cinacalcet hydrochloride is the first calcimimetic drug approved for the treatment of SHPT in adult dialysis patients. It regulates the synthesis and secretion of PTH by increasing the sensitivity of the calcium-sensing receptor (CaSR) to extracellular calcium ions . It is tEtelcalcetide is a second-generation calcimimetic that has been approved for the treatment of SHPT in adult hemodialysis patients. It interacts with the CaSR at a site distinct from cinacalcet . EtelcalAccording to 2017 KDIGO guidelines, the proposed PTH target is suggested to be maintained in the range of approximately two to nine times the upper normal limit (130–600 pg/mL) . The earBisphosphonates are currently the treatment of choice for osteoporosis in the general population. They are a group of chemically stable derivatives of inorganic pyrophosphate with a very high affinity for bone mineral  and inclDenosumab is a fully human monoclonal antibody that binds the receptor activator of nuclear factor-κB ligand (RANKL) with high affinity and specificity and it prevents the interaction of RANKL with its receptor RANK on osteoclasts and their precursors . By bindCKD–MBD is a very complex and multifactorial disease. Despite the big effort to improve the management of patients with CKD–MBD, several unmet needs still remain. In particular, the true cut-off of risk factors such as serum phosphate, PTH, FGF23, and the magnitude of association of novel drugs targeting MBD pathways and future CV, renal and mortality risk deserve further studies in the future.


Assessing nociception and sedation in mechanically ventilated patients in the ICU is challenging, with few reliable methods available for continuous monitoring. Measurable cardiovascular and neurophysiological signals, such as frontal EEG, frontal EMG, heart rate, and blood pressure, have potential in sedation and nociception monitoring. The hypothesis of this explorative study is that derived variables from the aforementioned signals predict the level of sedation, as described by the Richmond Agitation-Sedation score (RASS), and respond to painful stimuli during critical care.Thirty adult postoperative ICU patients on mechanical ventilation and receiving intravenous sedation, excluding patients with primary neurological disorders, head injury, or need for continuous neuromuscular blockage. Bispectral Index (BIS), EMG power (EMG), EMG-derived Responsiveness Index (RI), and averaged blood pressure variability (ARV) were tested against RASS measurements. The aforementioned variables together with blood pressure and Surgical Pleth Index (SPI) were explored before and after painful stimuli  at varying RASS levels, to test variable responsiveness.K) of 0.776 for BIS, 0.761 for EMG, and 0.763 for RI. In addition, BIS, EMG, and ARV demonstrated responsiveness to painful stimuli during deep sedation (RASS score ≤ -3).BIS, EMG, and RI predicted RASS levels with a prediction probability , offering novel tools for nociception-sedation monitoring of mechanically ventilated ICU patients requiring deep sedation. Sedation and analgesia are a crucial part of critical care but optimizing these in non-communicative patients can be challenging. Deep sedation is common, with a prevalence of 35% to 68% in mechanically ventilated patients, and excessive sedation is associated with adverse outcomes, such as a higher mortality and longer ICU stays –5. SeverOne of the main challenges in detecting and treating pain and stress in ICU patients is the lack of suitable monitors of nociception and analgesia , 2, 7, 8., implying a potential use of BIS for nociception-analgesia monitoring [Derived frontal electroencephalogram (EEG) and electromyogram (EMG) variables can be used as noninvasive neuromonitoring methods of sedation and anesthesia depth. The most widely used EEG derived variable is the Bispectral Index (BIS), which has been validated for perioperative sedation  and has nitoring . The Resnitoring . Both BInitoring , 15–19.The physiological stress responses to pain  can be blunted in ICU patients, mainly due to medication  , 9. The Short-term blood pressure variability (BPV) is an interesting variable for assessing nociception and analgesia, as the autonomic responses of heart rate and blood pressure are inherently linked to each other , 23, 24.The Surgical Pleth Index (SPI), a derived variable combining normalized pulse photoplethysmographic waveform amplitude (PPGA) and RR interval (RRI), monitors nociception by reflecting the changes in the balance of sympathetic and parasympathetic tone , 9, 23. The aims of this prospective and explorative study were to test the performance of sedation monitoring variables derived from EEG, EMG and hemodynamic measurements , against Richmond Agitation-Sedation scores (RASS), and their responsiveness to painful stimuli during critical care.The inclusion criteria for this study were adult patients, with a planned or unplanned postoperative admission to the ICU, on mechanical ventilation via an endotracheal tube, and receiving continuous intravenous sedation . Exclusion criteria were primary neurological disorders , the continuous use of NMBAs during monitoring, confirmed central nervous system infection, or a short data collection time (less than 12 h). Sparing bolus administration of NMBAs to facilitate ventilation were allowed, as frontal EMG is reasonably resistant to the effects of partial blockade.th of May 2007 to the 1st of April 2009, with dedicated study nurses gathering all data. Of the 32 recruited patients, 30 were included (2 excluded due to short data collection time). The study period was from arrival to the ICU until extubation, with continuous monitoring . During daytime one of two dedicated research nurses conducted computerized and standardized RASS assessments every 60 min (based on the RASS score), with increasing stimuli given every minute . All observed painful stimuli which were estimated to be significantly painful, and which require at least local anaesthesia, were documented . Invasive blood pressure data, including systolic (sysBP) and diastolic (diaBP) blood pressure, were monitored from a peripheral arterial line. Mean values of sysBP and diaBP were stored at 10 s intervals. The sysBP time series were used to derive average real variability (ARV) [A BIS sensor was positioned in the standard position on the patient’s forehead, from which BIS and EMG values were monitored with the E-BIS module of GE Datex-Ohmeda S/5 monitoring system . The Entropy sensor was positioned bilaterally on the forehead, above the BIS sensor [ty (ARV) , a matheN was 180, i.e., a 30-min time-window was used. SysBP measurements greater than 280 mmHg or lower than 50 mmHg and an increase of over 100 mmHg in 10 s were discarded as artifacts.where All patients were monitored continuously with 3-lead ECG and a peripheral arterial line with invasive blood pressure monitoring, and all ECG results were reviewed offline by a cardiologist (J.S.). Monitoring data were captured with the S/5 Collect SW .N), while the number of measurements are shown in low case (n). Blood pressure and heart rate by themselves are not predictive of the level of sedation or nociception [In this prospective and exploratory study, variables for RASS comparison were selected from variables used to monitor the depth of anesthesia or sedation . As the preliminary visual analysis suggested a close resemblance between RI and ARV, ARV results were compared against RASS too. Number of study patients shown in high case . PK is an established statistical method for quantifying the ability of an anesthetic depth indicator to decrease consistently with deepening anesthesia. Although it is more commonly used for binary categories, such as comparing the variable value of the responsive state against its value in a non-responsive state, the methodology can be similarly applied to more than two-ordered categories [K of 1 would indicate that the variable value will monotonically decrease with deepening sedation from RASS + 2 to RASS -5, whereas a PK of 0.5 would indicate that the variable’s capability for predicting RASS is equal to flipping a coin. As the data contained multiple samples from each patient, with different amounts of samples for each patient, we used the stratified bootstrapping method as proposed by Lüginbuhl et al. [K value using the jack-knife method for this subset of data (in this case 30 samples) [K values are the medians of the 1000 subset PK values. The value of each variable was recorded just prior to the start of each RASS assessment, so that the stimulus of the assessment itself does not affect the recorded variables.Associations of BIS, EMG, RI and ARV to RASS levels were analysed with prediction probability  . This prK values separately for each group with the presented random subsampling method.To evaluate EMG influence on BIS and RI, we divided all RASS observations to low and high EMG groups according to a threshold value of 30 dB . To evalWe were further interested in studying the responsiveness of the variables to painful stimuli at different RASS levels. For this analysis, we selected the mean value of each variable from a time period 2 to 5 min prior to each registered stimulus, and the mean value from a time period of 0 to 3 min after each stimulus. Successive stimuli occurring within 10 min of the earlier stimulus were not included in the analysis. For the analysis we selected all the variables used in the study, including systolic and diastolic blood pressures, SPI and SPI subcomponents of RRI and PPGA. Wilcoxon signed rank test with Bonferroni correction was applied to study whether pre and post stimuli values were from the same population, the type I error was set at 5% (two-sided) which resulted in a Bonferroni corrected limit of statistical significance at α = 0.0056.All statistical analyses were performed with Matlab 9.5 .All demographic data and data from the ICU treatment period are presented in Table K analysis of 406 pairs of RASS score and variable values  at different RASS levels are presented in Fig. In Table The correlation of EMG power versus BIS is presented in the top graph of Fig. As an example of similar behaviour of RI and ARV, the continuous monitoring data of a single patient can be seen in Fig. This explorative study shows that several easily measurable continuous physiological variables reflect the sedation level of ICU patients, as determined by the RASS scale, and also respond to painful stimuli in sedated, mechanically ventilated patients who are unable to report pain.K values of BIS, RI and EMG power. The variability of blood pressure, represented by ARV, showed no association with RASS levels. Interestingly, the PK value of BIS was not substantially better than the PK value of EMG power provided by the BIS monitor. It is a known fact that frontal EMG activity contaminates BIS values [Of the studied variables, EEG and EMG derived variables were associated with RASS levels, as was demonstrated by the moderate PS values , and pasS values , 16. TheS values . The BISS values , with hiS values . Based oS values , anestheS values , and in S values .Our results confirm the earlier findings of a correlation between BIS and frontal EMG in the ICU setting , 36, but. demonstrated a significantly higher incidence of hypertension (systolic blood pressure over 160 mmHg) in critical care patients when sedation was targeted to a RI level of 40 to 80, when compared to patients with a sedation target of RASS -3 to 0. This finding supports the hypothesis that RI mostly reflects sympathetic activity and has thus very limited applications in sedation titration [Our study suggests that the RI reflects autonomous nervous system responses, and its reasonable capability to detect deep sedation is partly explained by the fact that sedative drugs attenuate those responses. Figure itration .Frontal EMG was the last remaining response to painful stimuli in the deepest sedation level . BIS was also reactive in RASS levels -4 and -3, but we assume that these responses are mainly explained by the EMG activation. Nociception monitors during surgical anaesthesia exists, but their application to critical care has been limited . To our While HVR might be a potential tool for sedation-nociception monitoring, our data contained 19% of non-sinus rhythms, amount so high that it has a significant effect on the variable. In this study the finding was not expected, as previous studies do not report patient rhythm status. Another study of heart rate variability with only sinus rhythm might be interesting, however atrial arrhytmias and pacemaker rhythms are common in critical care patients.The study results are limited by the explorative nature of the study, and by the small sample size. All results should be treated as hypothesis-generating and need to be validated with further research. The RASS assessment followed a standardized protocol see , but witVariables derived from EEG (BIS) and EMG  are useful for non-invasive nociception-sedation monitoring in mechanically ventilated ICU patients. Previously EMG has been considered as a disrupting artefact for derived EEG parameters, but our results show that EMG might be used as a part of monitoring in the ICU, where NMBAs are not typically used. EMG power can be useful for detecting responses to painful stimulation in critical care patients who are unable to communicate. As the individual response of each physiological variable to nociceptive stimulus was dependent on the RASS level, a multimodal approach including several of these variables could be beneficial in evaluating the level and adequacy of analgesia.


Dietary protein restriction has long been a cornerstone of nutritional therapy for patients with chronic kidney diseases (CKD). However, the recommended amount of dietary protein intake is different across guidelines. This is partly because previous randomized controlled trials have reported conflicting results regarding the efficacy of protein restriction in terms of kidney outcomes. Interestingly, a vegetarian, very low protein diet has been shown to reduce the risk of kidney failure among patients with advanced CKD, without increasing the incidence of hyperkalemia. This finding suggests that the source of protein may also influence the kidney outcomes. Furthermore, a plant-dominant low-protein diet (PLADO) has recently been proposed as an alternative dietary therapy for patients with CKD. There are several potential mechanisms by which plant-based diets would benefit patients with CKD. For example, plant-based diets may reduce the production of gut-derived uremic toxins by increasing the intake of fiber, and are useful for correcting metabolic acidosis and hyperphosphatemia. Plant proteins are less likely to induce glomerular hyperfiltration than animal proteins. Furthermore, plant-based diets increase magnesium intake, which may prevent vascular calcification. More evidence is needed to establish the efficacy, safety, and feasibility of PLADO as a new adjunct therapy in real-world patients with CKD. Metabolites of dietary proteins are mostly excreted by the kidney. These substances accumulate in patients with chronic kidney disease (CKD) due to decreased glomerular filtration and tubular secretion. A myriad of these solutes, such as indoxyl sulfate and p-cresyl sulfate, have been identified as uremic toxins, potentially causing the damage of various organs, including the kidney and cardiovascular system . In addiIndeed, several observational studies have shown that a higher dietary protein intake is associated with a rapid decline in kidney function ,5. Altho2 (CKD stages G4 and G5), irrespective of the presence or absence of diabetes mellitus [In the KDIGO 2012 CKD guideline, lowering protein intake to 0.8 g/kg per day is recommended for those with a GFR of <30 mL/min per 1.73 mmellitus ,10. ThisIn contrast, the Kidney Disease Outcomes Quality Initiative (KDOQI) 2020 updated clinical practice guideline for nutrition in CKD recommends a low protein diet (LPD) (0.55 to 0.60 g/kg per day) or a very low protein diet (0.28 to 0.43 g/kg per day) supplemented with ketoacid/amino acid analogs (sVLPD) for non-diabetic and metabolically stable patients with pre-dialysis CKD stages G3 to G5 to reduce the risk of death and kidney failure and to improve quality of life . BecauseThe discrepancy between the two major guidelines described above would be explained by the mixed results of the previous RCTs regarding the efficacy of the protein restriction in patients with CKD.2 [p = 0.009). The latter finding suggests that the LPD could exhibit a reno-protective effect if implemented for a long period. One of the limitations of this study is that angiotensin-converting enzyme inhibitors were used only in 32 to 44% of the study participants. Thus, it is unclear as to whether the LPD improves kidney outcomes over the current standard therapies, including renin-angiotensin-aldosterone (RAS) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors [The Modification of Diet in Renal Disease (MDRD) study 1 is one of the largest studies that compared a usual protein diet (1.3 g/kg per day) with the LPD (0.58 g/kg per day) in 585 patients with a GFR of 25 to 55 mL/min per 1.73 m2 . It shouhibitors .2 to the LPD (0.58 g/kg per day) or sVLPD (0.28 g/kg per day supplemented by a keto acid-amino acid supplement), there were no significant differences in the slope of GFR or the rate of kidney failure between the groups [In the MDRD study 2, which randomized 255 patients with a GFR of 13 to 24 mL/min per 1.73 me groups . The meaIn the long-term follow-up data of the MDRD study 2, in which the median duration of follow-up until death was 10.6 years, the sVLPD group surprisingly showed an 82% higher rate of all-cause mortality compared to the LPD group . This re2  [Cianciaruso et al. reported the result of a 30-month extension study of an initial 18-month RCT comparing an LPD  with a moderate protein diet (0.80 g/kg per day) in 423 patients with an eGFR of <30 mL/min per 1.73 m1.73 m2) . The aveMore recently, Bellizzi et al. reported the ERIKA study, a pragmatic RCT in which participants received current tertiary nephrology care . This trTaken together, it remains unclear whether the LPD or sVLPD can slow the progression of CKD and reduce the risk of mortality, especially among those receiving the current standard medical treatment for CKD, such as RAS inhibitors and SGLT2 inhibitors. It is also an important issue to explore a way to improve the adherence to a protein restriction diet. According to the National Health and Nutrition Examination Survey (NHANES) in 2007 to 2010, the proportions of total protein intake attributable to animal and dairy protein are 46% and 16% in the US, respectively, while plant protein accounted for only 30% both in males and females; chicken and beef were the top two food categories for animal protein . A similLikewise, in the MDRD study 2, approximately 65% of the dietary protein was from animal sources . Therefo2 [Garneata et al. conducted an open-label, 15-month RCT comparing a vegetarian sVLPD  with a LPD  in 207 patients with an eGFR of <30 mL/min per 1.73 mp < 0.001). The number needed to treat for one year to avoid dialysis initiation was only 22.4. There were no significant differences in nutritional parameters between the groups. In the vegetarian sVLPD group, serum bicarbonate levels were significantly increased, while serum phosphate, urate, and urea levels were significantly decreased. Moreover, a remarkable reduction was observed in the rate of the primary kidney outcome  in the vegetarian sVLPD group compared to that in the LPD group  was associated with a lower rate of mortality, while a higher intake of less healthy plant foods  was associated with a higher rate of mortality . Therefo2) showed that healthy dietary patterns such as the DASH and Mediterranean diets were associated with lower odds of incident CKD and albuminuria [2 or proteinuria) in a community-based prospective cohort study of 9229 Koreans with normal kidney function [A plant-based diet may also have some favorable effects on the prognosis of patients with CKD . A meta-uminuria . More spfunction . Among pfunction . Conversfunction . Notablyfunction . These oAccordingly, a plant-dominant low-protein diet (PLADO) (dietary protein intake of 0.6 to 0.8 g/kg per day composed of >50% plant-based sources) has been proposed as an alternative dietary therapy for CKD ,35. KalaPatients with CKD have long been advised to restrict their consumption of vegetables and fruits in order to avoid hyperkalemia. However, it should be recognized that meat, fish, and poultry are also rich in potassium . In addi2 [Indeed, in the RCT by Garneata et al., the vegetarian sVLPD did not significantly increase serum potassium levels, even in patients with an eGFR of <30 mL/min per 1.73 m2 . This ma2 . These fPatients undergoing hemodialysis have also been recommended to restrict vegetables and fruits to avoid hyperkalemia. Although intervention studies examining the plant-based diets in hemodialysis patients are lacking, Gonzalez-Ortiz et al. reported that a higher adherence to a healthy plant-based diet  estimated from 3-day food records was not associated with hyperkalemia among 150 patients undergoing hemodialysis . The amoThere are several potential mechanisms by which patients with CKD would benefit from a plant-based diet .(1)Uremic toxins are involved in the progression of CKD and cardiovascular events . Patient(2)Metabolic acidosis is a risk factor for the progression of CKD, especially when pH is low . Acid lo(3)Elevated serum phosphate levels lead to vascular calcification and are associated with an increased risk of cardiovascular events and mortality in patients with CKD, although the benefits of phosphate-lowering therapies on clinical outcomes remain uncertain . Because(4)Plant proteins are less likely to induce glomerular hyperfiltration compared to animal proteins. Kontessis et al. have reported that soy protein neither increased GFR nor renal plasma flow as animal protein did among healthy individuals . Additio(5)A plant-based diet can increase the intake of magnesium . ExperimHypomagnesemia is not rare in patients with CKD. In a cross-sectional study of 5126 patients with pre-dialysis CKD, the prevalence of hypomagnesemia (serum magnesium levels of <1.8 mg/dL) was approximately 15% .There are several causes of hypomagnesemia in CKD patients. For example, dietary restriction of potassium limits the intake of magnesium. Diuretics and diabetes mellitus are known to enhance urinary magnesium excretion. Furthermore, an animal study has shown that tubular injury induces urinary magnesium wasting . Hypomagnesemia is associated with an increased risk of kidney failure in diabetic kidney disease . This asMagnesium has a strong physicochemical potential to inhibit calcium–phosphate crystallization. Indeed, in vitro and animal studies showed that magnesium suppresses vascular calcification ,62,63. IMagnesium is known to antagonize the maturation of calciprotein particles (CPPs) that are involved in vascular calcification . A high-Lower serum magnesium levels were associated with a higher risk of mortality in hemodialysis patients . Those wMild hypermagnesemia may be suitable for hemodialysis patients to maintain ionized magnesium levels. The ionized-to-total magnesium ratio is low in these patients, probably due to increased plasma anions such as phosphate, which form a complex with magnesium ions . TherefoIt may be a concern that excess magnesium may impede bone mineralization. However, the risk of hip fracture was not elevated in patients with mild hypermagnesemia .Interestingly, there is a significant interaction between magnesium and phosphate in terms of cardiovascular death . Higher According to the evidence discussed in this review, PLADO may serve as a new adjunct therapy to delay the progression of CKD. Additionally, this diet can be efficacious in managing complications of CKD, including metabolic acidosis, hyperphosphatemia, accumulation of uremic toxins, and glomerular hyperfiltration. Furthermore, increased magnesium consumption may prevent vascular calcification and phosphate-induced kidney injury. Current evidence does not suggest the risk of hyperkalemia under a plant-based diet in patients with advanced CKD, although close monitoring is recommended in the clinical setting. Further evidence is required to establish the efficacy, safety, and feasibility of this diet in real-world patients with CKD.


Chronic heart failure (CHF) affects the health care system with high social and economic costs due to recurrent hospital admissions or frequent ambulatory reassessments. Subclinical hypothyroidism (SCH) is commonly observed in patients with CHF and negatively affects myocardial function and remodeling and, ultimately, increases the risk of hospitalizations and all-cause and cardiovascular (CV) mortality. The role of levothyroxine replacement on relevant CV outcomes in patients with SCH and CHF is unclear.To assess the effect of levothyroxine (compared to placebo or no treatment) on the incidence of all-cause and CV mortality, major adverse CV events, and heart failure in patients with SCH and CHF.PubMed/MEDLINE, Cochrane Library, and ClinicalTrial.gov were searched for randomized clinical trials, non-randomized observational, multicentric, and comparative studies. No language restrictions were included. After duplicate removal, articles were screened and extracted for the synthesis according to a hierarchical strategy that included title, abstract, and full-text appraisal. The risk of bias was assessed by RoB2 and ROBIN-I tools. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was applied to rate the quality of evidence and grade the strength of recommendations.Two trials were included in the systematic review with considerable indirectness and inaccuracy that down-graded the level of evidence.No evidence supports the use of levothyroxine for treating SCH in CHF due to the lack of reliable and well-designed clinical trials.CV outcome and dose-response trials are needed to understand better the role of levothyroxine replacement treatment for a safer prescription in this clinical setting. Chronic heart failure (CHF) is characterized by structural and functional cardiac abnormalities, confirmed by high circulating levels of natriuretic peptide or signs and related symptoms of either pulmonary or systemic congestion . EndocriHerein we provide an overview of the current status of knowledge on the diagnosis and clinical significance of subclinical hypothyroidism (SCH) and a systematic review of the effect of levothyroxine treatment on cardiovascular outcomes in patients with SCH and CHF.SCH is defined as an elevated serum thyrotropin hormone (TSH) level with values of free thyroxine (fT4) and free triiodothyronine (fT3) within the normal range of reference . PrimaryThe prevalence of SCH and OH increases with aging  along wiGiven this evidence, levothyroxine may improve cardiovascular outcomes in patients with CHF and hypothyroidism, but it remains unclear when to start replacement and what is the optimal TSH target. In one observational study, the mortality rate was higher in the lowest (<0.1 mUI/L) and highest TSH categories (>4 mUI/L) than in the normal range of TSH (0.4 – 4 mUI/L). In addition, the risk of heart failure was elevated when TSH was below 0.4 mUI/L and above 10 mUI/L, especially in women and older patients. No increase in the risk of cardiovascular events, atrial fibrillation, and fracture across TSH concentrations was observed . In a 12A large amount of evidence suggests that hypothyroidism is linked to cardiovascular diseases (CVDs). The underlying mechanisms explaining this association are related to impaired lipid metabolism, low-grade inflammation, endothelial dysfunction, hyperhomocysteinemia, and hypercoagulative state –28. ThisSCH is accompanied by similar CV hallmarks , and it Given the importance of thyroid hormones in regulating the mechanisms that maintain cardiovascular health, such as lipids, endothelial function, blood pressure homeostasis, and myocardial remodeling, both hypo- and hyperthyroidism may be implicated in the pathogenesis of cardiovascular adverse events , 35.Although epidemiological data suggest that subclinical hypothyroidism may negatively affect cardiovascular outcomes in patients with CHF, the role of levothyroxine replacement in improving these outcomes or not should be better elucidated .More precisely, we conceived this review in order to respond to the following questions:Does levothyroxine replacement therapy compared to placebo or no treatment improve cardiovascular outcomes in patients with CHF and subclinical hypothyroidism? (- roidism? Table 1.The study population included adult patients (age >18 years) with an established diagnosis of CHF. Subclinical hypothyroidism was defined as 4.5 < TSH < 20 mUI/mL with normal values of fT4 and fT3.To this aim, a systematic search in PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were carried out by using the following strategies:“(levothyroxine) AND ((heart failure) OR (chronic heart failure))”.- Six-hundred-three results were found after searching PubMed/MEDLINE, 31 were found in the Cochrane Library, and 16 in ClinicalTrials.gov. The search strategy was restricted to randomized clinical trials (RTCs), non-randomized observational, multicentric, and comparative studies. No language restrictions were included. After duplicate removal, articles were screened and extracted for the synthesis according to a hierarchical strategy that included title, abstract, and full-text appraisal. The flow diagram summarizing the process of identification of studies has shown in As pre-specified, the risk of bias in included studies was assessed by RoB2 for individual randomized, parallel-group trials , and ROBData from excluded studies are listed in more detail in supplemental materials. Only two studies were finally included in the systematic review Table 2.In Zijlstra et al., no statistically relevant differences in terms of either CV benefits or harms were found among patients assuming levothyroxine versus placebo. A total of 44 fatal and non-fatal CV events were observed after a median follow-up of 17 months without any relevant difference between the two groups. Twenty-one deaths for any cause occurred during the follow-up (of which four cardiovascular deaths) without any relevant differences between the two groups. Similarly, the cases of new-onset atrial fibrillation and heart failure were equally distributed between the two groups Table 3.The role of SCH in the pathophysiology of chronic disorders, such as CHF has been well-recognized. Nevertheless, it is unclear whether levothyroxine treatment may have positive or rather detrimental effects on cardiovascular prognosis in this setting.Current evidence suggests that subclinical thyroid dysfunction, mostly SCH, increases along with advancing age, and the same is for CHF. A relevant proportion of patients diagnosed with both conditions is, hence, expected, especially among elderly patients (>70 years). Timely recognition of thyroid disorders in CHF patients is suggested in order to provide adequate treatments. However, the management of thyroid disorders, including SCH, is based on general recommendations instead of specific findings.Besides the mechanistic effects of thyroid hormones on myocardial remodeling, cardiac pump efficiency, and hemodynamic , the effCHF is also characterized by reduced T3 circulating levels, and the severity of left ventricle dysfunction  is paralleled with the seriousness of T3 deficiency. This condition is also known as the euthyroid sick syndrome, in which existing thyroid hormone imbalance does not reflect on actual hypothalamic-pituitary-thyroid axis dysfunction. The euthyroid sick syndrome is usually observed in acute and chronic severe diseases other than CHF, such as sepsis, undernourishment, and advanced malignancies. The role of the euthyroid sick syndrome in such severe clinical contexts is still debated, as it is unclear whether low T3 levels represent a consequence of the underlying diseases or it may contribute to poor prognosis. At the cardiovascular site, thyroid hormones are essential to sustain cardiocirculatory efficiency. As cardiac myocytes lack substantial levels of deiodinase, intramyocardial conversion of T4 in T3 is negligible; thus, systemic deficiency of T3 substantially reflects on intramyocardial T3 insufficiency.Observational prospective data suggest that hospitalized patients with heart failure and low T3 levels are at higher risk of all-cause and cardiac mortality than patients with normal levels of T3, thus confirming the protective role of T3 at the myocardial site . AlthougOur systematic review has been conceived to respond to the above-mentioned questions and search focalized on the effects of levothyroxine replacement in a population with CHF and SCH in terms of hard end-points, such as all-cause and CV mortality, CV events, and progression of heart failure. The results showed that most of the evidence in the field is provided by spontaneous trials focusing on surrogate end-points  rather than consistent ones.Two studies were finally included in this systematic review, despite some limitations: one RCT and one observational nationwide cohort study. The two studies are clinically diverse due to different designs, very different study populations, and comparisons, so a meta-analysis appeared inappropriate to provide a reliable synthesis.In Zijlstra et al., the study population had baseline SCH (TSH 4.6 – 19.9 mUI/mL), but only a minority of them had background CVD (35.9%), and only 38 patients had a history of CHF. Although the objective of this study was to determine the effects of levothyroxine compared to placebo on cardiovascular outcomes in older adults with SCH, the trial was designed to combine data from other two previously published RCTs with different aims , 49. In In Einfeldt et al., data were extracted from five registries  and included participants who had received a diagnosis of heart failure after the first hospital admission. The study purpose was to assess the effect of levothyroxine compared to no treatment on several hard CV end-points, but no information about the background thyroid function was available and, therefore, the number of patients with SCH is unknown. As another important issue, levothyroxine prescription may not be necessary a surrogate of hypothyroidism since levothyroxine could be prescribed to achieve TSH suppression . These data are lacking, affecting possible conclusions (indirectness of results). The statistical relevance of findings in a relative reduction in the risk of all-cause and CV mortality, MACE, and myocardial infarction could be mainly attributable to the considerable sample size of the study population. However, the clinical relevance of these results appears limited, especially considering the scant difference in the absolute risk reduction of observed events and given the increased incidence rate ratios of these events in the group of patients assuming levothyroxine compared with no treatment. Although the two study designs appear as close to the clinical question expressed in our PICO, the results of this systematic review suggest the existence of important limitations in terms of study population (both), intervention , and imprecision of results . Indirectness and imprecision of results characterize the findings of this systematic review, and the overall quality of evidence assessed according to the GRADE methodology is very low.In conclusion, current data do not draw reliable assumptions in this field, and the lack of evidence did not lead to either recommend/suggest or against the treatment of SCH in CHF patients.Specific clinical trials, both randomized and non-randomized intervention trials, are needed to define the role of levothyroxine treatment in patients with SCH and CHF. The study design should include a CVOT with a precise definition of the study population, criteria for both SCH and CHF, and outcomes . Also, dose-response trials could be useful to potentially identify a better TSH target for a safer prescription of levothyroxine in this clinical setting.Scopus id: Vincenzo Triggiani, 6603380071. Antonio Cittadini, 57200895552. Guiseppe Lisco, 57203761410.The raw data supporting the conclusions of this article will be made available by the authors, on reasonable request.VT conceived the systematic review; GL and VT searched databases and selected clinical trials after pre-specified critical appraisal; GL drafted the manuscript; VT and AC read the full text and provided feedback. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chronic kidney disease (CKD) is a global health problem, affecting more than 850 million people worldwide. The number of patients receiving renal replacement therapy  has increased over the years, and it has been estimated that the number of people receiving renal replacement therapy will more than double from 2.618 million in 2010 to 5.439 million in 2030, with wide differences among countries. The main focus of CKD treatment has now become preserving renal function rather than replacing it. This is possible, at least to some extent, through the optimal use of multifactorial therapy aimed at preventing end-stage kidney disease and cardiovascular events. Sodium/glucose cotransporter 2 inhibitors (SGLT2i) reduce glomerular hypertension and albuminuria with beneficial effects on progression of renal damage in both diabetic and non-diabetic CKD. SGLT2 inhibitors also show great benefits in cardiovascular protection, irrespective of diabetes. Therefore, the use of these drugs will likely be extended to the whole CKD population as a new standard of care. Chronic kidney disease (CKD) is a global health problem, affecting more than 850 million people worldwide . CKD morThe Global Burden of Disease study has shown that, from 1990 to 2016, the incidence of CKD increased by 89% to 21,328,972, prevalence increased by 87% to 275,929,799, death due to CKD increased by 98% to 1,186,561, and disability-adjusted-life years increased by 62% to 35,032,384 worldwide mainly because of population growth and aging [Management of CKD has changed in the last 30 years. Thirty years ago, management was mainly focused on dialysis because medical (conservative) therapy was considered ineffective even for moderate degrees of CKD (serum creatinine level ≥ 1.5–2.0 mg/dL) . HoweverUnfortunately, however, management of CKD remains suboptimal because of numerous unmet needs. First, awareness of CKD is still low. Despite the increasing burden, CKD remains substantially underdiagnosed, particularly in the earlier stages where there is the greatest potential to slow progression –16.In Italy, awareness of CKD is estimated to be overall low (less than 10% of patients affected by CKD), and even in the more advanced stages (less than 20% at CKD stages 3–5) . This isAn important problem related to low awareness is the late referral of patients with CKD to nephrologists. It has been shown that early referral leads to a reduction in mortality and hospitalization, whereas unreferred patients have a higher risk of developing ESKD and a higher mortality rate –20. On tAn additional but relevant barrier to efficacious treatment of CKD is the suboptimal effectiveness of current nephroprotective agents. In the last decades, many randomized clinical trials (RCTs) testing new therapies have failed to demonstrate efficacy and have raised concerns on treatment-related adverse effects. On the other hand, sodium/glucose cotransporter 2 inhibitors (SGLT2i) and atrasentan have shown positive effects. The positive results obtained by atrasentan have not translated to marketing of the drug for use in clinical practice due to the reduced interest by the producer related to expiration of the atrasentan patent . TherefoThese concepts have recently been highlighted by the new guidelines on diabetic kidney disease (DKD), which recommend treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for CKD patientswith diabetes and albuminuria. According to the guidelines, these medications must be titrated to the highest approved tolerated dose and every effort should be made to maintain this therapy . NeverthFinally, large gaps exist in the  care of non-diabetic CKD patients . More CKThe cost of CKD care is high, especially when prevention strategies are not implemented . In the Elshahat and colleagues  estimateCKD is a public health problem, which involves not only nephrologists but also GPs and numerous non-nephrologist clinicians and diabetologists . It has For the reasons mentioned above, early identification of CKD by screening for kidney disease, followed by risk stratification and treatment, has the potential to substantially reduce the morbidity and mortality of CKD and its related complications, such as CV disease, as well as the costs related to the management of advanced CKD. However, there is no accepted systematic strategy for early detection and treatment of CKD.Despite effective methods to diagnose and treat CKD in its earliest stages, there is a lack of consensus on whether health systems and governments should implement CKD screening programs. Professional associations have been discordant on whether or not to screen for CKD . In partEarly Identification and Intervention in CKD”. Three themes mainly related to the patients were highlighted during the conference as being important underlying principles for CKD screening strategies: patients overwhelmingly prefer earlier CKD screening and diagnosis; patient education has the potential to improve self-management and disease prognosis; economic rationale must favor some program of early CKD screening/risk stratification/treatment, given the costs of kidney failure to health care systems and society [To address this ongoing controversy, in October 2019, the Kidney Disease: Improving Global Outcomes (KDIGO) organization held a Controversies Conference entitled “ society . The con society .Efforts for the early detection of CKD should first be implemented in individuals with established CKD risk factors, mainly hypertension, diabetes and CV disease, given the higher expected prevalence of CKD among these individuals. Identifying and treating all cases of CKD would be the most complete approach to improving kidney health and reducing the burden of kidney disease. However, population-wide CKD screening  programs are known to have potential drawbacks, including higher costs and greater barriers to implementation than targeted high-risk screening. CKD screening and treatment programs should also be implemented in other high-risk individuals and populations based on comorbidities, environmental exposures, or genetic factors. CKD screening for persons with these risk factors should be guided by tailored clinical assessment and joint decision making, rather than a uniform approach. In these patients, the initiation, frequency, and cessation of CKD screening should be tailored based on kidney and CV risk profiles and individual preferences. Moreover, the timing and frequency of the screening should be tailored based on the patient’s characteristics:  the point in life when screening should begin should be based on the estimated likelihood of that individual having CKD, rather than on age alone; the frequency of repeat testing should not be uniform for all persons, but rather should be guided by each individual’s risk of developing CKD, based in part on the results of previous testing .2 and ACR < 30 mg/g [The diagnosis of CKD among older adults is currently a controversial topic, as they experience the greatest burden of CKD and are at the highest risk for certain complications, such as CV disease and ESKD. There is concern that CKD is overdiagnosed among older adults and there have been calls for an age-adapted definition. However, underdiagnosis of CKD in older adults also carries consequences because older adults have the highest prevalence of CKD, and CKD has an impact on their physical and cognitive functions, medication safety, and CV prognosis. Although there is potential harm associated with overdiagnosis of CKD in older adults, CKD should be properly diagnosed and risk stratified in older adults using all available measurements, including cystatin C testing in those with a serum creatinine-based eGFR of 45–59 mL/min per 1.73 m 30 mg/g .For the reasons mentioned above, CKD screening and risk stratification must consist of an assessment of both eGFR and urinary albumin-creatinine ratio (UACR). However, despite guideline recommendations, many clinicians currently fail to assess albuminuria in patients with reduced eGFR or diabetes .Early diagnosis is crucial to prevent progression of CKD. GPs are the starting point in CKD patient care, therefore they require some skills to guarantee the best management of the disease by choosing the right treatment and avoiding progression, complications, and dialysis. Serum creatinine levels should be carefully evaluated, and values should be interpreted according to the patient’s muscle mass, age, limb amputation, and height . GPs sho2, as well as persistent proteinuria predict a poor outcome of CKD [Extensive evaluation of patients with a decrease in GFR and proteinuria is suggested in all cases. A persistent GFR of < 60 mL/min per 1.73 me of CKD . Thus, qe of CKD .Frequent follow-up is fundamental for patients with early-stage CKD to slow progression and avoid complications. In this scenario, some nephrotoxic medications -related outcomes. In most trials, a risk reduction for major adverse cardiovascular events (MACEs), i.e., myocardial infarction, stroke, or CV death, was demonstrated . Some ofThe CREDENCE study was the first double-blind randomized trial designed to evaluate the effect of canagliflozin on renal outcomes in people with type 2 diabetes and eGFR of 30 to < 90 mL/min and albuminuria. The primary outcome was a composite of ESKD, a doubling of serum creatinine level, or death from renal or cardiovascular causes; the secondary outcomes were a renal-specific composite , a composite of CV death or hospitalization for heart failure, all-cause mortality, a composite of CV death, myocardial infarction, or stroke. The study involved 4,401 patients with type 2 diabetes and albuminuric kidney disease who were randomized to receive canagliflozin (100 mg daily) or placebo. The results showed a decrease in the risk of kidney and CV events  in patients treated with canagliflozin compared to the placebo group .P = 0.11 for superiority). In the subgroup of patients with CKD, the results were similar  [The VERTIS CV trials randomly assigned 8246 patients with T2D and atherosclerotic cardiovascular disease to receive two doses of ertugliflozin or placebo. The primary outcome was the noninferiority of ertugliflozin to placebo with respect to a composite CV end-point . Altogether, 1199 patients who were randomized to Ertuglifozin and 608 who were randomized to placebo had an eGFR < 60 ml/min. The study showed that among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events  .2 of body surface area, new onset ESKD, or death from renal or CV causes) and death from any cause. The results showed a decreased rate of CV death or hospitalization in patients treated with dapagliflozin compared to those treated with placebo [DECLARE-TIMI 58 was designed to evaluate the effect of dapagliflozin on CV outcomes in patients with type 2 diabetes. Participants were randomized to receive dapagliflozin or placebo. The primary outcome was a composite of MACE and death or hospitalization for heart failure. Secondary outcomes were a renal composite , with or without type 2 diabetes. Moreover, 48% of patients had eGFR < 60 mL/min. Patients were randomized to receive empagliflozin (10 mg once daily) or placebo, as well as the standard of care. The primary outcome was designed as a composite of CV death or hospitalization for worsening heart failure. Patients treated with empagliflozin presented a lower risk of CV death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of type 2 diabetes .DAPA HF was a phase 3 study that evaluated the effect of dapagliflozin on CV outcomes and mortality in people with HFrEF, with or without type 2 diabetes. Forty-one percent of patients had eGFR < 60 mL/min; 4744 participants were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo and the composite of worsening heart failure or CV death was analyzed as the primary outcome. The results showed that the risk of worsening heart failure or death from CV causes was lower among the patients enrolled in the treatment group compared to those in the placebo group, regardless of the presence or absence of type 2 diabetes [The SOLOIST WHF trial was designed to evaluate the efficacy and safety of SGLT2 inhibitors after an episode of decompensated heart failure. It was a multicenter, double-blind trial that enrolled 1222 patients randomized to receive sotagliflozin or placebo with follow-up for a median of 9 months. The primary outcome was the total number of deaths from CV causes, hospitalizations, and urgent visits due to heart failure. The results showed the efficacy of sotagliflozin in decreasing deaths, hospitalizations, and urgent visits due to CV causes . The stuDAPA CKD was a double-blind, placebo-controlled, phase 3 study that assessed whether treatment with dapagliflozin, compared to placebo, reduced the risk of renal and CV events in CKD patients with or without type 2 diabetes. The primary outcome included a composite of CV and renal outcome, such as a sustained decrease ≥ 50% in eGFR, ESKD, renal or CV death. The secondary outcome was CV death or hospitalization for heart failure. The results showed that the effects of dapagliflozin were similar in participants with and without type 2 diabetes. Moreover, no differences were found between patients with eGFR > 45 mL/min or < 45 mL/min, or between patients with proteinuria > 1000 mg/day or ≤ 1000 mg/day .Recently, a prespecified subgroup analysis was conducted to evaluate the effects of dapagliflozin on kidney, CV, and mortality outcomes according to the presence or absence of type 2 diabetes and according to the underlying cause of CKD, such as diabetic nephropathy, chronic glomerulonephritis, ischemic or hypertensive CKD, or from other or unknown causes. A total of 386 study sites in 21 countries were included in the analysis. The results showed a reduction in major adverse kidney and CV events, as well as in all-cause mortality in CKD patients, with or without diabetes . A post-P < 0.001), regardless of the presence of diabetes [The results from the EMPEROR-Preserved trial were published recently. This was a double-blind study that included 5,988 patients with class II–IV heart failure and an ejection fraction of more than 40%. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or placebo, in addition to their usual therapy. The aim of the study was to evaluate the effects of empagliflozin on major heart failure outcomes in patients with heart failure with preserved ejection fraction . The resdiabetes . A lowerdiabetes . InteresThe clinical studies mentioned above are summarized in Table In general, some heterogeneity across the different classes of SGLT2 inhibitors for selected outcomes has been found , which requires further exploration. On the other hand, other CV benefits, such as reduction in hospitalization risk for heart failure, showed only moderate heterogeneity among the drugs .Blood pressure reduction, glucose lowering, and RAAS inhibition have shown limited effectiveness in the prevention and treatment of DKD. Accordingly, there has been only modest improvement in the prevention of ESKD over the last 2–3 decades  may reduce the benefit of the treatment, and especially so in patients with minimal or no albuminuria . It has 2. However, glycosuria and the glucose-lowering effect of SGLT2is are greatly reduced when GFR is below 45 ml/min. Thus, renal protection by SGLT2 inhibitors seems to be independent of the urinary excretion of glucose as well as of the glucose-lowering effect [A meta-analysis of available Cardiovascular Outcome Trials suggests that renal protection is maintained even when eGFR is < 60 mL/min per 1.73 mg effect .In conclusion, SGLT2 inhibitors have rapidly become the standard of care for DKD to delay progression to ESKD, even when a reduction in GFR limits their antihyperglycemic effect. Although this class of drugs has only been tested on top of RAAS inhibitors (and not in head-to-head comparisons), by indirect comparison it appears that SGLT2 inhibitors have a much greater renal protective potential compared to ACE inhibitors and ARBs (about 40% reduced rank regression (RRR) compared to 15–18%). Furthermore, RAAS inhibitors are not for all patients as they are less effective in the non-albuminuric phenotype and may worsen GFR in ischemic nephropathy. Conversely, SGLT2 inhibitors show a better safety profile than RAAS inhibitors.Moreover, a prespecified analysis of the DAPA CKD trial aimed to evaluate the effects of dapagliflozin on kidney, CV, and mortality outcomes, regardless of the presence or absence of type 2 diabetes. The study, which involved more than 4,000 patients , showed a reduction in the risk of major adverse kidney and CV events and all-cause mortality in patients with diabetic and non-diabetic CKD . InteresThis new vision of nephroprotective therapy encompasses the need to shift from testing a single intervention to evaluating the effectiveness of multiple interventions under the umbrella of “personalized medicine”. It is in fact growing the hypothesis of gaining better renal and patient outcomes when SGLT2 inhibitors are combined with low protein diets , 74, thaIt is worth noting that the guidelines of of the main scientific associations have recognized the importance of using this class of drugs in diabetic patients with CV diseases and/or CKD. The 2019 European Society of Cardiology Guidelines  recommenCKD management has changed drastically during the last 30 years, shifting the focus from renal replacement therapy to preservation of renal function. This is possible through the optimal use of multifactorial therapy, which aims to prevent ESKD and reduce the risk of a CV event. Unfortunately, numerous unmet needs are involved in the non-optimal management of the disease. First, there is little awareness of CKD, together with the related problem of the late referral of patients with CKD to nephrologists.On the other hand, early identification of CKD by screening for kidney disease, followed by risk stratification and treatment, offers the potential to substantially reduce the morbidity and mortality of CKD, its related complications, and the high cost of dealing with advanced CKD. Efforts for early CKD detection should focus on individuals with established CKD risk factors. Because GPs are the first to be involved in the care of patients with CKD, they need to acquire some skills to guarantee the best management of the disease, choosing the right treatment to avoid CKD progression, complications, and dialysis. In addition, better communication between GPs and nephrologists, together with early treatment could positively affect the outcome of CKD and improve nephroprotection.https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga). Accordingly, future guidelines will likely recommend the use of SGLT2 inhibitors also in CKD patients without type 2 diabetes. The future challenge for clinical research will be to identify the best combination of SGLT2 inhibitors with other traditional (dietary protein restriction and RAAS inhibitors) and non-traditional  nephroprotective interventions. Ongoing trials will shed light on the effectiveness of the combination of SGLT2 inhibitors with the MRA, Finerenone (CONFIDENCE study-NCT05254002), and the ERA, Zibotentan (ZENITH study- NCT04724837).Finally, the suboptimal effectiveness of current nephroprotective agents  is still an important barrier to the effective management of the disease. SGLT2 inhibitors, which were originally developed to treat type 2 diabetes, have demonstrated protective cardio-renal benefits and may aid in weight loss without causing marked hypoglycemia. Despite their benefits, prescription of these agents is still low, even among eligible at-risk patients . Numerou


Asthma is a disease with high incidence and prevalence, and its severe form accounts for approximately 10% of asthmatics. Over the last decade, the increasing knowledge of the mechanisms underlying the disease allowed the development of biological drugs capable of sufficiently controlling symptoms and reducing the use of systemic steroids. The best-known mechanisms are those pertaining to type 2 inflammation, for which drugs were developed and studied. Those biological treatments affect crucial points of bronchial inflammation. Among the mechanisms explored, there were IgE , interleukin 5 (Mepolizumab and Reslizumab), interleukin 5 receptor alpha  and interleukin 4/13 receptor (Dupilumab). Under investigation and expected to be soon commercialized is the monoclonal antibody blocking the thymic stromal lymphopoietin (Tezepelumab). Seemingly under study and promising, are anti-interleukin-33 (itepekimab) and anti-suppressor of tumorigenicity-2 (astegolimab). With this study, we want to provide an overview of these drugs, paying particular attention to their mechanism of action, the main endpoints reached in clinical trials, the main results obtained in real life and some unclear points regarding their usage. Asthma is a chronic airways disease, driven by inflammation and characterized by bronchial hyperresponsiveness and reversible expiratory flow limitation . AlthougThe increasing knowledge of the pathogenic mechanisms of asthma allowed us to identify several biochemical processes underlying bronchial inflammation. Mainly, two different groups of asthma phenotypes were identified in relation to the inflammatory pathway involved in the immunity cascade. These two groups are named T2 or T2-high (eosinophilic) and non-T2 or T2-low . The T2 Before diagnosing a patient with severe asthma, an accurate therapy titration up to the maximal dosage and a correct adherence to the prescribed therapy are absolutely necessary . Precautp value 0.002) [Omalizumab (OMA) was the first humanized recombinant MAB approved for patients with severe uncontrolled allergic asthma. It binds circulating IgE, inhibiting their binding to the high-affinity receptor on mast cells and basophils . OMA is e 0.002) .p < 0.001), fewer hospitalizations (reduction of 81.9%), and clinically significant improvement in ACT scores when compared with the 12 months before treatment [The favorable results observed in clinical trials were confirmed by numerous real-life investigations carried out worldwide, such as the PROSPERO study including 806 patients taking OMA for 12 months and experiencing a significant reduction in exacerbations  is a humanized monoclonal antibody, belonging to the class of IgG1κ, able to block the interaction between the α-subunit and IL-5R on the eosinophil cell surface. The inhibiting action of the drug induces an inactivation of eosinophil maturation, activation and growth [d growth ,33. MEP Similarly to the previously mentioned drugs, MEP trials had, as their primary endpoint, the efficacy of the drug in reducing exacerbations and the role of the drug in OCS sparing. After questionable results, in a patient sample pool that was selected , the regThe real-life experience of MEP highlighted interesting aspects for which, at the moment, no in-depth analysis has been carried out in the RCTs. Pharmacoeconomic surveys highlighted how virtuous the drug is and capable of self-financing part of the annual expenditure, even if only by reducing the indirect costs due to absenteeism from work and not even taking into consideration the amount that could be saved in terms of reduction of comorbidities from chronic steroid therapy . In addiReslizumab (RES) is an MA, belonging to the class of IgG4κ, which, as well as MEP, prevents the binding of IL-5 to its receptor alpha [p < 0.0001) versus placebo [or alpha . Despiteor alpha  for the or alpha . The cutor alpha . Another placebo . Long-te placebo ,60. As for MEP, RES demonstrated efficacy and efficiency in real life evaluations, also showing a good short- and long-term safety profile .Benralizumab (BEN) is a humanized, afucosylated monoclonal antibody able to bind the alpha subunit of interleukin-5R; it is also an anti-eosinophilic drug, but with a different mechanism than those described above. The binding of eosinophil’s alpha subunit can generate apoptosis through antibody-dependent, cell mediated cytotoxicity. Although at the blood level, the eosinophil count, after administration of the drug, falls to zero, bronchoscopic studies demonstrate that eosinophilia reduces more than 90% of airway mucosa and sputum [d sputum . The efficacy of BEN was confirmed in clinical trials and real-life settings. The most important trials, CALIMA and SIROCCO, demonstrated the role of the drug (30 mg subcutaneously first every 4 w for 3 months and then every 8 w) in reducing exacerbations, improving Forced Expiratory Volume in the 1st second (FEV1) and reducing the use of OCS in treated patients ,51. As for the other drugs, and also for BEN and RL, evidence of their efficacy as described in clinical trials is confirmed . SimilarDupilumab (DUP) is a fully human monoclonal antibody binding IL-4Rα that, by being common to both IL-4 and IL-13, is capable of inhibiting the signaling of both ,11. DUP Although there are few studies, considering the brief commercialization of the DUP, in this case, the real-life studies have also allowed us to confirm the effectiveness of the drug. The authors of a multicenter work, lasting for 1 year, also proved the drug’s safety in patients who have experienced hypereosinophilia, with values higher than 1500 cells/uL (25% of the sample) .As previously mentioned, the role of cytokines produced by epithelial tissue has been found to be central in the development of the disease and together with IL-4, IL-5 and Il-13, also IL-25, IL-33 and TSLP were identified as possible therapeutic targets in asthma. In severe asthmatic patients, RCTs evaluated the efficacy of anti-TSLP (tezepelumab), anti IL-33 human monoclonal antibody (itepekimab) and an anti-IL-33r  (astegolimab). RCTs with Tezepelumab demonstrated a reduction of annualized asthma exacerbation rate by 56%, in patients with more than 300 eosinophils/µL, treated with 210 mg of drug administered subcutaneously every 4 weeks and by 41% in the one with less than 300 cells/µL . In clinAnti IL-33 targeted drugs, Itepekimab, was evaluated at a dose of 300 mg, with a biweekly subcutaneous administration, in moderate-severe asthmatic in therapy with ICS and LABA . Astegolimab, administered subcutaneously every 4 weeks at the dose of 70 mg or 490 mg (but not 210 mg), is able to decrease exacerbations, in comparison to placebo administration, in a phase 2b RCT involving patients with severe asthma, also including those with low eosinophil counts .That described so far clearly demonstrates the efficacy of biologic drugs in the treatment of patients with severe type 2 asthma . The mecMonoclonal antibodies have been found to be effective drugs in adjunctive therapy for uncontrolled severe asthma in individuals with type 2 inflammation.Indeed, the drugs that are currently on the market showed a good efficacy and safety in controlling the exacerbations, reducing the use of systemic corticosteroids and improving the quality of life of regularly treated patients. In the near future, other drugs will be available in order to offer a therapeutic alternative, and also in patients for whom the current therapies are not sufficient and, in some cases, even for those who are found to have an endotype more distant from type 2 inflammation. For these patients, the therapeutic choice remains limited. With the continuation of this research, it will also be possible to provide answers to questions that are still unanswered, such as the duration of the therapies and what the process of choice of biological drugs in patients who have the characteristics to respond to multiple drugs can be.