Lithium‐based batteries possessing energy densities much higher than those of the conventional batteries belong to the most promising class of future energy devices. However, there are some fundamental issues related to their electrodes which are big roadblocks in their applications to electric vehicles (EVs). Nanochemistry has advantageous roles to overcome these problems by defining new nanostructures of electrode materials. This review article will highlight the challenges associated with these chemistries both to bring high performance and longevity upon considering the working principles of the various types of lithium‐based  batteries. Further, the review discusses the advantages and challenges of nanomaterials in nanostructured electrodes of lithium‐based batteries, concerns with lithium metal anode and the recent advancement in electrode nanostructures. In contrast, to improve the specific capacity of Li‐ion battery new anode materials are introduced which store Li+ in different way.+ by breaking the bonds between the host atoms, thus enhanced the capacitive performance of electrode.–1, respectively but result in volume expansion up to 300%.The huge consumption of fossil fuels by the increasing population is ringing the alarm bell for the environment. Thus, green energy has attracted intensive attentions since current “fossil fuels” are being depleted with the developing society and concerns about environment have become serious.+ with oxygen and sulfur give rise to new types of lithium‐based devices named as lithium air (Li‐air) and lithium sulfur (Li‐S) batteries.–1 for Li‐air and Li‐S batteries can be achieved considering a complete conversion reaction of Li+ with oxygen and sulfur to form Li2O2 and Li2S, respectively.–1) reaches to the energy density of the gasoline (13 000 Wh kg–1).2) is a great challenge associated with Li‐air battery since air is a mixture of various gases and these gases act as poison for Li‐air cell and destroy its capacity resulting in poor cyclic life.To overcome the challenges and limitations of alloy forming negative electrodes of Li‐ion battery, new energy storage mechanisms are introduced utilizing the similar concept with Li‐ion battery to improve its energy density equivalent to that of gasoline.This review summarizes the recent developments in lithium‐based batteries, different chemistries of lithium‐based batteries and electrode nanostructures, challenges associated with these nanostructures and their solutions. It includes the contributions both from the author's group and scientific community to highlight the advancement and important aspects on lithium‐based batteries. It will first explain the working principals of lithium‐based batteries . It will also outline the various challenges associated with lithium‐based batteries both at electrode structure and cell operation. Moreover, it will present the advantages and disadvantages of nanostructures over the conventional anode and cathode materials. Further, it will summarize the various methodologies developed to overcome the challenges associated with electrode nanostructures both at the level of synthesis and structure design. The controlled synthesis leading to advanced electrode materials and catalysts, providing an ideal system to study synergistic effect of various hybrid structures for enhanced performance. The review will lead towards the future of lithium‐based systems  with possible solution to the associated problems.2The working mechanism and structure of each type of cell is elaborated in the respective sections. In general all types of batteries  have similar cell assembly that consists of two electrodes  and electrically insulating separator but are permeable for ions and electrolyte. However, keep in mind that Li‐air cell also needs a continuous oxygen supply. But the cell chemistries in all these lithium‐based systems are quite different from each other; this is explained below.2.1+ moves spontaneously from the negative electrode towards the positive one through the electrolyte. Consequently, an electron flows from the negative to the positive electrode via an external circuit generating an electrical power, as shown in Figure+ and electrons as they move from the positive to the negative electrode. The chemical reactions occurring both at the anode and the cathode of a commercial Li‐ion battery is represented below.x is equal to 0.5 then the half reaction at the negative electrode will deliver its theoretical capacity of 372 mAh g–1. Furthermore, in the case of overcharge up to 5.2 V and over‐discharge or supersaturating the cathode, this results in the production of irreversible byproducts leading to destruction of cell. The respective chemical reactions are presented in Equations The Li‐ion battery received tremendous attention of researchers and became the major source of energy storage in portable electronics after the first release by the Sony company in early 1990s.2.22. The general cell assembly for Li‐air battery is presented in Figure + is released from the anode and reacts with dissolved oxygen in the electrolyte on the surface of the porous cathode catalyst.2O2) has very low solubility and deposits on the pores of cathode catalyst.The Li‐air battery consists of a similar assembly to Li‐ion battery: an anode of lithium metal or lithiated compounds of other metals, an electrolyte, a separator and a “breathing” air electrode that has the ability to catalyze O2.3+ and electrons in the system. Thus, as the produced Li+ and electrons move towards the positive electrode through the electrolyte and external circuit, this respectively results in an electrical current in the circuit. Consequently, Li+ and electrons reduce the sulfur at the cathode surface to produce the lithium sulfide. The chemistry of the overall cell is explained by the chemical reactions presented in Equation A Li‐S battery is composed of four main components similar to other lithium‐based batteries: an anode composed of lithium metal/lithiated compound of other metals, an organic electrolyte, a separator and a cathode consisting of sulfur or hybrids of sulfur with other metals/carbon. Cell operation starts with the discharge reaction due to the charged state of sulfur cathode. Initially at the anode, the oxidation reaction occurs to release Liα‐S8 is most stable at room temperature and when react with Li+ cyclo‐S8 reduces and form higher order polysulfide anions. Further with continuous reaction lower order polysulfide are also formed which are soluble in organic electrolytes.Sulfur atoms show strong tendency to catenation and form various homo‐atomic chains or cyclic rings. Among them orthorhombic 3+ for both insertion and conversion processes ultimately providing oppurtunities to tailor high energy density/power density devices for practical applications. However, a great advancement in the field of lithium‐based batteries has overcome many of the challenges that are big obstacles in their application to the field of portable electronics or short distance traveling EVs. Despite these considerable advancements, there still remains a number of challenges to be addressed before the usage in long distance traveling or heavy duty storage systems, e.g., storage of electricity in grid station or from the intermittent energy productions systems such as solar cells.Future research demands nanostrucutured materials with high active surface areas which could offer large sites for intercalation of Li3.1The major challenges associated with electrode materials of Li‐ion battery are listed here with thier possible solutions. Due to these problems, the obtainable capacity is lower than the theoretical capacity and results in lower energy density that is insufficient for the intended applications. A low energy efficiency could arise due to large polarization, which becomes more severe at higher charge–discharge rates along wtih poor cyclic life due to capacity fading with successive cycles.3.1.1It is a well‐known fact that most of the electrode materials bear low conductivities that cause poor conduction of electrons, which affect the storage of lithium. In addition, it is necessary that every material should have sufficient ability to efficiently receive the electrons and to deliver to the external circuit. Furthermore, due to low intrinsic conductivities, several materials have failed to utilize all of their redox sites, as no pathways exist for electron transfer between redox site and external circuit.3.1.2Lithium storage in several materials strongly depends on their morphology, thus if morphology of electrode material changes during lithium insertions and extraction, it could drastically affect the performance and cyclic life. Furthermore, any phase or morphology changes might cause the aggregation of newly segregated product resulting in loss of the electrical contact, ultimately leading to destruction of cell operation. Further the morphological changes also brings fresh surface of electrode materials in contact with electrolyte that rebuild solid electrolyte interface film (SEI) which cause irreversible loss of capacity.3.1.3+ result in severe volume increase that produces strains in the electrodes. Thus, as a result, isolation of the electrode material from the current collector causes electrical insulation or short circuiting of cell. Further, because of electrical insulation, the inaccessibility of Li+ to access the redox sites in active materials cause drastic capacity fading and poor cyclic life. These volume changes are more associated with the high theoretical capacity materials such as Si, Ge, and Sn.+ and forms thin SEI film on the surface of electrode.+. To this day, there is no good control over the chemical composition, grain size, thickness, and spatial distribution of the SEI film. In this case, nanostructures cause a big problem due to their high surface area and energies, but controlling these factors or protecting the surface with inactive metals or carbon coatings may result in better control over the SEI film.The volume changes of electrode materials during alloying and de‐alloying with Li3.22, N2, NH3, H2O, etc.) decrease their efficiency.In addition to the challenges presented for Li‐ion, the performance of Li‐air battery is also limited  because of some fundamental issues related to its working and operation: it has a much poorer cyclic life than the available Li‐ion battery. These issues are related to obstacles in the air flow, deposition of discharge products and over‐potential with ongoing charge‐discharge process. Further poisoning of cathode catalysts by the other gases present in air  and solid network (electrons). In this regard, microscale materials  with large pores to maintain the flow of required species  and decorated with nanoscale redox active materials (having capability to efficiently reduce the oxygen) are the best options to improve the efficiency and cyclic life of Li‐air battery. However, the deposition of discharge products (Li2O2 or LiO2) on the electrode is another issue that affects the efficiency of cathode catalyst and fade the capacity of the Li‐air battery, resulting in limited cyclic life. Basically, these depositions block the air pathway and cover the redox sites, thus inhibiting further catalysis of oxygen. Furthermore, the deposited product makes a continuous layer which causes electric shut down of battery due to its electrical insulation properties; further, the resistance of Li2O2 increases with increase of the thickness of the deposited film and causes a drop in working voltage. It is observed that Li2O2 is a bulk insulator in nature with a bandgap (DFT: > 1.88 eV and GW: 4.91 eV) which emphasizes that small increase in Li2O2 thickness will largly affect the electronic conduction. The proposed solution to this problem is to develop bi‐functional catalysts that have the ability to undergo oxygen reduction (discharging) and, in the reverse process, evolution of oxygen (charging) by breaking the deposited products and making the air flow pathways clear for the next discharge process.In contrast to the Li‐ion battery, the electrode of the Li‐air battery should have sufficient porosity and high conductivity to maintain the continuous transport of oxygen, Li3.2.2To commercialize the Li‐air cell, it is compulsory that it can work using oxygen from atmospheric air and deliver the same specific energy as obtained in the lab utilizing the pure oxygen. But when it is tested in atmospheric air, it fails to deliver the same performance because of insufficient supply of oxygen and presence of unwanted gases. Thus, it requires a compressor for continuous supply of air and purifier to remove the contents of carbon dioxide and water. These unwanted gases react with discharge products and stop the reversible cycling of battery. However, to this day, most of the work has been carried out on the cathode catalyst and electrolytes of Li‐air battery. Few reports have also presented the replacement of lithium metal anode with lithiated compounds to stop severe volume changes and unwanted reactions on the surface of anode, but no progress regarding this issue is reported yet.3.2.32O molecules in aqueous electrolyte is helpful to dissolve the reaction products, and thus inhibits the air blokage and mass loss, but the presence of water drastically affects the stability of the lithium anode. Thus, a sacrificial membrane or development of seramic SEI film can protect the lithium anode. The other class is nonaqueous electrolytes, which are free of water and follow the reaction mechanism through the formation of peroxide that is reversible in storage, but these have limited anodic oxidative stability due to the existance of carbonates. Thus the development of catalyst or electrolyte additives is the possible solution to this problem.An appropriate loading and distribution of an active catalyst on the cathode surface to operate the charging–discharging process is another complication associated with the Li‐air battery. The mostly active catalyst was supported on carbon and then attached with electron collector metal mesh using binder (non‐conductive in nature) similar to that of Li‐ion battery. Thus, homogenous dispersion in proper ratios of these three components to maintain the electrical conductivity is critical as use of a binder decreases the conductivity. To resolve this problem, the catalyst should be grown on a three‐dimensional (3D) carbon network with uniform distribution for direct use, which can provide multiple advantages such as better attachment and distribution of catalyst and free of non‐conductive binder.3.2.4The working electrode potential of the Li‐air battery is 2.6–2.7 V, but it decreases during discharging while increasing during the charging process. This change in potential is called over‐potential and badly affects the performance of Li‐air cell. The over‐potential arises due to the deposition of discharge products  during discharging process and failure of catalyst to completely recover the redox sites during charging. Another reason for increasing over potenstioal is mass and ionic loss due to the blockage of transport pathway by deposited products.3.3−30 S cm–1), higher volume changes (80%) during its conversion reaction with lithium.The Li‐S battery has almost similar challenges as associated with Li‐ion battery because of same working phenomenon and assembly of cell. Most of the challenges are associated with sulfur electrode due to its high resistance . Further as the discharge continue, the larger polysulfide anions are reduced to smaller ones Li2Sx (2 < x ≤ 6). Mostly, two discharge plateaus are present in the discharge curve of Li‐S cell at 2.3 and 2.1 V regardless the type of liquid electrolytes that shows the conversions of α‐S8 to Li2S4 and Li2S4 to Li2S.+ diffusion. This kind of movement further increases the internal temperature of cell and causes the thermal explosions of Li‐S battery.Because of its unique structure sulfur shows strong catenation tendencies, as it forms homoatoms chains and cyclic rings. Among these, 4FigureIt is well‐known fact that nanomaterials have a lot of advantages over their counter bulk materials, especially when we are talking about the electrode materials of lithium‐based batteries. 4.14.1.1Nanomaterials with a high surface‐to‐volume ratio increase the contact area between the electrolyte and electrode, resulting in more exposed redox sites which deliver higher power and energy density. Furthermore, availability of the larger surface area inhibits electrode polarization; in the case of the Li‐air battery, it offers more space for the redox reaction on surface, thus effectively improving the ORR and OER reaction and reducing electrode polarization.4.1.2The low‐dimension materials are mechanically strong and offer high resistance to any structural damage. Furthermore, their structure can easily be tuned to overcome the volume changes of the electrodes of lithium‐based batteries. Nano‐designing also inhibits any phase change of electrode material, thus preventing isolation of the electrode material and resulting in improved electrochemical properties.4.1.3+ storage sites are better and can be selected according to nature of particular materials.Nanomaterials offer new lithium storage mechanisms regardless of the simple accumulation of the ions at insertion sites, such as redox reactions at surface, storage of lithium at interfaces and nanopores which exist inherently in nanostructures. Furthermore, these storage mechanisms have no effect on the structure of electrode material, thus stable charge‐discharge can continue for a long time.4.1.4It is observed that several materials which are inactive in their bulk states towards lithium storage can efficiently store the lithium at nanoscale and can perform the catalysis of oxygen. The reason behind such a shift in the nature of materials at nanoscale is because of the presence of several partially bonded atoms at surface and higher surface energies.4.2As well as various advantages of nanostructures, there are several challenges that need to be kept in mind before establishing a nanostructure for lithium‐based batteries.4.2.1Nanomaterials show higher inter‐particle resistance and decrease the electrical connection among the particles. This resistance further increases if some volume changes occur in the electrode during reversible storage of lithium.4.2.2The smaller dimensions, higher surface energies, larger surface areas, and unsatisfied bonds of surface atoms result in severe agglomeration of nanomaterials that badly affects the lithium storage mechanism.4.2.3Several nanomaterials are thermodynamically unstable under electrical fields, thus critically affecting their use as electrode in lithium batteries.5Nanotechnology has a revolutionary role in determining the new electrode materials and their unique nanostructures to bring breakthroughs in the lithium‐based batteries towards their real applications in EVs. The following sections highlight the recent advancements in the electrode field of lithium‐based batteries including Li‐ion, Li‐air, and Li‐S batteries.5.1–1).2 and carbon (coke) were used as positive and negative electrodes, respectively. The electrolyte was composed of LiPF6 dissolved in a mixture of propylene carbonate and diethyl carbonate.–1).+ storage. Initially, the storage of Li+ occurs through the insertion phenomenon in the existing vacancy in anode materials. However, the low capacity remains a big challenge because most of the vacancies are not available for reversible storage of Li+.+ and the commercially available Li‐ion battery are using same phenomenon of energy storage for portable electronics. Although an improvement in capacity resulted from the alloying mechanism, the concurrent large volume changes that led to the structural disintegration of electrode significantly compromised the performance.+, demonstrating high reversibility with improved capacity.The Li‐ion battery was first introduced in 1991 and became the major energy storage device because of its high energy density 150 Wh kg0 Wh kg–1+. The emergence of graphene in 2004+ and facilitate efficient intercalation kinetics even at higher current densities. It is also observed that graphene offers nice hierarchal structures by simple growth of graphene on graphene and it further avoids the use of a binder , thus bringing a flexible electrode structure that delivers higher performance due to its large surface area.+ storage ability.It is well‐known that conventional graphite cannot deliver high power densities as anode of Li‐ion battery due to sluggish diffusivity of Li3S4 has been considered a promising anode material for Li‐ion battery due to its high theoretical capacity (702.8 mAh g–1). However, capacity fading and poor cyclability because of low conductivity and production of polysulfide anions are big issues related to pure Co3S4.3S4 nanotubes are deposited on graphene using pre‐synthesized sacrificial nanowires (NWs) of Co(CO)0.35Cl0.20(OH)1.10 and C2H5NS as S source.3S4 while helping to preserve its structure. Furthermore, due to the porous nature of graphene, it successfully inhibits the dissolution of polysulfide anions.3S4 electrode as shown in Figure3S4 is another example to demonstrate doped graphene nanoparticles (NPs) composite for Li‐ion battery anode, heteroatom present in graphene sheets provides anchoring sites to NPs.–1), low cost, environmentally benign nature and safety make Ni3S4 a promising candidate for anode of Li‐ion battery. A hydrothermal reaction was carried out to sulfurize the Ni2(CO3)(OH)2 using C2H5NS in the presence of NG at moderate conditions , as confirmed by x‐ray diffraction studies  and capacity retention (98.9 vs. 45.2%) compared to pure Ni3S4  is a good characterization tool to measure the effect of nitrogen doping, removal of oxygenated groups, different phases and to explore the synergism among various constituents of hybrid structure.+ diffusion and conductivity of hybrid, thus improving the cyclic life and performance. Owing to its spatial 2D layered structure and good electronic properties, MoS2 also received tremendous attention from researchers and great advancement occurred to develop MoS2 anode for Li‐ion battery. The unique structures offer sandwich layers of S‐Mo‐S that are attached together by weak Van der Waals attractions with an inter‐layer spacing of 0.62–0.69 nm.2 suitable as anode material application at a low‐potential; during its conversion reaction MoS2 converts to Mo and formation of Li2S occurred by the uptake of Li+.l‐cysteine can easily assist the layer‐by‐layer hybrid formation of graphene and MoS2 and the resulted structure appear as a 3D network that brings very exciting results regarding capacitance, rate capability and improved cyclic life.+ is similar to that of metal sulfides and is distinctly different from the classical storage of Li+ via intercalation and de‐intercalation process.+ reaction with metal oxides and the formation of conversion products  happened.2O causes capacity loss in the initial cycles and results in the formation of insulating layer on the surface of electrode, which results in poor capacity retention. The origins of the irreversible capacity loss in metal oxides were addressed via probing changes in the structural and electronic properties of hollow Co3O4 NPs during its conversion reaction with Li+ using electrochemical Co3O4 transistor devices that function as an anode of Li‐ion battery. It is found that in the first lithiation process, initially conductivity increased due to the production of metallic Co but at the same time a decrease in conductivity was found during de‐lithiation process due to the remittance of Li2O.FigureRedox chemistry via conversion reaction provides higher energy densities, thus a rapid transition in research form intercalation to conversion occurred.+ produce stress in the electrode, resulting in structural disintegration, ultimately leading to battery failure or poor cyclic life. Several strategies have been reported including control on morphology, hybrid structures, coatings, and doping with carbon, highly conductive, hard and inactive metals and void engineered structures to accommodate the volume changes.3O4 was used to assist the 1D growth of Ge/EDA. Further, annealing under reducing atmosphere brings unique structure (0D‐in‐ID) of NWs that are composed of carbon coated NP along with the additional sheath of carbon on NWs. This 0D‐in‐1D structures results in high capacitance with good capacity retention after long cyclic life because carbon coating around individual particles protect surface reactions and maintain faster highway for electron transfer. The void engineering is widely used to accommodate the volume changes of high capacity anode materials.Figure+.2SnO4 was pinned on NG by hydrothermal method and the successive annealing under reducing atmosphere results in Co3Sn2@Co‐NG  elements  have given birth to a new generation of Li‐ion battery electrode materials and have shown effective improvement both in energy density and power density. Due to higher theoretical specific capacities and energy densities, these materials have become the major area of intrest for the research community to develop new electrode materials.m Figure b. To ver+ Figure c. As a r5.22 that displays flat operating voltage of 3.9 V vs. Li+/Li among the most of lithium insertion cathode materials.+ inside the electrode was enhanced by shortening the diffusion path by developing nanostructures. The insertion sites of Li+ are also increased by creating higher vacancies and developing nano‐morphologies of these materials or by increasing inter layer spaces.2, LiMn2O4 is also a strong candidate but display sluggish reaction kinetics and structural instability, which are big limitations towards progress. Recently by controlling the particle size to improve the reaction kinetics and doping of metals to increase the working potential, a unique cathode (Li[Ni0.45Co0.1Mn1.45]O4) material was designed .4 is also considered an optimistic electrode material with a specific theoretical capacity of 175 mAh g–1, but the aforementioned problems are also associated with this advanced cathode material. It was suggested that by tuning its morphology  and developing continuous thin carbon sheath to protect the structure and enhanced conductivity for faster electronic and ionic movements. Simply by changing the time and temperature, two different morphologies were synthesized using high temperature liquid‐phase reduction method to observe the effect of morphology on electrochemical performance of LiFePO4. The rhombic shape nanocrystals shows a higher performance then rod shaped one due to smaller size and higher active sites available on surface. Further, it is also concluded that carbon coating significantly enhanced the capacity and improved the rate capability.4). Escherichia coli bacteria have been frequently utilized to remove the phosphorus contamination from wastewater. These bacteria were used as precursors for the synthesis of LiMPO4 by mixing them with equimolar ratios of metal and lithium ions sequentially and subsequently heating was done to obtain LiMPO4 nanocrystals of 20 nm. The obtained structures contain fully carbon coated particles with coating thickness of 3–6 nm that brings high ionic diffusion in the nanocrystals. The as‐synthesized nanocrystals of LiFePO4 deliver 140 and 75 mAh g–1 specific capacity at 0.1C and 10C, respectively. In contrast to layered transition LiMO and LiMPO, compounds of iron are also promising candidates as cathode of Li‐ion battery due to their higher theoretical energy density and environment friendly nature. The higher energy density of iron compounds (fluoride and sulfide) based on their conversion mechanism instead of traditional insertion mechanism of transition metal oxides and phosphates. As an example, FeF3 delivers large theoretical capacity of 712 mAh g–1 if one considers the complete conversion of FeF3 to LiF and metallic Fe occurring at a voltage regime of 1.5 V by 3e− transfer. However, iron fluoride are large bandgap materials thus brings more difficulties to develop iron fluoride‐based cathodes for Li‐ion battery. Recently, graphene was utilized to overcome the large bandgap to speed up the redox reaction in iron fluoride.3 have severe concerns with environment benignity. Thus researchers explored FeS2 because of its higher theoretical capacity of 894 mAh g–1 compared to that of layered cathode materials that deliver maximum 200 mAh g–1.2 octahedral nanocrystal using polyvinylpyrrolidone (PVP) as solvent and FeCl2 as iron precursor. Sulfur was introduced in the presence of NaOH to convert FeS2  and retention compared to the commercial LiCoO2 (556 Wh kg–1) as shown in Figure The high energy density of Li‐ion battery makes them a promising candidate for EVs, but their low power density brings a hurdle for its application to EVs. The reason behind the low power density of Li‐ion battery is slow reaction kinetics and poor electrical conductivity of cathode materials. The commercial Li‐ion battery cathodes are composed of LiCoOed Figure8a. The5.32O2 that is insoluble in the electrolyte thus deposit on cathode catalyst and block the pathway of air, resulting in failure of battery operation.Figure–1), low over potential increment (≈0.355 V), long cyclic life (200 cycles) and high energy efficiency (86.6%).–1 with longer cyclic life of 50 cycles.The working operation of the Li‐air battery mainly depends on the structure and composition of the breathing air electrode. Because the main product of oxygen catalysis is Li5.4–1), low price, natural abundance and environmentally benignity make sulfur a promising material to be used as electrode in Li‐S battery.–1 and 2800 Wh L–1, respectively by considering the complete formation of Li2S that may be successfully applied to electrify the road transportation.+.2‐LiTFSI] with a hydrofluoroether co‐solvent. The resulted Li‐S battery delivered 1000 mAh g–1 capacity with excellent capacity retention up to 100 cycles.+.Currently a particular attention is devoted to super batteries that have the energy density up to several hundred watt‐hour per kilogram, which are in fact regarded as the sole electrochemical systems. Among these systems, Li‐S battery is at advanced state of development due to a series of recent breakthroughs that overcame several operational issues. The high theoretical capacity 1672 mAh g2 mAh g–1−30 S cm–1) causes the poor transfer capability of ions and electrons of sulfur electrode leading to low capacity and poor capacity retention.2S, different size particles  of Li2S were synthesized by chemical route and then coated with carbon through chemical vapor deposition (CVD) as shown in Figure–1). However, the open ends of graphene cannot control movement of polysulfide anions across the cell and their dissolution in electrolyte. One possible solution to overcome this issue is to use solid electrolyte to further improve the performance by solving the problem of polysulfide anions dissolution but the slow transfer rate of ions remains a point to ponder. Furthermore, the synthesis of graphene sheets with dense nanopores on surface of graphene through chemical activation of rGO via hydrothermal process were achieved.–1) and good cyclic stability. Another rational strategy to overcome the problem of low conductivity, volume expansion and dissolution of polysulfide anions is by developing sulfur‐graphene stacked‐up hybrid structure that is further covered by rGO to stop the leakage of polysulfide anions.2 were deposited by a modified Stöber method. To develop porous carbon tube on it, octadecyltrimethoxysilane was introduced as carbon source and then annealing was done. After etching the SiO2 by NaOH, sulfur was introduced simply by melt infiltration method  hybrid structures were also reported to resolve the concerns related to stability of Li‐S battery, the smaller band‐gap of titanium dioxide can effectively deliver the electrons to sulfur if the sulfur has strong electrochemical coupling with titanium dioxide and shows excellent capacity of 1342 mAh g–1 with capacity retention of 99%.Furthermore, lower conductivity of sulfur , lowest negative redox potential of –3.040 V vs. SHE (standard hydrogen electrode) and lower gravimetric density (0.59 g cm–3) make it a “holy grail” for energy storage systems.+ at the contact surface electrode/electrolyte due to formation of LiOH are the major issues in the application of lithium metal anode for these high energy density devices. Furthermore, these dendrites have higher reactivity and produce the dead lithium from their interface that detach from electrode and does not contribute to capacity.+ from electrolyte. In addition, the SEI film is non‐conductive to electrons thus resistances become larger with the formation of dendrite and increase the diffusion path for Li+ thus slowers the reaction kinetics.6, LiBF4 and HF etc.) to electrolyte, use of elastically strong polymeric electrolytes, nanostructures of lithium containing compounds then the formation of dendrites can control.+/Li, but these kind of coating introduce fundamental issues as reducing lithium diffusion, increase resistances to electrons and also hinders the electrode‐electrolyte redox reaction.7B6 have also been developed to overcome the volume changes and formation of dendrites.2 and current energy distribution to recover the metallic lithium for long cyclic life with excellent capacity retention. FigureThe lithium metal with highest theoretical specific capacity 3860 mAh g0 mAh g–16Thanks to the high energy densities, long cyclic life, safety, and enviromental beniginity of lithium‐based batteries, the dream of a continuous supply of energy to portable electronices and short‐distance traveling EVs is coming true. A series of research has been done to improve the energy storage mechanisim of Li‐ion battery by introducing new nanostructures and their hybrids with graphene/carbon that can overcome several issues, such as structural changes, low conductivity and poor capacity, stability concerns of Li‐air battery by developing new breathing catalyst having the ability of ORR and OER to keep the air pathway clear and limited electronic flow caused by the deposition of reaction products. Further, development of electrolytes and several additives is also helpful to improve the cyclic life of the Li‐air battery. Moreover, polysulfide shuttles are also controlled by developing new hybrid structures of sulfur that limits the dissolution of polysulfide anions. The concerns using lithium metal anode are also resolved by introducing new lithiated anodes for Li‐air and Li‐S batteries. However, to achieve the standards set by USABC, new synthesis methods should be developed for electrode nanostructures that can be industrially acceptable. Definition of new stable designs and/or hybrids of nanostructures of electrodes is needed that can overcome the problems of large volume changes, electrical insulation, formation of homogenous SEI film and meanwhile brings higher packing density along with access to all redox sites for larger volumatric density. Porous breathing cathodes with larger surface area bi‐functional catalysts that can maintain higher electrical conductivity and successfully reduce and oxidize oxygen with ongoing discharge‐charge process. Sulfur containing closed structures should be developed for Li‐S battery that act as micro‐electrochemical reactors, inhibiting the dissolution of sulfur while control its volume change and enanhced its conductivity. Protection of lithium metal anode from side‐reactions to form surface dendrites and conversion to LiOH by reacting with hydroxal ions produced from decomposition of electrolyte at catalyst surface. Future work on lithium‐based batteries should explore the fundamental characterizations of reaction products, the battery chemistry and the stability concerns of electrodes and electrolytes inside the battery with ongoing charge‐discharge process.


PSS)s after the first‐generation sirolimus‐eluting stent, we need a further observation using coronary imaging modalities to evaluate the risk of very late stent thrombosis due to PSSs and to continue or to resume the dual antiplatelet therapy if necessary.If we had a case with angiographic peri‐stent contrast staining( Although the first‐generation drug‐eluting stent (DES), sirolimus‐eluting stent (SES), substantially reduced late loss, and thus, restenosis rate, novel issues such as a risk of very late stent thrombosis (VLST) have arisen A 76‐year‐old male patient with acute ST‐elevation myocardial infarction was transported to emergency center of our hospital by ambulance. He had history of stent implantations with a bare metal stent (BMS) at distal right coronary artery (RCA) 13 years ago and that with two SESs at each of proximal LAD and mid‐LCX 9 years ago in another hospital. He had been taken 100 mg aspirin as a poststent antiplatelet therapy till admission. Emergent coronary angiography showed total occlusion at one SES site of the LAD and in‐stent restenosis (ISR) with 75% luminal narrowing at another SES site of the LCX Fig. A and B. The mechanism of VLST after DES implantation is assumed thrombus formation associated with incomplete neointimal coverage over the stent struts Unfavorable outcomes after SES implantation such as loss of neointimal coverage or ISA might be associated with impaired wound healing response at the stent‐injured vessel sites, including at late‐stage relapse and prolongation of local inflammatory reaction that was strongly suppressed at acute stage after implantation We reported a case with VLST after SES implantation beyond 9 years. It was assumed that the etiology of VLST in this case was due to the late acquired ISA. Using observation by OCT and coronary angioscopy, the different features of angiographic PSSs, ISA and MIH were found in the same patient. If we had a case with angiographic PSSs after the first‐generation SES, we need a further observation using imaging modalities such as OCT and/or coronary angioscopy to evaluate the risk of VLST due to PSSs and to continue or to resume the DAPT if necessary.None declared.MK and SA: managed the patient's course and wrote the primal draft. IK, HN, SK, TN, SY and MS: aided in manuscript editing and also contributed to the literature searching. TI: contributed substantially to make the design of this report and also approved the final version of the manuscript.


The second most common cause of hospitalization due to adverse drug reactions in the UK is renal dysfunction due to diuretics, particularly in patients with heart failure, where diuretic therapy is a mainstay of treatment regimens. Therefore, the optimal frequency for monitoring renal function in these patients is an important consideration for preventing renal failure and hospitalization. This review looks at the current evidence for optimal monitoring practices of renal function in patients with heart failure according to national and international guidelines on the management of heart failure (AHA/NICE/ESC/SIGN). Current guidance of renal function monitoring is in large part based on expert opinion, with a lack of clinical studies that have specifically evaluated the optimal frequency of renal function monitoring in patients with heart failure. Furthermore, there is variability between guidelines, and recommendations are typically nonspecific. Safer prescribing of diuretics in combination with other antiheart failure treatments requires better evidence for frequency of renal function monitoring. We suggest developing more personalized monitoring rather than from the current medication‐based guidance. Such flexible clinical guidelines could be implemented using intelligent clinical decision support systems. Personalized renal function monitoring would be more effective in preventing renal decline, rather than reacting to it. Diuretics can lead to acute kidney injury, which is one of the most common causes of hospital admission due to adverse drug reactions.There have been no published studies investigating the optimal frequency of renal function monitoring in patients with heart failure on diuretics and other potential nephrotoxic agents.There is variability in national and international guidelines regarding monitoring of renal function in heart failure patients with many of these being based on expert opinion.Personalized guidance schemes for monitoring renal function based on patient and disease characteristics, including drug treatment, need to be developed.Heart failure is an important cause of morbidity and mortality in the UK, and is likely to increase in prevalence as the population ages. Heart failure incidence overall is 1%, rising to around 12% in patients over 75 years. It currently affects up to 900 000 patients in the UK Here we review reasons for renal decline in heart failure syndromes and explore the evidence for renal function monitoring, including optimal frequency.An association between decline in cardiac function and renal function is well documented. Heart failure itself is associated with high risk of renal dysfunction and development of CKD Type 1: Acute heart failure causes acute kidney injury (AKI)Type 2: Chronic heart failure causes CKDType 3: AKI or acute renal failure causes acute cardiac failureType 4: CKD causes chronic cardiac dysfunction, including heart failureType 5: An acute or chronic systemic disorder causes both cardiac and renal failure There are five types of CRS, the classification of which reflects the presumed primary and secondary problem The mechanism of renal injury in CRS is not clear but is likely to be multifactorial. The interaction between heart and renal failure can be described in terms of heart failure pathophysiology, renal responsive changes and the drugs to which patients are exposed.Heart failure states cause increased central venous pressure (CVP). As the ventricles dilate and cardiac output decreases, preload increases, which is reflected in increased CVP. This venous back pressure can be transmitted to the renal vasculature causing chronic renal venous congestion, which in turn reduces glomerular blood flow by reducing the pressure gradient between afferent and efferent arterioles In addition, right ventricular dilation in heart failure (which increases CVP) lowers cardiac output by several mechanisms. First, the direct effect of over‐dilation causes decreased ventricular contractility (Frank–Starling relationship) angiotensin, which promotes vasoconstriction, and aldosterone, which promotes sodium retention Changes in renal perfusion are likely to account for much of the renal deterioration in patients with heart failure. However, the situation can be aggravated by drugs used to manage heart failure such as diuretics, which reduce intravascular volume and renal perfusion Drugs used to manage heart failure can reduce renal function by various mechanisms. This is particularly relevant in CRS types 1 and 2 where heart failure leads to renal failure.NKCC transporter in the loop of Henle, resulting in an efflux of water and reduction of intravascular volume. While this is beneficial for symptomatic heart failure with volume overload, it decreases total blood volume and thus reduces blood pressure contributing to renal hypoperfusion and compensatory systemic and renal vasoconstriction to maintain blood pressure. Since the function and perfusion of glomeruli rely on a constant flow from the renal arterioles, any reduction in flow in this way leads to renal decline, and if the patient's compensatory mechanisms fail, it can quickly deteriorate into AKI These drugs promote natriuresis by reducing sodium reabsorption via the sodium–chloride transporter in the distal tubule. Their hypotensive effects may also be useful for achieving blood pressure targets in patients with ischaemic heart disease while the naturietic effect can have protective effects against pulmonary oedema. The hypokalaemic effect can counter‐balance the potassium raising effects of ACEis/angiotensin receptor blockers (ARBs) and potassium‐sparing diuretics These drugs inhibit the ROMK2 to maintain electrical neutrality. In addition, the diuretic‐induced naturesis causes upregulation of ENaC, which is aldosterone‐sensitive. Enhanced ENaC activity also increases cortical collecting tubule acid secretion, which can cause metabolic alkalosis, which itself can be aggravated sometimes in renal failure because of impaired acid–base homeostasis As with loop diuretics, renal function can deteriorate acutely as a consequence of the hypovolaemia, resulting in AKI, or gradual progression of CKD. Hypokalaemia results from increased sodium delivery to the cortical collecting duct with consequent increased uptake by the sodium epithelial channel ENaC and an increase in potassium excretion via the channel high risk medications and a background of pre‐existing renal disease may cause subsequent renal deterioration, if not titrated appropriately Many studies have shown a prognostic benefit of ACEis/ARBs in both heart failure and renal failure. Their effect on blocking the RAA system causes a predictable increase in serum creatinine because of their effect on intraglomerular haemodynamics. As serum creatinine currently remains the main biomarker for measuring renal filtration function, an acute decline in renal function might be apparent on initiation or dose escalation of these drugs. The extent of the rise in serum creatinine may indicate whether it is a physiological or pathological response, with a total rise of up to 20% generally considered acceptable. Combination of ACEis/ARBs with other Bisoprolol is the most commonly used β‐blocker in heart failure, and is known to improve prognosis endothelin‐1 and thromboxane prostaglandins, which promote vasoconstriction in response to sclerosis and injury. These effects result in renal arteriole vasodilation, which improves blood flow and protects renal perfusion amlodipine seems to have renoprotective effects in CKD patients, especially when paired with ARBs Heart failure patients often suffer from hypertension, especially if the primary cause is due to ischaemic heart disease. These patients are likely to be prescribed hypotensive agents such as calcium channel blockers. By reducing systemic blood pressure, these agents may also carry a potential risk of reducing perfusion and filtration pressure through the kidney, causing renal ischaemia and decline in function over time aspirin can cause an idiosyncratic reaction causing tubulo‐interstitial nephritis, which can lead to AKI. This is rare at low doses of 75 mg, although the risk is slightly higher if combined with other nonsteroidal anti‐inflammatory drugs (NSAIDs) and analgesics This is commonly used in secondary prevention of ischaemic heart disease because of its antiplatelet effects. Rarely, Spironolactone and eplerenone have shown significant benefit in heart failure outcomes, but they can also lead to serious adverse effects. As with loop and thiazide diuretics, they can increase risk of dehydration and hypoperfusion. They also cause potassium retention which can lead to hyperkalaemia, the risk being higher in CKD. Hyperkalaemia increases risk of arrhythmias, morbidity and mortality. Concurrent use of aldosterone antagonists with ACEis increases risk of hyperkalaemia and so should be used with caution Digoxin has positive inotropic and negative chronotropic effects. There have been very few studies of the effects of digoxin on renal function in patients with heart failure and CKD, but it seems to have no effect on renal dysfunction in small doses. Conversely, since digoxin excretion is mainly renal, accumulation can occur in severe kidney dysfunction, leading to digoxin toxicity and potentially cardiac arrhythmias This is now used infrequently in patients with heart failure, and is used mainly in patients with concomitant atrial fibrillation. NO) availability in blood. NO is a potent vasodilator of systemic vasculature which lowers blood pressure and potentially increases renal arterial flow. This effect has been demonstrated during intravenous administration in an acute setting ISDN combined with hydralazine has been shown to decrease mortality in patients with renal failure These drugs both increase nitric oxide  AKI is a rapid deterioration in renal function, usually over days to weeks. It is defined arbitrarily by a rise in serum creatinine or a fall in urine output, according to internationally accepted criteria such as the KDIGO classification. In clinical practice it is far more common to use the serum creatinine criteria, as hourly urine output is rarely recorded routinely outside intensive care and renal units. AKI is first defined as an increase in serum creatinine by 50% from baseline within 7 days, or an absolute increase in creatinine by 26.5 μmol lOne early warning system is the clinical classification of worsening renal function (WRF). WRF is a state of pre‐AKI that is specific to heart failure patients. It has a more gradual biomarker (creatinine) increase than AKI, occurring over 6–12 months rather than 7 days, which makes it easier to detect on routine screening than the criteria for AKI –1 absolute increase in creatinine; or 20% decrease in eGFR. While these criteria are similar to AKI definition, the important difference is the much longer timescale. More recently, WRF has been divided into three classes based on severity of renal decline , Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Database of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science and CINAHL. Studies of interest were further reviewed for inclusion of heart failure guidance. Selection of clinical guidelines was agreed by consensus of clinical investigators for relevance to this review. Cited studies within these publications were scrutinized. Search strategy for other related references can be found in the http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY Key protein targets and ligands in this article are hyperlinked to corresponding entries in days to 2 weeks) is recommended if changes are made to the drug regimen. More detailed monitoring is suggested for patients with “significant comorbidities or deterioration” though this is not elaborated on further. These are relatively nonspecific monitoring recommendations open to interpretation by clinicians.The NICE clinical guidelines for the management of chronic heart failure advise a minimum frequency of 6‐monthly monitoring for patients with stable CHF. Increased frequency (of Appendix D of the NICE guideline for chronic heart failure). Regular follow‐up monitoring of renal function is advised every 3 months if the patient continues to take ACEis or ARBs. The guidance advises against use of these medications with baseline potassium >5 mmol l–1 and recommends discontinuation at ≥6 mmol l–1. Maximum permitted fall in renal function after ACEi/ARB initiation or titration is suggested to be 25% decrease in eGFR or 30% increase in creatinine from pretreatment levels. ACEi or ARB dose should be reduced or the drug discontinued if these limits are exceeded. Any lesser degree of renal deterioration warrants further testing after 1–2 weeks, but the dose should not be decreased unless these limits are exceeded.For ACEis and ARBs, more specific guidance exists. Checking baseline renal function on initiation of the drug is recommended, with dose titration 2‐weekly, monitoring renal function each time until target dose is reached. Cross‐referencing to NICE clinical guidelines for CKD, renal function monitoring is advised 1–2 weeks after initiation or dose increment. More specific guidance for renal function monitoring in patients with heart failure is given in the appendices  also advises on monitoring of renal function in CHF. For ACEis and ARBs, renal function and electrolyte monitoring is recommended 1–2 weeks after initiation or dose increase. Renal function should then be monitored “frequently and serially until potassium and creatinine have plateaued”, but no specific frequency is suggested.–1 from baseline with a maximum acceptable serum potassium of 5.5 mmol l–1. If these limits are reached, other high‐risk agents should be reviewed and discontinued first. If renal function does not improve, ACEis or ARB dose should be halved before re‐checking renal function after 1–2 weeks. If there is still no improvement, specialist opinion should be sought. At no point is there a recommendation to stop ACEis/ARBs and the only contraindications mentioned are angioedema and bilateral renal artery stenosis.Maximum acceptable increase in creatinine after ACEis or ARB introduction is considered to be 50% or 266 μmol lFor β‐blockers, renal function monitoring is also recommended 1–2 weeks after initiation or dose change. Dose should be reviewed in the event of hypotension, bradycardia, or fatigue but renal dysfunction is not specifically mentioned.–1 or above and stopped if above 6 mmol l–1. Monitoring with loop diuretics is mentioned but no specific time interval suggested Guidance regarding aldosterone antagonists is, as with NICE, more comprehensive due to the increased risk of hyperkalaemia. The recommendation is similar to that of NICE with renal function testing at 1 week, then at 2, 3, 4, 6 months then 6‐monthly thereafter if stable. Dose should be halved with serum potassium of 5.5 mmol let al.'s practical recommendations for heart failure, the same source used by NICE but follows it more closely than does NICE. This is apparent in the quoted maximum acceptable creatinine rise before intervention is deemed necessary. NICE uses its own limit of 30% increase in creatinine compared with McMurray's (and SIGN's) 50% increase from baseline. It is clear from the wording of the publication by McMurray et al. that the higher threshold was designed to prioritize prescription of ACEis, ARBs and cardiovascular outcomes in heart failure rather than discussing renal decompensation It is worth noting that this SIGN guidance is also derived from McMurray large decrease in renal function as a result.The European Society of Cardiology (ESC) guidelines acknowledge the high prevalence of CKD in HF and the frequent onset of WRF as a risk factor for future morbidity, AKI and hospital admission. They advise caution when using thiazide and loop diuretics in the context of declining renal function, but they encourage continuation of ACEis and ARBs unless there is a –1 from baseline. Deterioration above this level should trigger a review of other high‐risk medicines followed by halving of the dose of ACEi or ARB with repeat renal function check after 1–2 weeks. ACEis and ARBs should be discontinued if creatinine increases by 100% or more, or 310 μmol l–1 or if eGFR drops below 20 ml min–1 1.73 m–2 or if potassium exceeds 5.5 mmol l–1.–1 and discontinuation at 6 mmol l–1.For aldosterone antagonists, ESC advises renal function and electrolyte checks at baseline, 1 week, then 1, 2, 3, 6, 9 and 12 months after initiation, then 4‐monthly when stable. For hyperkalaemia, they advise halving the dose at 5.5 mmol lFor diuretics, ESC recommends renal monitoring at baseline, then 1–2 weeks after initiation or dose change. Discontinuation of diuretics is recommended in the event of worsening renal impairment or dehydration.The ESC recommendations are based predominantly on expert opinion. No specific references are given with respect to renal monitoring, although they are similar to NICE and SIGN guidelines Table .furosemide, the most common diuretic in heart failure, is titrated up based on daily weight of the patient to achieve daily weight loss of 0.5–1.0 kg, followed by a lower maintenance dose to keep weight at the target. The dose can then be adjusted in primary care or by the patient, as necessary, over the longer term. For ACEis and ARBs, advice is to start at a low dose then monitor renal function after 1–2 weeks then “periodically thereafter” according to the clinician's judgement, including after dose increases. Risks of renal decline in patients with diabetes and hypertension are noted.A pragmatic approach to diuretic prescribing is described. It is suggested that For aldosterone antagonists, a more stringent monitoring regimen is advised, with the option of an alternate day starting dose for patients with CKD and monitoring after 2–3 days then at 7 days for all patients. Thereafter monthly monitoring is advised every 3 months if renal function is stable. This monitoring schedule should then be repeated every time the dose changes.Sources of this guideline included nine trials involving ACEis, six relating to ARBs, 25 to diuretics and five to aldosterone antagonists. The guideline also cross‐referenced ESC and NICE guidelines.–1 as the main predictor for mortality in inpatients with heart failure Compared with other guidelines, advice on renal monitoring is less specific although there is generally a more cautious approach with respect to the risk of worsening renal function. ACEi and ARB guidance is similar to other guidelines but a more cautious approach is adopted to aldosterone antagonists. This reflects the high risk of hyperkalaemia observed in its referenced studies reaching up to 36% in certain population‐based registries and an associated increase in mortality Despite widely acknowledged potential detrimental effects of loop and thiazide diuretics on renal function, only the ESC guidelines provide specific monitoring advice regarding their use in heart failure. This contrasts with guidance regarding aldosterone antagonists, which is comprehensive and specific in each guideline, reflecting evidence for risk of hyperkalaemia, which is a predictor of mortality With loop diuretics, the risks may actually be at least as great as with aldosterone antagonists. In patients with heart failure, use of loop diuretics is associated with more severe renal decline, higher risk of hospital admission and increased mortality rate. The renal decline is dose‐dependent with higher doses causing more rapid decline in eGFR Paucity of renal function monitoring guidance for loop and thiazide diuretics, compared with aldosterone antagonists, probably relates to the fact that trials of the latter were conducted relatively recently. Lack of guidance for renal monitoring with diuretics may partially explain why diuretics are the second most common cause for UK hospital admissions due to adverse drug reactions bumetanide have shown that its diuretic effect occurs <1 h after oral administration. Maximal effect is achieved after the first dose, with diminishing effect of subsequent oral doses (up to 25% less than the first dose for the same concentration) hydrochlorothiazidePharmacokinetic studies show that different diuretic agents have different durations of action in patients with heart failure, with different times from initiation to observed pharmacological effect Table . Studiesresistance to the diuretic so that increasing doses are required over time These observations have implications for both diuretic dosing and monitoring of renal function. The greatest change in renal function biomarkers (such as serum creatinine) would be expected after the first dose and higher subsequent doses of the drug may be required for the same effect. In a patient with symptomatic heart failure, this may result in a progressive increase in diuretic dose with an accompanying greater risk of decline in renal function and AKI. This is compounded by the need for increasing doses of thiazide and loop diuretics as GFR falls No simple monitoring schedule is applicable for any one class of diuretic. Patient and drug factors are both important, with consideration of both the acute and maintenance phases of the diuretic action. A regimen of 1–2 weeks' monitoring (recommended by ESC) may reach the steady state effect of the diuretic, but it does not take account of the risk of chronic slow deterioration in renal function. As discussed, monitoring of adequate frequency and duration is not reflected in current guidelines from NICE, SIGN and AHA, which rely predominantly on clinician judgement.The effects of ACEis and ARBs on renal function are well documented medication‐based prescribing (and monitoring) approach in a complex condition such as heart failure.For β‐blockers and other antihypertensives that may be used in heart failure, only SIGN provides specific advice on renal monitoring. Other guidelines discuss symptomatic side‐effects of β blockade such as dizziness, fatigue and hypotension but do not advise specifically on monitoring of renal function. This demonstrates one of the problems of a predominantly medication based. With scarcity of evidence, much of the guidance reflects expert opinion or adverse effect data from clinical trials. No studies have specifically addressed optimal timing of renal function monitoring, which has contributed to the potentially confusing variation in the published medication‐based guidance.The approach of current heart failure guidelines to renal function monitoring can be described as –1, SIGN, ESC and ACCF would recommend halving of the spironolactone dose rather than review of the ACEi, even though the temporal relationship might suggest that the ACEi was the main adverse factor for this individual patient.For example, if a patient is taking a stable dose of spironolactone and then starts an ACEi, causing serum potassium to increase to 5.6 mmol lLinking monitoring guidance to individual drug classes disassociates it from the patient, so that if one particular drug is discontinued, the guidance is assumed to stop with it. This creates the danger that the role of the heart failure pathology itself in causing renal deterioration will be ignored. Monitoring may become more concerned with detection of adverse effects rather than detection and reduction of progressive decline in renal function. This is reflected in current guidance for patients with apparently stable renal function, where only NICE has specific advice (of 6‐monthly testing). This does not take account of individual patient risk factors such as age and comorbidities.In addition, guideline development is complicated by the fact that most patients with heart failure are prescribed multiple drugs . Few studies have addressed the effect of such complex combinations on renal function in the medium–long term. For those studies that have, exclusion criteria might render the conclusions inapplicable to many patients with comorbidities.patient‐based monitoring regimen should be developed. This would consider both medication and individual risk factors, and suggest a monitoring interval based on a patient's combined risk, facilitating early intervention (such as dose adjustment) to reduce risk of renal deterioration, hospital admission and mortality.To rationalize guidance for monitoring of renal function and to minimize risk of WRF and AKI in vulnerable patients, a –1 might represent normal GFR in a young person with high muscle mass or very low GFR in an older malnourished person.Serum creatinine has, for decades, remained by far the most widely used assay for measuring renal function in primary and secondary care. It is a product of normal striated muscle turnover and is a marker of renal filtration function rather than of acute renal damage, because to a large extent it is filtered freely by the glomerulus. Despite the longevity of this assay, creatinine is far from ideal as a marker of renal function. Firstly, it does not increase linearly with fall in GFR; indeed GFR can fall significantly below normal with little or no increase in serum creatinine. Secondly, it is also inaccurate at low GFR because the small degree of active tubular secretion of creatinine can confound the serum level. Conversely, drugs such as trimethoprim can cause spuriously high serum creatinine by blocking its tubular secretion. Thirdly, creatinine is a particularly poor marker of renal function at extremes of muscle mass. Serum creatinine of 130 μmol lIt is also essential to understand that while increase in serum creatinine over time suggests deterioration in renal function (and defines AKI and its stages), it does not provide any information on the underlying renal pathology. To take contrasting examples, a 50% increase in creatinine from baseline might result from dehydration, with no histological changes, or it might result  from an intrinsic renal pathology such as glomerulonephritis. Clearly the clinician needs to apply clinical context and common sense to interpretation of the creatinine result. Identification of more specific blood and urine biomarkers for renal injury and function is currently highly topical and of commercial interest but none is likely to be used widely in the next few years.Estimated GFR is derived from serum creatinine using formulae that include age, sex and ethnicity. Different formulae are described, the most commonly used being MDRD and CKD‐EPI. A key point about use of eGFR is that it was developed and validated in populations with steady or slowly declining renal function. It is valid to use eGFR to monitor renal function over months and years, but for more acute changes in renal function, serum creatinine should be used.–1 to 200 μmol l–1 over 6 months following introduction and titration of a drug is likely to be of greater concern than serum creatinine that has remained stable at 220 μmol l–1 over the same period.In monitoring renal function in the context of initiation and titration of drugs, often the trend in creatinine (or eGFR over months) is more important than the absolute value. Serum creatinine rising from 100 μmol lPersonal risk factors other than medication need to be considered for effective patient‐based monitoring. These include sex, age, smoking status and comorbidities such as diabetes and CKD baseline renal function nearly always declines over years, as is the natural history of most aetiologies of CKD. The average annual fall in eGFR over 4 years can be used as a measure of the rate of long‐term decline Rate of renal decline is itself a risk factor for further renal deterioration. Serum creatinine results inevitably fluctuate in patients with heart failure, often because of changes in their cardiac condition and associated changes in their drug regimen. Comorbidities and other acute illnesses may also contribute to variation of creatinine between time points. However, the underlying or This is the time taken from initiation of monitoring of renal function to a change in clinical management to avoid an undesirable outcome. Typically, this would simply involve the time taken for a patient to come back to clinic for a blood test, the waiting time for the result and the subsequent action which might involve another clinic visit or telephone call. In primary care this can be time consuming, especially if it relies on transportation of blood samples to a hospital laboratory. With further time for patient recall, the intervention lag could range from 2–5 days. The delay could be reduced with telephone follow‐up and use of recent advances in telemonitoring of clinical symptoms and signs By incorporating a patient's drug regimen, personal risk factors, baseline renal function and time required to intervene, a flexible monitoring system could be developed to improve renal outcomes in patients at high risk. Simply increasing frequency of renal monitoring for all patients with heart failure would have significant cost implications and is unrealistic in a publicly funded health service. Identification of patients at greatest risk of renal decline together with more efficient monitoring systems is likely to be the most cost‐effective way of improving outcomes including hospital admission.Stream application, which collates hospital data from numerous sources, and uses predictive analytics to identify patients at highest risk of deterioration, allowing early intervention to avoid AKI in hospital inpatients This type of personalized care requires an automated system to analyse individual risk factors and derive clinical guidance for each patient. This could be aided by recent advances in machine learning and virtual‐intelligence‐aided clinical‐decision tools, which allow both rapid and intelligent assessment of biomarkers for clinical use patient‐based approach to monitoring.Renal dysfunction contributes substantially to morbidity and mortality in patients with heart failure The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. M.P. is an NIHR Senior Investigator and is also supported by the MRC Centre for Drug Safety Science.This research was supported by the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care North West Coast (NIHR CLAHRC NWC).Appendix S1 Search strategies for databases used in this reviewClick here for additional data file.


Toraymyxin was approved by the Japanese National Health Insurance system for the treatment of endotoxemia and septic shock in 1994. Since then, PMX (defined as direct hemoperfusion with Toraymyxin) has been safely used in more than 100 000 cases in emergency and intensive care units in Japan. Toraymyxin is currently available for use in clinical settings in 12 countries outside of Japan. We reviewed and analyzed the development, clinical use, and efficacy of Toraymyxin, and assessed the current status of Toraymyxin use for the treatment of severe sepsis and septic shock. Our review shows that PMX appeared to be effective in improving hemodynamics and respiratory function in septic shock requiring emergency abdominal surgery. Recent large‐scale ranomized controlled trialscould not demonstrate whether prognosis is improved by PMX. However, the latest meta‐analysis revealed that PMX significantly decreased mortality in patients with severe sepsis and septic shock. Combination of PMX with continuous hemodiafiltration and longer duration of PMX might be an effective strategy to improve survival in such patients.Toraymyxin Endotoxins are one of the major constituents of the cell walls of Gram‐negative bacteria. Endotoxins are recognized by Toll‐like receptor 4 that activates macrophages and other leukocytes to produce various inflammatory mediators. Endotoxins appeared to play a major role in the pathogenesis of Gram‐negative bacterial infections and in triggering toxic symptoms in patients with sepsis and septic shock. A recent review has shown that co‐detection of Gram‐negative bacteria and endotoxemia is predictive of an increased risk of mortality compared to the detection of neither.®  has been developed as a direct hemoperfusion column that contains polymyxin B‐immobilized fiber to bind endotoxins in patients’ blood.Polymyxin B is an antibiotic that displays strong bactericidal activity against Gram‐negative bacteria; it binds to and inactivates endotoxins.A narrative literature review was carried out using PubMed, MEDLINE and Google scholar search engines regarding PMX (defined as direct hemoperfusion with Toraymyxin). We describe the history of the development of Toraymyxin and comment on its clinical efficacy and current status with respect to its use for the treatment of severe sepsis and septic shock.2Initial research into polymyxin B‐immobilized fibers began in 1981 at the Department of Surgery, Shiga University of Medical Science, Japan, as a collaboration between our research group and Toray Medical Co., Ltd  in Europe were published in 2005, showing that treatment with PMX was safe and improves cardiac and renal dysfunction in patients with sepsis or septic shock.Toraymyxin is currently available for use in clinical settings in 12 countries outside of Japan  , PMX‐05R® (40 mL), and PMX‐01R® (8 mL)  had been developed, which detects endotoxins in whole blood by using autologous neutrophil‐dependent chemiluminescence.4The latest international guidelines, Surviving Sepsis Campaign: international guidelines for the management of severe sepsis and septic shock, 2012, was published in 2013.The Japanese guidelines for the management of sepsis were published by the Japanese Society of Intensive Care Medicine in 2013.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis‐3) was published by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine in 2016.52/FiO2) was increased by 32 units  , left ventricular stroke work index (P=.015 at day 2), and oxygen delivery index (P=.007 at day 2) compared with controls. Furthermore, the need for continuous renal replacement therapy (CRRT) after study entry was significantly reduced in the PMX group (P=.043). There were no statistically significant differences in the change in endotoxin or interleukin (IL)‐6 levels, organ dysfunction as assessed using the SOFA scores, or 28‐day mortality. Together, these results showed that PMX treatment was safe and that it improved cardiac and renal dysfunction as a result of sepsis or septic shock.There are four RCT conducted outside of Japan as listed in Table P=.001) and vasopressor requirement (measured as inotropic score) significantly decreased from 29.9 (before treatment) to 6.8 . In contrast, in the conventional therapy group, the mean arterial pressure  and inotropic score  did not change significantly with treatment. PaO2/FiO2 ratio increased significantly  in the PMX group but not in the conventional therapy group . Moreover, the SOFA score, which is an indicator of the severity of organ dysfunction, was improved in the PMX group compared to the conventional therapy group . Although the goal was to enrol 120 patients in this study, interim analysis revealed that the risk of mortality in the conventional treatment group was significantly higher than in the PMX group; thus, the EUPHAS study was terminated halfway. A Cox proportional hazard analysis was used for survival analysis in the EUPHAS study; however, some researchers questioned the analytical approach used in this study. Odds ratio (OR) of the crude 28‐day mortality rates was not statistically significant , using Fisher's exact test. AmaralP=.049), consistent with a statistically significant decrease in risk. They also showed that the difference of 60‐day mortality may not decrease with time.Cruz et al.The ABDO‐MIX trial was conducted in France.The EUPHRATES trial conducted in the USA and CanadaP=.007; I2=72%). In the subgroup analysis, they also showed that four studies published in Japan showed significantly lower mortality in the PMX group than in the control group ; however, three studies published in other countries failed to show a significant decrease in mortality in the PMX group . They discussed that a meta‐regression analysis revealed a significant negative slope between effect size of PMX therapy and baseline mortality rate in individual studies. Further, in this meta‐analysis, they suggested that a beneficial effect with PMX might be greater in patients with higher baseline mortality risk.In their latest meta‐analysis, Terayama et al.P=.696).P=.003).The effect of postoperative PMX on mortality in patients with septic shock as a result of lower gastrointestinal tract perforation was examined by propensity‐matched analysis using the Japanese Diagnosis Procedure Combination (DPC) inpatient database.The combination of PMX and continuous hemodiafiltration (CHDF) as CRRT appears to be more beneficial for patients with septic renal dysfunction than CHDF alone; combination treatment significantly decreases the concentration of circulating IL‐6 and improves patient survival  and almost all studies published in Japan included patients with septic shock as a result of abdominal infections. The EUPHAS 2 registry was conducted by 57 centers collecting retrospective data for 357 patients with severe sepsis and septic shock.6PMX appeared to be effective in hemodynamics and respiratory function in patients with septic shock requiring emergency abdominal surgery. The recent large‐scale RCT could not demonstrate whether the prognosis is improved by PMX; however, the recent meta‐analysis revealed that PMX therapy significantly decreased mortality in patients with severe sepsis and septic shock. The combination of PMX with CHDF and longer duration of PMX might be an effective strategy to improve the survival of patients with severe sepsis and septic shock.Conflict of Interest: Authors declare no conflicts of interest for this article.


Migration of men who have sex with men (MSM) from rural to urban areas is common across low‐ and middle‐income countries and is widely believed to contribute to elevated HIV risk among migrant MSM in urban areas. Little consensus exists on whether their risk is due to their transplantation or their being from resource‐constrained rural areas. This study seeks to clarify the relationship between migration and HIV risks by comparing differences in HIV‐related risky sexual behaviours and healthcare utilization across competing conceptualizations of migratory statuses.In July 2016, MSM ≥16 years old currently residing in one of eight urban cities in China were recruited for an online cross‐sectional survey, which collected information on socio‐demographics, sexual behaviours, HIV care‐seeking behaviours, and healthcare utilization. Based on a question about residency status, each participant was classified as an urban local resident, urban transplant, or rural transplant. Multivariable multinomial logistic regression was used to examine the associations between risky behaviours and healthcare utilization among these three groups.Among 2007 MSM, the proportion of local, urban transplant and rural transplant were 32% (648/2007), 24% (478/2007), and 44% (881/2007), respectively. Compared with urban local resident MSM, urban transplant MSM were more likely to have ever tested for HIV (adjusted odds ratio (aOR) = 1.39, 95% confidence interval (CI): 1.08 to 1.80). Compared with urban transplant MSM, rural transplant MSM were less likely to have utilized any governmental sexual health services in the past three months , ever tested for HIV , ever initiated antiretroviral therapy (ART) , and ever purchased sex . No other significant differences were found in sexual behaviours among three groups.The widely used local/migrant categorization obscures important differences in HIV risk present between urban/rural subgroups among them. Previous studies of HIV risks in Chinese “migrant” may have failed to consider the role of structural factors such as discrimination or barriers to healthcare when interpreting their findings of higher HIV prevalence in this population. Low ART uptake among rural transplant MSM in this study is particularly concerning and underscore the need for HIV‐related interventions tailored for this group. Scholars have documented notable trends globally in MSM's migrating from rural area or small cities to larger cities, where the anonymity of city life permits less traditional sexual lifestyles and same sex partners are relatively easier to find In China, MSM account for more than one‐third of new HIV cases In order to better distinguish the effects of transplant status  versus place of origin status  on HIV risk in so‐called “migrant” MSM in China, we analysed data from an online survey conducted among MSM living in urban areas, in which we compared associations between each type of statuses with common HIV‐related risky sexual behaviour and healthcare utilization. Specifically, we classified participants according to whether they were transplants as well as by their place of origin status . In so doing, this analysis identifies distinctive sources of HIV risk faced by MSM in the following three categories: urban local resident, urban transplant, and rural transplant. Our findings can both guide future interventions in this population as well as ongoing research on the role of migration in the spread of HIV.22.1Study data were collected through an online survey conducted between July and August 2016 in eight urban cities  from Guangdong and Shandong Provinces, China. Participants were recruited from Blued , China's most widely used location‐based gay social networking mobile phone application, comparable with Grindr in the west. Based on users' geolocation, Blued account holders living in one of the eight study cities at the time of study were recruited via a private advertisement message sent from Blued's official account. The private message delivered to users' account mailbox. The message included information on the study background and the terms of survey participation (i.e. risks and benefits), and also provided a link to the survey. Users who clicked on the link were directed to the survey hosted by Sojump Survey Software .Eligible participants were born biologically male, were currently living and planning on living in their respective cities for the next 12 months, had oral or anal sex with another man at least once during his lifetime, and were at least 16 years of age. To minimize issues of repeat surveys by the same individuals, we used a screening system in which participants have to verify their phone numbers before taking the survey. A participant must submit the verified code that sent to his phone to enter the survey. Each phone number could only be associated with a single survey submission. Multiple attempts of survey‐taking would be blocked by the system. Eligible survey participants were invited to take part in the survey after signing an online consent form. Participants who completed the survey received 50 Chinese yuan mobile top‐up (about 7 USD) as monetary compensation after finishing the survey.33.1hukou, to measure one's migratory status. The hukou refers to China's national household registration system, through which citizens access legal status and social services such as social welfare, public healthcare and education. Every hukou contains two pieces of information: location of registered residence (i.e. an address) and classification as urban or rural. The hukou status is assigned based on where the resident was born hukouhukou is thought to be the proxy for the environment in which one was born and raised. It has been widely used in the existing HIV literature to classify individuals into “migrants” and non‐migrants In this study, we classified the participants into three exposure categories: (1) MSM local to the urban area where they lived , (2) those who had transplanted from another urban area (“urban transplant”), and (3) those who transplanted from a rural area . We used each individuals' reported household registration type, or hukou but who had relocated to one of the eight study cities for >6 months within the last year. Rural transplant MSM were defined as MSM with a rural hukou who had relocated to one of the eight study cities and had been living there for >6 months in the past year. Given our sample composition, our analysis did not include any MSM living in rural area, restricting our ability to consider the role of rural MSM living in their local setting.Our definition of a “transplant” as someone who had been living outside of from his registered residence place for more than half of the previous (>6 months) 12 months, was based on definitions of temporary residence defined in the National Bureau of Statistics of China Our outcomes included HIV‐related risk behaviours and healthcare utilization. For the former, the variables included lifetime history of buying or selling sex, any condomless sex and multiple sexual partners in the past three months; for the latter, the variables included the utilization of any government sexual health services in the past three months, ever tested for HIV, and ever initiated antiretroviral therapy (ART) among those who reported being HIV infected. Most HIV‐related sexual health services in China are provided by public disease control agencies. Some community‐based organizations may also provide similar services through programs that mostly supported by government funding 3.2Participants reported socio‐demographic information, such as age, education, marital status, annual income, sexual orientation, and status of disclosure of sexual orientation. Education and income levels were categorized according to the conventions of the Chinese national population census, with those reporting a high school education or less classified as “less educated”3.3hukous. In contrast, odds ratios comparing rural transplants to urban transplants showed the effect of being a rural origin on HIV‐related outcomes as it applied to transplant MSM . Multi‐nonnominal logistic regression models were then used to compare odds ratio of reporting HIV‐related risk behaviours and healthcare utilization among the three groups. Odds ratios comparing urban transplants to urban local residents were used to measure the effect of being a transplant on HIV‐related outcomes as it applied to MSM with urban M Figure . Model a3.4The study obtained approval from the ethics review committees at the Guangdong Provincial Centre for Skin Diseases and STI Control, the University of North Carolina at Chapel Hill, and the University of California, San Francisco prior to survey launch.4Among 2007 eligible participants who completed the survey. The proportion of the local, urban transplant and rural transplant was 648 (32%), 478 (24%), and 881 (44%), respectively. The median age of the participants was 25 years old (Range: 16 to 64). A majority of men reported an education level higher than high school (64.4%), were classified as lower income (70.9%), never married (85.5%), and self‐identified as gay (72.1%) . The same group was also significantly more likely to report a below‐median annual income compared with urban local residents and urban transplants . In terms of marital status, urban local residents were the most likely to be never married , though the difference was of borderline significance.4.1In adjusted models comparing transplants from other urban areas with urban local residents Table , MSM who4.2In adjusted models comparing urban and rural transplants Table , MSM of 5Our comparison of the associations between a three‐category definition of migrant status and HIV‐related outcomes suggest that the vulnerabilities faced by this group are layered and multifaceted. When compared by their transplant status, for example, urban transplant MSM were found to have higher odds of having ever tested for HIV compared with their local counterpart. When transplant MSM were compared across urban/rural status, however, those of rural backgrounds had a lower odds of reporting risky behaviours and of accessing to the HIV‐related healthcare, relative to their urban counterpart. These findings urge a rethinking of the widely used but loosely defined term, “migrant,” as it is used refer to underlying processes driving the HIV epidemic in Chinese MSM. Although migration likely plays an important role in the spread of HIV in China The relative lack of differences in reported sexual behaviours among our study participants of different migration backgrounds departs from existing research on this topic in China Compromised HIV testing and other healthcare utilization patterns among rural transplants suggests that attributes specific to their rural backgrounds pose unique challenges when such individuals relocate to a new city. Past findings on health‐seeking behaviours among Chinese migrant MSM have only documented disparities in healthcare utilization across local versus transplants The overall rate of ART uptake observed in our sample of MSM living with HIV  is a far from the UNAIDS goal of 90% of HIV infected persons on treatment Our study findings have important policy implications. First, urban health authorities should consider ways to improve healthcare utilization, particularly among those from rural areas. Formal mechanisms to solicit feedback from patients, members of the LGBTQ community, and persons of rural background in the city and countryside should be considered as part of intervention design. Community participatory methods such as crowdsourcing may also be helpful for soliciting community feedback Given the government focus on mitigating the rapidly growing HIV epidemic among Chinese MSM, more research on the impact of migration can be expected in the future Findings of this study should be considered in light of several limitations. First, our sample did not allow us to fully distinguish between rural transplant's risk attributable to being of a rural background versus that of being a transplant, since the sample did not include rural MSM residing in the local rural area. Second, our participants were recruited from a mobile APP‐based convenience sample, which may under‐sample older or less educated individuals or people in the stable relationship, thereby restricting the generalizability of our study findings 6Our findings suggest that higher HIV prevalence rates in the so called “migrant MSM” documented by past studies may be due to their structural barriers to accessing HIV prevention interventions rather than from individual risk behaviours. By adopting a more nuanced migratory status as the exposure, our study showed that rural background among transplants is a more salient predictor of the poor healthcare utilization. More tailored interventions regarding healthcare access facilitation and HIV awareness should be conducted among rural transplant MSM. Further research guided by more nuanced measures of migratory status will also help elucidate the intersection between male same sex behaviours, migration, and HIV in China and other LMIC.We declare no completing interests.CW and JT conceived the study. CL, RF, WT, CW, JT and MS contributed to the study design. CL, SP, WT and MS provided statistical support. CL and RF drafted the manuscript with inputs from WT, BC, SP, CW, JT and MS. All authors have seen and approved the final version of the manuscript.This work was supported by National Institutes of Health  1R01AI114310); University of North Carolina (UNC)‐South China STD Research Training Centre ; UNC Center for AIDS Research (NIAID 5P30AI050410); University of California San Francisco Center for AIDS Research (NIAID P30 AI027763); and the Bill & Melinda Gates Foundation to the MeSH Consortium (BMGF‐OPP1120138); National Center for Advancing Translational Sciences (UL1TR001111) at the National Institutes of Health. The listed grant funders played no role in any step of this study.Table S1. Adjusted odds ratios comparing odds of reporting listed governmental sexual health services utilization in the past three months in urban transplant versus urban local resident MSM (referent), N = 2007Table S2. Adjusted odds ratios comparing odds of reporting listed governmental sexual health services utilization in the past three months in rural transplant versus urban transplant MSM (referent), N = 2007Table S3. Adjusted odds ratios comparing odds of reporting listed governmental sexual health services utilization in the past three months in urban local resident versus rural transplant MSM (referent), N = 2007Table S4. Adjusted odds ratios comparing odds of reporting listed HIV related outcomes in urban local resident versus rural transplant resident MSM (referent), N = 2007Click here for additional data file.