Clinical practice guideline for the management of lipids in adults with diabetic kidney disease: abbreviated summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2024.

The contribution of chronic kidney disease (CKD) towards the risk of developing cardiovascular disease (CVD) is magnified with co-existing type 1 or type 2 diabetes. Lipids are a modifiable risk factor and good lipid management offers improved outcomes for people with diabetic kidney disease (DKD).The primary purpose of this guideline, written by the Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) working group, is to provide practical recommendations on lipid management for members of the multidisciplinary team involved in the care of adults with DKD.

Association and progression of multi-morbidity with Chronic Kidney Disease stage 3a secondary to Type 2 Diabetes Mellitus, grouped by albuminuria status in the multi-ethnic population of Northwest London: A real-world study.

INTRODUCTION: The prevalence of Diabetic Kidney Disease (DKD) secondary to Type 2 Diabetes Mellitus (T2DM) is rising worldwide. However, real-world data linking glomerular function and albuminuria to the degree of multi-morbidity is lacking. We thus utilised the Discover dataset, to determine this association. METHOD: Patients with T2DM diagnosed prior to 1st January 2015 with no available biochemical evidence of CKD were included. Patients subsequently diagnosed and coded for CKD3a in 2015, were grouped by the degree of albuminuria. Baseline and 5-year co-morbidity was determined, as were prescribing practices with regards to prognostically beneficial medication. RESULTS: We identified 56,261 patients with T2DM, of which 1082 had CKD stage 3a diagnosed in 2015 (224-CKD3aA1,154-CKD3aA2,93-CKD3aA1; 611 patients with CKD3a but no uACR available in 2015 were excluded from follow up). No statistically significant difference was observed in the degree of co-morbidities at baseline. A significant difference in the degree of hypertension, retinopathy, ischaemic heart disease and vascular disease from baseline compared to study end point was observed for all 3 study groups. Comparing co-morbidities developed at study end point, highlighted a statistical difference between CKD3aA1 Vs CKD3aA3 for retinopathy alone and for hypertension and heart failure between CKD3aA2 Vs CKD3aA3. 40.8% of patients with CKD3aA2 or A3 were prescribed Renin Angiotensin Aldosterone inhibitors (RAASi) therapy between June-December 2021. Survival analysis showed 15% of patients with CKD3aA3 developed CKD stage 5 within 5 years of diagnosis. DISCUSSION: CKD3a secondary to DKD is associated with significant multimorbidity at baseline and 5 years post diagnosis, with CKD3aA3 most strongly associated with CKD progression to CKD 5, heart failure, hypertension and retinopathy compared to CKD3aA1 or CKD3aA2 at 5 years post diagnosis. The lack of uACR testing upon diagnosis and poor prescribing of RAASi, in those with CKD3aA2/A3, raises significant cause for concern. CONCLUSION: DKD is associated with significant multimorbidity. Significant work is needed to be done to ensure patients undergo testing for uACR, to allow for future risk stratification and ability to be started on prognostically beneficial medication.

Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021.

Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here.

Differences in Prevalence of Muscle Wasting in Patients Receiving Peritoneal Dialysis per Dual-Energy X-Ray Absorptiometry Due to Variation in Guideline Definitions of Sarcopenia.

BACKGROUND: Muscle wasting is associated with increased risk for mortality. There is no agreed universal definition for muscle wasting (sarcopenia), and we wished to determine whether using different criteria altered the prevalence in patients treated by peritoneal dialysis. METHODS: We measured lean body and appendicular lean mass indices in 325 outpatients by dual-energy x-ray absorptiometry, comparing muscle mass with that used to define muscle wasting (sarcopenia) by various clinical guideline publications. RESULTS: Lean body and appendicular lean mass indices did not differ by sex: female, 17.7 ± 4.6 kg/m2; male, 17.4 ± 4.3; female, 6.9 (5.6-8.5) kg/m2; male, 6.7 (5.3-8.3), respectively. Depending on the criteria, the prevalence of muscle wasting varied from 2.2%-31.3% for women and 25.1%-75.6% for men. Male patients were older (58.3 ± 16 vs 53.4 ± 15.7 years). Criteria based on cutoffs derived from young healthy patients gave the higher prevalence rates. The prevalence of muscle wasting was not associated with dialysis adequacy, estimated protein intake, duration of dialysis treatment, comorbidity, diabetes, or ethnicity. The prevalence of sarcopenic obesity was low (<5% females, 7% males). CONCLUSION: We found that the prevalence varied markedly depending on the cutoff criteria used to define muscle wasting. Very few patients had sarcopenic obesity. The higher prevalence for males requires further study but was not associated with dialysis treatment. Our study highlights the need for agreed criteria to define pathologic muscle wasting from that which is age associated to allow for interventional screening programs.

Understanding GRADE: an introduction.

OBJECTIVE: Grading of recommendations, assessment, development, and evaluations (GRADE) is arguably the most widely used method for appraising studies to be included in systematic reviews and guidelines. In order to use the GRADE system or know how to interpret it when reading reviews, reading several articles and attending a workshop are required. Moreover, the GRADE system is not covered in standard medical textbooks. Here, we explain GRADE concisely with the use of examples so that students and other researchers can understand it. BACKGROUND: In order to use or interpret the GRADE system, reading several articles and attending a workshop is currently required. Moreover, the GRADE system is not covered in standard medical textbooks. METHODS: We read, synthesized, and digested the GRADE publications and contacted GRADE contributors for explanations where required. We composed a digested version of the system in a concise way a general medical audience could understand. RESULTS: We were able to explain the GRADE basics clearly and completely in under 1500 words. CONCLUSIONS: While advanced critical appraisal requires judgment, training, and practice, it is possible for a non-specialist to grasp GRADE basics very quickly.

Electrochemical kinetic investigations of the reactions of [FeFe]-hydrogenases with carbon monoxide and oxygen: comparing the importance of gas tunnels and active-site electronic/redox effects.

A major obstacle for future biohydrogen production is the oxygen sensitivity of [FeFe]-hydrogenases, the highly active catalysts produced by bacteria and green algae. The reactions of three representative [FeFe]-hydrogenases with O(2) have been studied by protein film electrochemistry under conditions of both H(2) oxidation and H(2) production, using CO as a complementary probe. The hydrogenases are DdHydAB and CaHydA from the bacteria Desulfovibrio desulfuricans and Clostridium acetobutylicum , and CrHydA1 from the green alga Chlamydomonas reinhardtii . Rates of inactivation depend on the redox state of the active site 'H-cluster' and on transport through the protein to reach the pocket in which the H-cluster is housed. In all cases CO reacts much faster than O(2). In the model proposed, CaHydA shows the most sluggish gas transport and hence little dependence of inactivation rate on H-cluster state, whereas DdHydAB shows a large dependence on H-cluster state and the least effective barrier to gas transport. All three enzymes show a similar rate of reactivation from CO inhibition, which increases upon illumination: the rate-determining step is thus assigned to cleavage of the labile Fe-CO bond, a reaction likely to be intrinsic to the atomic and electronic state of the H-cluster and less sensitive to the surrounding protein.

How oxygen attacks [FeFe] hydrogenases from photosynthetic organisms.

Green algae such as Chlamydomonas reinhardtii synthesize an [FeFe] hydrogenase that is highly active in hydrogen evolution. However, the extreme sensitivity of [FeFe] hydrogenases to oxygen presents a major challenge for exploiting these organisms to achieve sustainable photosynthetic hydrogen production. In this study, the mechanism of oxygen inactivation of the [FeFe] hydrogenase CrHydA1 from C. reinhardtii has been investigated. X-ray absorption spectroscopy shows that reaction with oxygen results in destruction of the [4Fe-4S] domain of the active site H-cluster while leaving the di-iron domain (2Fe(H)) essentially intact. By protein film electrochemistry we were able to determine the order of events leading up to this destruction. Carbon monoxide, a competitive inhibitor of CrHydA1 which binds to an Fe atom of the 2Fe(H) domain and is otherwise not known to attack FeS clusters in proteins, reacts nearly two orders of magnitude faster than oxygen and protects the enzyme against oxygen damage. These results therefore show that destruction of the [4Fe-4S] cluster is initiated by binding and reduction of oxygen at the di-iron domain-a key step that is blocked by carbon monoxide. The relatively slow attack by oxygen compared to carbon monoxide suggests that a very high level of discrimination can be achieved by subtle factors such as electronic effects (specific orbital overlap requirements) and steric constraints at the active site.

Dynamic electrochemical investigations of hydrogen oxidation and production by enzymes and implications for future technology.

This tutorial review describes studies of hydrogen production and oxidation by biological catalysts--metalloenzymes known as hydrogenases--attached to electrodes. It explains how the electrocatalytic properties of hydrogenases are studied using specialised electrochemical techniques and how the data are interpreted to allow assessments of catalytic rates and performance under different conditions, including the presence of O2, CO and H2S. It concludes by drawing some comparisons between the enzyme active sites and platinum catalysts and describing some novel proof-of-concept applications that demonstrate the high activities and selectivities of these 'alternative' catalysts for promoting H2 as a fuel.

The difference a Se makes? Oxygen-tolerant hydrogen production by the [NiFeSe]-hydrogenase from Desulfomicrobium baculatum.

Protein film voltammetry studies of the [NiFeSe]-hydrogenase from Desulfomicrobium baculatum show it to be a highly efficient H2 cycling catalyst. In the presence of 100% H2, the ratio of H2 production to H2 oxidation activity is higher than for any conventional [NiFe]-hydrogenases (lacking a selenocysteine ligand) that have been investigated to date. Although traces of O2 (<< 1%) rapidly and completely remove H2 oxidation activity, the enzyme sustains partial activity for H2 production even in the presence of 1% O2 in the atmosphere. That H2 production should be partly allowed, whereas H2 oxidation is not, is explained because the inactive product of O2 attack is reductively reactivated very rapidly, but this requires a potential that is almost as negative as the thermodynamic potential for the 2H(+)/H2 couple. The study provides further encouragement and clues regarding the feasibility of microbial/enzymatic H2 production free from restrictions of anaerobicity.

Hydrogen production under aerobic conditions by membrane-bound hydrogenases from Ralstonia species.

Studies have been carried out to establish the ability of O2-tolerant membrane-bound [NiFe] hydrogenases (MBH) from Ralstonia sp. to catalyze H2 production in addition to H2 oxidation. These hydrogenases are not noted for H2-evolution activity, and this is partly due to strong product inhibition. However, when adsorbed on a rotating disk graphite electrode the enzymes produce H2 efficiently, provided the H2 product is continuously removed by rapidly rotating the electrode and flowing N2 through the gastight electrochemical cell. Electrocatalytic H2 production proceeds with minimal overpotentiala significant observation because lowering the overpotential (the electrochemically responsive activation barrier) is seen as crucial in developing small-molecule catalysts for H2 production. A mutant having a high KM for H2 oxidation did not prove to be a better H2 producer relative to the wild type, thus suggesting that weak binding of H2 does not itself confer a tendency to be a H2 producer. Inhibition by H2 is much stronger than inhibition by CO and, most significantly, even O2. Consequently, H2 can be produced sustainably in the presence of O2 as long as the H2 is removed continuously, thereby proving the feasibility for biological H2 production in air.

A comparison of phosphaferrocene and phospharuthenocene ligands in Rh+-catalysed enamide hydrogenation reactions: superior performance of the phospharuthenocene.

Enantiopure Cp*-substituted 3,4-dimethyl-5-phenylphosphametallocene-2-methanols (M=Fe, Ru) have been prepared from the corresponding 2-carboxy-(-)-menthylphospholide anion and elaborated into 2-CH(2)PPh(2) phosphametallocenes (13: M=Fe; 14: M=Ru) and 2-CH(2)PtBuR substituted phospharuthenocenes (R=tBu, Me). The crystal structures of complexes [Rh(1,5-cod)(eta(2)-L)](+)BF(4)(-) (L=13, 14) reveal significantly different aryl group configurations. Comparative studies of the hydrogenation of para-substituted N-acetylcinnamate esters with these pre-catalysts show a superior performance for the phospharuthenocene derivative in terms of both rate and enantioselectivity.

Biosynthesis of the red antibiotic, prodigiosin, in Serratia: identification of a novel 2-methyl-3-n-amyl-pyrrole (MAP) assembly pathway, definition of the terminal condensing enzyme, and implications for undecylprodigiosin biosynthesis in Streptomyces.

The biosynthetic pathway of the red-pigmented antibiotic, prodigiosin, produced by Serratia sp. is known to involve separate pathways for the production of the monopyrrole, 2-methyl-3-n-amyl-pyrrole (MAP) and the bipyrrole, 4-methoxy-2,2'-bipyrrole-5-carbaldehyde (MBC) which are then coupled in the final condensation step. We have previously reported the cloning, sequencing and heterologous expression of the pig cluster responsible for prodigiosin biosynthesis in two Serratia sp. In this article we report the creation of in-frame deletions or insertions in every biosynthetic gene in the cluster from Serratia sp. ATCC 39006. The biosynthetic intermediates accumulating in each mutant have been analysed by LC-MS, cross-feeding and genetic complementation studies. Based on these results we assign specific roles in the biosynthesis of MBC to the following Pig proteins: PigI, PigG, PigA, PigJ, PigH, PigM, PigF and PigN. We report a novel pathway for the biosynthesis of MAP, involving PigD, PigE and PigB. We also report a new chemical synthesis of MAP and one of its precursors, 3-acetyloctanal. Finally, we identify the condensing enzyme as PigC. We reassess the existing literature and discuss the significance of the results for the biosynthesis of undecylprodigiosin by the Red cluster in Streptomyces coelicolor A3(2).