Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

Nature Reviews Nephrology, Journal Year: 2021, Volume and Issue: 17(5), P. 319 - 334

Published: Feb. 5, 2021

Language: Английский

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Molecular mechanisms and therapeutic targets for diabetic kidney disease

Kidney International, Journal Year: 2022, Volume and Issue: 102(2), P. 248 - 260

Published: June 3, 2022

Diabetic kidney disease has a high global burden and substantially increases the risk of failure cardiovascular events. Despite treatment, there is substantial residual progression with existing therapies. Therefore, an urgent need to better understand molecular mechanisms driving diabetic help identify new therapies that slow reduce associated risks. initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, fibrotic processes contribute progression. This review summarizes evidence on drivers onset progression, focusing inflammatory mediators—factors are largely unaddressed as primary treatment targets for increasing supporting key roles pathophysiology disease. Results from recent clinical trials highlight promising drug therapies, well role dietary strategies, treating Chronic (CKD), characterized albuminuria, low estimated glomerular filtration rate (eGFR), or both,1GBD Kidney Disease CollaborationGlobal, regional, national chronic disease, 1990-2017: systematic analysis Global Burden Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text PDF PubMed Scopus (1156) Google Scholar affect over 840 million people worldwide.2Jager K.J. Kovesdy C. Langham R. et al.A single number advocacy communication-worldwide more than 850 individuals have diseases.Kidney Int. 2019; 96: 1048-1050Abstract (DKD), damage due diabetes, leading attributable cause CKD, occurring approximately 40% type 2 diabetes (T2D) 30% those 1 (T1D).1GBD Scholar,3Alicic R.Z. Rooney M.T. Tuttle K.R. disease: challenges, progress, possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref (753) The DKD expected increase parallel rise prevalence,3Alicic projected nearly 50%, 537 783 people, next 24 years.4International Diabetes FederationIDF Atlas.10th ed. International Federation, 2021Google improve diagnosis management DKD, including target related (CV) risk.1GBD Mechanisms can be broadly classified fibrotic.3Alicic Scholar,5Pérez-Morales R.E. Del Pino M.D. Valdivielso J.M. al.Inflammation disease.Nephron. 143: 12-16Crossref (57) Scholar,6Mora-Fernández Domínguez-Pimentel V. de Fuentes M.M. al.Diabetic physiology therapeutics.J Physiol. 2014; 592: 3997-4012Crossref (99) In this review, current understanding drive pathogenesis presented basis advancing therapeutic interventions. Hyperglycemia induces hyperfiltration hypertension, hemodynamic long been recognized initiate propagate diabetes.3Alicic Glomerular exacerbated levels amino acids, example, after protein overfeeding, hormonal changes poor glycemic control, level glucagon.7Rhee C.M. Kalantar-Zadeh K. Novel approaches hypoglycemia burnt-out disease.Curr Opin Nephrol Hypertens. 2022; 31: 72-81Crossref (0) Scholar, 8Tuttle Bruton J.L. Effect insulin therapy renal response acids hypertrophy non-insulin-dependent diabetes.Kidney 1992; 42: 167-173Abstract 9Tuttle Perusek M.C. al.Effect strict control enlargement insulin-dependent mellitus.N Engl Med. 1991; 324: 1626-1632Crossref (142) 10Tuttle Puhlman M.E. Cooney S.K. Short R.A. Effects glucagon hemodynamics diabetes.Am Physiol Renal 2002; 282: F103-F112Crossref These circulating mediators primarily act perfusion through afferent arteriole dilation.3Alicic Scholar,8Tuttle addition, activation renin angiotensin system local hyperfiltration. Angiotensin II production within constricts efferent arteriole, thereby, contributes higher pressure. stimulates expression proinflammatory profibrotic via barotrauma also direct cellular effects.3Alicic Scholar,10Tuttle sodium-glucose cotransporter-2 (SGLT2) now another important modulator hemodynamics. It expressed luminal surface epithelial cells proximal convoluted tubule responsible 90% filtered reabsorption.11Alicic Neumiller J.J. Johnson E.J. al.Sodium-glucose cotransporter inhibition disease.Diabetes. 68: 248-257Crossref (55) Scholar,12Vallon Gerasimova M. Rose M.A. al.SGLT2 inhibitor empagliflozin reduces growth albuminuria proportion hyperglycemia prevents Akita mice.Am 306: F194-F204Crossref (318) hyperglycemic conditions, SGLT2 activity adaptation reclaim urine, but maladaptive consequence worsening hyperglycemia.11Alicic Scholar,13Heerspink H.J. Perkins B.A. Fitchett D.H. al.Sodium inhibitors mellitus: effects, potential mechanisms, applications.Circulation. 2016; 134: 752-772Crossref Therapeutically, lowers blood decreasing reabsorption at resulting glucosuria.13Heerspink restore tubuloglomerular feedback distal delivery sodium chloride macula densa, where solute generates adenosine by-product triphosphate utilization. Adenosine acts paracrine manner enhance arteriolar vasoconstriction, suppress release juxtaglomerular cells, perhaps constriction.11Alicic Scholar,14Kidokoro Cherney D.Z.I. Bozovic A. al.Evaluation function mice using vivo imaging.Circulation. 140: 303-315Crossref (124) 15Ortiz-Capisano Atchison D.K. Harding P. al.Adenosine inhibits A1 receptor-TRPC-mediated pathway.Am 2013; 305: F1209-F1219Crossref 16Heerspink H.J.L. Perco Mulder S. al.Canagliflozin inflammation fibrosis biomarkers: mechanism action beneficial effects disease.Diabetologia. 62: 1154-1166Crossref (145) 17Vallon Thomson S.C. tubular hypothesis nephron disease.Nat Rev 16: 317-336Crossref (102) relative balance between constriction may vary age. physiological studies humans normal GFR, younger T1D demonstrated constriction, whereas older T2D had dilation.18van Bommel E.J.M. Lytvyn Y. al.Renal hyperfiltering function.Kidney 97: 631-635Abstract (17) Irrespective precise vasoregulatory whole, restoration hypertension and, hyperfiltration.14Kidokoro Scholar,18van prompts series intracellular promote (Figure 1).3Alicic Scholar,19Zhao L. Zou Liu F. Transforming factor-beta1 disease.Front Cell Dev Biol. 8: 187Crossref (34) Scholar,20Reidy Kang H.M. Hostetter T. Susztak Molecular disease.J Clin Invest. 124: 2333-2340Crossref (448) Altered metabolism advanced glycation end products (AGEs), reactive oxygen species, kinase C Janus (JAK)-signal transducer activator transcription (STAT) pathways.20Reidy Podocytes exposed AGE nuclear factor κB–associated upregulation messenger RNA variety much 25-fold.21Pichler Afkarian Dieter B.P. Immunity translating biomarkers targets.Am 312: F716-F731Crossref (108) Scholar,22Anderberg R.J. Meek R.L. Hudkins K.L. al.Serum amyloid A podocytes.Lab 2015; 95: 250-262Crossref podocytes endothelial AGEs bind receptor (RAGE), produce nucleotide-binding oligomerization domain–like pyrin domain containing 3 inflammasome.21Pichler Scholar,23Shahzad Bock Dong W. al.Nlrp3-inflammasome non-myeloid-derived aggravates nephropathy.Kidney 87: 74-84Abstract (234) Scholar,24Sakai N. Wada Revisiting nephropathy: Nlrp3 inflammasome resident cells.Kidney 12-14Abstract Together, κB induce interleukins (IL), IL-1β IL-18, respectively.24Sakai Moreover, serum A, RAGE activator, perpetuates feed-forward cycle gene 1).21Pichler signals lead ongoing mediators, factors, immune cell recruitment.19Zhao Scholar,21Pichler Notably, newer glucose-lowering agents, glucagon-like peptide-1 agonists (GLP-1 RAs), prevent CKD T2D, independent their effects.25Neuen B.L. Young Heerspink prevention patients diabetes: meta-analysis.Lancet Endocrinol. 7: 845-854Abstract (339) 26Cannon C.P. Perkovic Agarwal al.Evaluating canagliflozin events mellitus according baseline HbA1c, HbA1c <7%: CREDENCE trial.Circulation. 141: 407-410Crossref (65) 27Mann J.F.E. Buse J.B. Idorn al.Potential protection liraglutide semaglutide: Exploratory mediation analysis.Diabetes Obes Metab. 2021; 23: 2058-2066Crossref (3) 28Tuttle Lakshmanan Rayner B. al.Dulaglutide versus glargine moderate-to-severe (AWARD-7): multicentre, open-label, randomised trial.Lancet 2018; 6: 605-617Abstract (233) 29Kang Jardine M.J. offer benefit beyond diabetes.Nat 17: 83-84Crossref (12) By ameliorating glucotoxicity influx into potent anti-inflammatory effects. preclinical models suppresses hyperglycemia-induced species generation formation attenuates surrounding tubulointerstitial fibrosis.11Alicic Scholar,30Ojima Matsui Nishino al.Empagliflozin, exerts antifibrotic experimental nephropathy partly suppressing AGEs-receptor axis.Horm Metab Res. 47: 686-692Crossref Scholar,31Eleftheriadis Pissas G. Tsogka unifying model human effect dapagliflozin.Int Urol 52: 1179-1189Crossref GLP-1 RAs downregulate pathways nonpancreatic organs.32Alicic Cox Incretin drugs biological evidence.Nat 227-244Crossref (27) rodent RA decreased oxidative stress, transforming factor-beta (TGF-β1), intercellular adhesion molecule-1, tumor necrosis factor-α, IL-1β, macrophages kidney.32Alicic stress nicotinamide adenine dinucleotide phosphatase oxidase cyclic monophosphate–dependent heme oxygenase-1.33Kawanami D. Takashi outcomes mechanisms.Front Pharmacol. 11: 967Crossref (22) Scholar,34Yang H. Li Wang Z. al.Exendin-4 ameliorates ischemia-reperfusion injury rat.J Surg 182: 825-832Abstract (25) Inhibition signaling proposed suppression cytokine chemokine expression.32Alicic exposure occur diet hyperglycemia.20Reidy Scholar,35Uribarri J. Woodruff Goodman al.Advanced foods practical guide reduction diet.J Diet Assoc. 2010; 110: 911-916.e912Abstract (746) Dietary escape gastrointestinal absorption interact colonic microbiota,36Yacoub Nugent Cai restriction bacterial gut microbiota peritoneal dialysis patients; randomized open label controlled trial.PLoS One. 12e0184789Crossref (63) Scholar,37Snelson Coughlan products: digestion, modulation microbial ecology.Nutrients. 22: 215Crossref (82) triggering mediators.38Garay-Sevilla Beeri M.S. la Maza M.P. al.The endproducts development non-infectious diseases: narrative review.Nutr Res Rev. 33: 298-311Crossref (6) Activation RAGE-dependent causes mucosal barrier dysfunction translocation systemic circulation.39Raman K.G. Sappington P.L. Yang intestinal hemorrhagic shock.Am Gastrointest Liver 2006; 291: G556-G565Crossref Scholar,40Snelson Tan S.M. Clarke al.Processed permeability microvascular diseases.Sci Adv. 7eabe4841Crossref As progresses, greater amounts ammonia urea shift toward Gram-negative bacteria gut. Lipopolysaccharides walls toll-like receptor-4 production, recruitment lipopolysaccharides.41Zhang Meng microbiome mellitus.Diabetes Pract. 172: 108645Abstract Scholar,42Ramezani Raj D.S. microbiome, targeted interventions.J 25: 657-670Crossref (397) Exposure podocytes, these lipopolysaccharides injury, inflammation, fibrosis.43Ma Chadban S.J. Zhao C.Y. al.TLR4 promotes podocyte interstitial nephropathy.PLoS 9: e97985Crossref Diabetes-associated protective short-chain fatty disruption.41Zhang Scholar,44Mosterd Kanbay van den Born al.Intestinal derived metabolites inmodulation progression.Best Pract Endocrinol 35: 101484Crossref 45Reichardt Duncan S.H. al.Phylogenetic distribution three propionate microbiota.ISME 1323-1335Crossref (530) 46Diener Reyes-Escogido M.L. Jimenez-Ceja L.M. al.Progressive shifts reflect prediabetes treatment-naive Mexican cohort.Front (Lausanne). 602326Crossref (2) Complex especially essentially "diseases diseases," such present major challenges deciphering reproducible genetic contributions susceptibility severity.47Cole Florez J.C. Genetics complications.Nat 377-390Crossref (163) Advances acquiring large datasets genome-wide association yielded insights shed light predisposition DKD. Missense mutations COL4A3 gene, encodes structural component basement membrane (GBM), known Alport syndrome.48Salem R.M. Todd J.N. Sandholm al.Genome-wide study highlights biology involved collagen.J 30: 2000-2016Crossref Recently, variant (rs55703767) linked "diabetic nephropathy" T1D, suggesting disordered collagen expression.48Salem was most evident glycated hemoglobin. less GBM thickening glomerulosclerosis among either who biopsy data. Thus, "second-hit" phenomenon operative consequences hyperglycemia, damage. Variants genes (DDR1, COLEC11, BMP7) various phenotypes.48Salem contrast variants, APOL-l G1/G2 alleles observed African ancestry nondiabetic often when accompanied "second hit," viral illness interferon state.49Friedman D.J. Pollak M.R. APOL1 genetics applications.Clin 294-303Crossref (11) Another APOL-1 (rs9622363) recently reported meta-analysis American it progression.50Guan Keaton Dimitrov identifies novel loci diabetes-attributed end-stage Americans.Hum Genomics. 13: 21Crossref Among European cohort GABRR1 (rs9942471) highly microalbuminuria.51van Zuydam N.R. Ahlqvist E. subjects diab

Language: Английский

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Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3086 - 3086

Published: March 7, 2024

Diabetic kidney disease (DKD) is a major cause of chronic (CKD), and it heightens the risk cardiovascular incidents. The pathogenesis DKD thought to involve hemodynamic, inflammatory, metabolic factors that converge on fibrotic pathway. Genetic predisposition unhealthy lifestyle practices both play significant role in development progression DKD. In spite recent emergence angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid antagonists (NS-MRAs), current therapies still fail effectively arrest Glucagon-like peptide 1 receptor agonists (GLP-1RAs), promising class agents, possess potential act as renal protectors, slowing Other including pentoxifylline (PTF), selonsertib, baricitinib hold great promise for due their anti-inflammatory antifibrotic properties. Multidisciplinary treatment, encompassing modifications drug therapy, can decelerate Based treatment heart failure, recommended use multiple drugs combination rather than single-use Unearthing mechanisms underlying urgent optimize management Inflammatory (including IL-1, MCP-1, MMP-9, CTGF, TNF-a TGF-β1), along with lncRNAs, not only serve diagnostic biomarkers, but also therapeutic targets. this review, we delve into We explore additional value combing these develop novel strategies. Drawing from understanding pathogenesis, propose HIF AGE epigenetic targets future.

Language: Английский

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Preventing CKD in Developed Countries

Kidney International Reports, Journal Year: 2019, Volume and Issue: 5(3), P. 263 - 277

Published: Dec. 18, 2019

Chronic kidney disease (CKD) is an important public health concern in developed countries because of both the number people affected and high cost care when prevention strategies are not effectively implemented. Prevention should start at governance level with institution multisectoral polices supporting sustainable development goals ensuring safe healthy environments. Primordial CKD can be achieved through implementation measures to ensure fetal (kidney) development. Public prevent diabetes, hypertension, obesity as risk factors for important. These approaches cost-effective reduce overall noncommunicable burden. Strategies nontraditional factors, including nephrotoxin exposure, stones, infections, environmental exposures, acute injury (AKI), need tailored local needs epidemiology. Early diagnosis treatment such obesity, hypertension key primary CKD. tends occur more frequently progress rapidly among indigenous, minority, socioeconomically disadvantaged populations. Special attention required meet these Effective secondary relies on screening individuals detect treat early, using established emerging strategies. Within high-income countries, barriers accessing effective therapies must recognized, overcome obstacles, training support identify CKD, appropriately implement clinical practice guidelines.

Language: Английский

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Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A Post Hoc Analysis from the CREDENCE Trial

Journal of the American Society of Nephrology, Journal Year: 2020, Volume and Issue: 31(12), P. 2925 - 2936

Published: Sept. 30, 2020

Significance Statement Studies of renin-angiotensin system inhibitors have consistently shown that the magnitude albuminuria reduction during first months treatment is associated with risk for kidney and cardiovascular outcomes. Whether or not association between early changes in these outcomes also occurs sodium-glucose cotransporter 2 (SGLT2) inhibition unclear. This post hoc analysis Canagliflozin Renal Events Diabetes Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that, people type diabetes CKD, SGLT2 inhibitor canagliflozin results an sustained albuminuria. It shows were independently long-term These findings highlight importance monitoring to assess prognosis. Background The events primarily based on trials blockade. unclear whether this inhibition. Methods enrolled 4401 patients CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). assessed canagliflozin’s effect how change (baseline week 26) primary outcome (ESKD, doubling serum creatinine, death), major adverse events, hospitalization heart failure death. Results Complete data other covariates available 3836 (87.2%) participants CREDENCE trial. Compared placebo, lowered UACR by 31% (95% confidence interval [95% CI], 27% 36%) at 26, significantly increased likelihood achieving a 30% (odds ratio, 2.69; 95% CI, 2.35 3.07). Each decrease over 26 weeks was lower hazard (hazard [HR], 0.71; 0.67 0.76; P <0.001), (HR, 0.92; 0.88 0.96; death 0.86; 0.81 0.90; <0.001). Residual levels remained strong independent factor overall each arm. Conclusions In use early, reductions albuminuria, which

Language: Английский

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Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors

Cell Reports, Journal Year: 2020, Volume and Issue: 32(4), P. 107954 - 107954

Published: July 1, 2020

Diabetic kidney disease (DKD) increases the risk for mortality and is leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates progression DKD, especially in patients advanced Herein, we show that diabetes, mTORC1 activity increased proximal tubule cells (RPTCs) along enhanced tubule-interstitial fibrosis; this prevented by SGLT2i. Constitutive activation RPTCs induces fibrosis failure abolishes renal-protective effects SGLT2i diabetes. On contrary, partial inhibition prevents decline function. Stimulation turns on a pro-fibrotic program cortex, whereas its diabetes reverses alterations gene expression. We suggest RPTC critical node mediates dysfunction protective regulating fibrogenesis.

Language: Английский

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The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

Diabetes Care, Journal Year: 2021, Volume and Issue: 44(8), P. 1805 - 1815

Published: July 7, 2021

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report change the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations lower risk.DECLARE-TIMI 58 randomized 17,160 type diabetes, creatinine clearance >60 mL/min, and either atherosclerotic disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 yearly thereafter. The UACR over time measured as a continuous categorical variable (≤15, >15 <30, ≥30 ≤300, >300 mg/g) by treatment arm. composite ≥40% sustained decline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, end-stage kidney disease, renal death; specific all except death.Baseline available 16,843 (98.15%) participants: 9,067 (53.83%) ≤15 mg/g, 2,577 (15.30%) <30 4,030 (23.93%) 30-300 1,169 (6.94%) mg/g. Measured variable, improved from baseline 4.0 years dapagliflozin, compared placebo, across eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement more common versus placebo (hazard 1.45 [95% CI 1.35-1.56], Cardiorenal reduced subgroups of mg/g (P 0.0125, Pinteraction = 0.033), renal-specific 0.05, 0.480).In DECLARE-TIMI 58, demonstrated favorable effect categories, including normal albumin excretion. results suggest role SGLT2i also primary prevention diabetic disease.

Language: Английский

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Improving the residual risk of renal and cardiovascular outcomes in diabetic kidney disease: A review of pathophysiology, mechanisms, and evidence from recent trials

Diabetes Obesity and Metabolism, Journal Year: 2021, Volume and Issue: 24(3), P. 365 - 376

Published: Nov. 15, 2021

Based on global estimates, almost 10% of adults have diabetes, whom 40% are estimated to also chronic kidney disease (CKD). Almost 2 decades ago, treatments targeting the renin-angiotensin system (RAS) were shown slow progression disease. More recently, studies reported additive benefits antihyperglycaemic sodium-glucose co-transporter-2 inhibitors in combination with RAS both CKD and cardiovascular outcomes. However, these recent data showed that patients continue progress failure or die from kidney- cardiovascular-related causes. Therefore, new agents needed address this continuing risk. Overactivation mineralocorticoid (MR) receptor contributes inflammation fibrosis, suggesting it is an appropriate treatment target diabetes CKD. Novel, selective non-steroidal MR antagonists being studied patients, results two large recently completed clinical trials one such treatment, finerenone, significantly reduces events compared standard care. This review summarizes pathogenic mechanisms type examines potential benefit novel disease-modifying inflammatory fibrotic factors patients.

Language: Английский

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What’s New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 570 - 570

Published: Dec. 29, 2022

Diabetic kidney disease (DKD) is the leading cause of chronic disease, including end-stage and increases risk cardiovascular mortality. Although treatment options for DKD, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 mineralocorticoid antagonists, have advanced, their efficacy still limited. Thus, a deeper understanding molecular mechanisms DKD onset progression necessary development new innovative treatments DKD. The complex pathogenesis includes various different pathways, can be broadly classified into inflammatory, fibrotic, metabolic, hemodynamic factors. Here, we summarize recent findings in basic research, focusing on each factor advances Collective evidence from clinical research studies helpful definitive regulatory systems. Further comprehensive exploration warranted to advance our knowledge establish novel preventive strategies.

Language: Английский

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Prognosis and risk factors of chronic kidney disease progression in patients with diabetic kidney disease and non-diabetic kidney disease: a prospective cohort CKD-ROUTE study

Renal Failure, Journal Year: 2022, Volume and Issue: 44(1), P. 1310 - 1319

Published: Aug. 8, 2022

Diabetic kidney disease (DKD) is emerging rapidly as the leading cause of chronic (CKD) worldwide. In this 3-year prospective, multicenter cohort study, a total 1138 pre-dialysis CKD patients were recruited. Patients categorized into two groups according to etiologies DKD and non-diabetic (NDKD). Propensity score matching was performed adjust for confounding factors, resulting in 197 being assigned NDKD groups, respectively. The primary endpoints 50% estimated glomerular filtration rate (eGFR) decline initiation replacement therapy (KRT). secondary all-cause death development cardiovascular (CVD) events. We found that have higher risk develop eGFR endpoint (HR:2.30, 95%CI [1.48–3.58], p < 0.001) KRT (HR:1.64, [1.13–2.37], 0.05) than patients. cumulative incidence significantly (26.90% vs.13.71% 35.03% vs. 22.34%, respectively). Cox regression analyses showed increased systolic blood pressure (SBP), DKD, decreased serum albumin (Alb), stages factors endpoint; SBP, Alb, creatinine (Scr), stages, presence proteinuria CVD age, hemoglobin (Hb), Alb events endpoint. Appropriate preventive or therapeutic interventions should be taken control these predictive delay complications, thereby improving prognosis reducing burden high-risk populations.

Language: Английский

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