An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines

Diabetes Obesity and Metabolism, Journal Year: 2020, Volume and Issue: 22(S1), P. 3 - 15

Published: April 1, 2020

Abstract Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, cause end‐stage kidney disease (ESKD) that requires treatment dialysis or renal transplantation, and associated significantly increased cardiovascular morbidity mortality. DN clinical syndrome characterized by persistent albuminuria progressive decline function, but it increasingly recognized the presentation course diabetes heterogeneous. The term diabetic (DKD) now commonly used encompass spectrum people who have either reductions function. In this article, approach diagnosis DKD will be discussed, as its prognosis. general principles management also reviewed reference current international guidelines.

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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Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

Cell Death and Disease, Journal Year: 2018, Volume and Issue: 9(11)

Published: Nov. 13, 2018

Abstract Renal fibrosis, especially tubulointerstitial is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For long time, interests in renal fibrosis have been concentrated on fibroblasts myofibroblasts. However, recent years, growing numbers studies focused role tubular epithelial cells (TECs). TECs, rather than victim or bystander, are probably neglected mediator responding to variety injuries. The maladaptive repair mechanisms TECs may be key point this process. In review, we will focus fibrosis. We follow fate cell depict intracellular changes after injury. then discuss how mechanism becomes maladaptive, finally intercellular crosstalk interstitium that ultimately proceeds

Language: Английский

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Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: March 14, 2019

Abstract Extracellular vesicles (EVs) that are derived from mesenchymal stromal cells (MSCs) have been shown to reprogram injured by activating regenerative processes. We herein investigate the potential therapeutic effect of EVs, shed human bone marrow MSCs and liver stem-like (HLSCs), on progression reversion fibrosis in a mouse model diabetic nephropathy, as induced streptozotocin. After development stem cell-derived EVs were administered weekly mice for four weeks. The EV treatment, but not fibroblast treatment was used control, significantly ameliorated functional parameters, such albumin/creatinine excretion, plasma creatinine blood urea nitrogen, which altered mice. Moreover, renal develops during nephropathy inhibited cell EV-treated animals. A correlation found between down regulation several pro-fibrotic genes tissues anti-fibrotic HLSC MSC EVs. comparative analysis miRNA content highlighted some common specific patterns miRNAs target predicted genes. In conclusion, inhibit prevent its diabetes-induced chronic kidney injury.

Language: Английский

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Diabetic Kidney Disease: Challenges, Advances, and Opportunities

Kidney Diseases, Journal Year: 2020, Volume and Issue: 6(4), P. 215 - 225

Published: Jan. 1, 2020

<b><i>Background:</i></b> Diabetic kidney disease (DKD) is the most common cause of end-stage renal (ESRD). Regardless intensive treatments with hyperglycemic control, blood pressure and use renin-angiotensin system blockades, prevalence DKD remains high. Recent studies suggest that spectrum has been changed many progresses have made to develop new for DKD. Therefore, it time perform a systemic review on developments in field <b><i>Summary:</i></b> Although classic clinical presentation characterized by slow progression from microalbuminuria macroalbuminuria hyperfiltration at early stage progressive decline function late stage, recent epidemiological patients variety presentations rates ESRD. Some without albuminuria but display prominent vascular interstitial fibrosis histology. are more susceptible acute injury, which might contribute fibrosis. A large portion type 2 diabetic could overlapping nondiabetic glomerular disease, therefore, biopsy required differential diagnosis these patients. Only small eventually progress failure. However, we do not sensitive specific biomarkers identify high-risk Genetic factors strong association identified yet. combination circulating tumor necrosis factor receptor (TNFR)1, TNFR2, injury molecular 1 provides predictive value progression. Artificial intelligence enhance values combining parameters biological markers. Sodium-glucose co-transporter-2 inhibitors should be added standard care Several promising drugs trials. <b><i>Key Messages:</i></b> Over last years, our understanding much improved halt coming. better diagnostic tools, markers, treatment options still urgently needed help us manage this detrimental disease.

Language: Английский

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Development and internal validation of machine learning algorithms for end-stage renal disease risk prediction model of people with type 2 diabetes mellitus and diabetic kidney disease

Renal Failure, Journal Year: 2022, Volume and Issue: 44(1), P. 562 - 570

Published: April 4, 2022

Diabetic kidney disease (DKD) is the most common cause of end-stage renal (ESRD) and associated with increased morbidity mortality in patients diabetes. Identification risk factors involved progression DKD to ESRD expected result early detection appropriate intervention improve prognosis. Therefore, this study aimed establish a prediction model for resulting from type 2 diabetes mellitus (T2DM).Between January 2008 July 2019, total 390 Chinese T2DM confirmed by percutaneous biopsy were enrolled followed up at least 1 year. Four machine learning algorithms (gradient boosting machine, support vector logistic regression, random forest (RF)) used identify critical clinical pathological features build ESRD.There 158 outcome events (40.51%) during 3-year median follow up. The RF algorithm showed best performance predicting ESRD, showing highest AUC (0.90) ACC (82.65%). identified five major factors: Cystatin-C, serum albumin (sAlb), hemoglobin (Hb), 24-hour urine urinary protein, estimated glomerular filtration rate. A nomogram according aforementioned predictive was constructed predict incidence ESRD.Machine can efficiently incident participants. Compared previous models, importance sAlb Hb highlighted current model.HighlightsWhat already known? prognosis intervention.What has found? Machine construct DKD. found be CysC, sAlb, Hb, eGFR, UTP.What are implications study? In contrast treatment participants early-phase or without mild damage, emphasis should placed on indicators function, nutrition, anemia, proteinuria advanced delay rather than age, sex, control hypertension glycemia.

Language: Английский

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Role of mitochondria in pathogenesis and therapy of renal fibrosis

Metabolism, Journal Year: 2024, Volume and Issue: 155, P. 155913 - 155913

Published: April 11, 2024

Language: Английский

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Mechanisms, Biomarkers, and Treatment Approaches for Diabetic Kidney Disease: Current Insights and Future Perspectives

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(3), P. 727 - 727

Published: Jan. 23, 2025

Diabetic Kidney Disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Among individuals with type 1 diabetes mellitus (T1DM), 30–40% are at risk developing DKD. This review focuses on mechanistic processes, available and emerging biomarkers for diagnosing, monitoring, preventing DKD, as well treatment options targeted DKD patients. A literature search was conducted PubMed Scopus using specific keywords. Inclusion exclusion criteria were applied to select articles used this review. The highlights various mechanisms involved in progression more severe stages. Additionally, several have been identified, which aid diagnosing monitoring disease. Furthermore, numerous approaches being explored address underlying causes Advanced research exploring new medications remission; sodium-glucose cotransport (SGLT2) inhibitors finerenone, particular, gaining attention their novel renoprotective effects. a major complication diabetes, marked by complex multifactorial mechanisms. Thus, understanding these processes essential therapies potentially reverse progression. Biomarkers show promise early diagnosis progression, while current strategies underscore importance multifaceted approach.

Language: Английский

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Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

Diabetes Obesity and Metabolism, Journal Year: 2020, Volume and Issue: 22(S1), P. 16 - 31

Published: April 1, 2020

Abstract Diabetic kidney disease (DKD) is the primary cause of chronic around globe and one main complications in patients with type 1 2 diabetes. The standard treatment for DKD drugs controlling hyperglycemia high blood pressure. Renin angiotensin aldosterone system blockade sodium glucose cotransporter (SGLT2) inhibition have yielded promising results DKD, but many diabetic on such treatments nevertheless continue to develop leading failure cardiovascular comorbidities. New therapeutic options are urgently required. We review here avenues based insights into mechanisms that recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon‐like peptide‐1 agonist, endothelin A inhibition, anti‐inflammatory agents, autophagy activators epigenetic remodelling. involvement several molecular pathogenesis, together genetic variability this condition, makes it difficult target heterogeneous patient population a single drug. Personalized medicine, taking account mechanistic variability, may therefore improve renal protection DKD.

Language: Английский

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Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway

Bioscience Reports, Journal Year: 2018, Volume and Issue: 39(1)

Published: Dec. 21, 2018

Background and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which associated with increased oxidative stress impaired nuclear factor erythroid 2-related 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that secreted the rhythm of light/dark cycle, has antioxidative effects in reducing acute injury (AKI). However, molecular mechanism melatonin protection against I/R state diabetes still unknown. In present study, we hypothesized attenuates renal by activating silent information regulator protein 1 (SIRT1) expression Nrf2/HO-1 Methods: Control or streptozotocin (STZ)-induced Type diabetic rats were treated without for 4 weeks. Renal was achieved clamping both left right pedicles 30 min followed reperfusion 48 h. Results: undergoing prevented from I/R, aspects histopathological score, cell apoptosis, kidney, accompanied decreased expressions SIRT1, Nrf2, HO-1 as compared those control rats. All these alterations attenuated treatment; but beneficial abolished selective inhibition SIRT1 EX527. Conclusion: These findings suggest could attenuate diabetes, possibly through improving SIRT1/Nrf2/HO-1

Language: Английский

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