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Diabetic Kidney Disease: 2021 Update Diabetic nephropathy research advancements Nephropathy, or Resaerch Kidney Sdvancements, refers to nephro;athy deterioration of kidney functioning Hypoglycemic unawareness awareness resources patients affected by nephropatjy 1 and type 2 advancemenst. Important Diabetic nephropathy research advancements : All contributions to this Research Topic must be within the scope of the Diabeticc and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review. No records found. total views article views downloads topic views. With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area!Diabetic nephropathy research advancements -
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To date, diabetic kidney disease is the leading cause of kidney failure, and the single highest cause of diabetic mortality. Nevertheless, research has yet to reveal a definitive mechanism for the association between hyperglycemia and damage to the kidneys.
Through this topic, the heterogeneity of diabetic nephropathy eitology and the underlying molecular mechanisms will be explored. To this end, genetic and epigenetic factors associated with nephropathy will be considered as well as the role of oxidative stress and ferroptosis.
Also pertinent to this topic, is how the oxidative-stress pathway can be modulated to prevent or reverse diabetic nephropathy. Additionally, a special focus will be given to early biomarkers that can lead to better understanding and early detection of the disease are of great interest.
Subsequently, a large prospective study further confirmed that AKI itself can also predict major adverse outcomes including doubling of serum creatinine or ESRD in patients with diabetes [ 27 ]. Results of the latest research are in line with the above; they found that AKI events were associated with progression to renal replacement rate and also with a greater severity of subsequent AKI [ 28 ].
This may explain why some DKD patients have an early decline of GFR with a minimal amount of albuminuria. Not all DKD patients have identical progression rates.
In general, about one-third of patients will progress to MA in 15—20 years after the diagnosis of diabetes and normoalbuminuria. One-third of patients with MA do not progress after treatments, but another one-third of them will deteriorate to macroalbuminuria within 10 years.
In the next 10 years, one-third of those with macroalbuminuria will develop to ESRD. Only one-third of the ESRD patients will be still alive in the following 5 years.
Since the progression rate is so different among individual patients with DKD, we need to develop new biomarkers that allow us to predict the progression rate of GFR at the early stage of DKD.
When patients of all types of diabetes have been included, the incidence rate of ESRD has been 1—9 per 1, patient-years [ ]. In type I diabetes patients, the cumulative risk of ESRD and the incidence of renal replacement rate have decreased markedly during the past 5 decades [ 33 ] but that is not obvious in type 2 diabetes patients [ 34 ].
Studies suggest that intensive glycemic control did not reduce significantly clinical renal end points, including doubling of serum creatinine, ESRD, and death from renal disease in type 2 DM [ 35 ]. Many studies have been undertaken to develop the biomarkers for early detection of these high-risk DKD patients.
MA is a dynamic marker at the early stage of DKD and therefore could not be used to predict the progression of DKD [ 36 ].
In addition, progression of DKD is not necessarily associated with proteinuria, and thus, proteinuria is also not a sensitive marker for DKD progression. Although intensive glycemic control is able to reduce nephropathy in both type 1 [ 37 ] and type 2 diabetes [ 38 ], hemoglobin A1c at the early stage of DKD does not predict the late progression of DKD [ 39 ].
As for kidney pathology, structural predictors of loss of renal function in American Indians with type 2 diabetes include mean glomerular volume, glomerular basement membrane GBM width, mesangial fractional volume per glomerulus, glomerular filtration surface density, nonpodocyte number per glomerulus, foot process width, podocyte detachment, and endothelial fenestration [ 40 ].
However, it is unusual to perform kidney biopsy at early DKD. In addition, an autopsy study suggests that histological findings do not necessary correlate with clinical presentation in diabetic patients [ 41 ].
Searching for genetic factors is another important approach. Unfortunately, none of the genetic factors have been found to have a strong association with the progression of DKD.
Family Investigation of Nephropathy and Diabetes Research Group recently reported that no genome region showed linkage across all ethnic groups.
The Genetics of Kidneys in Diabetes GoKind study showed no single major gene that contributes to an increased risk of diabetic nephropathy DN emerged from the analysis of their data [ 42 ].
Many groups have investigated blood and urine biomarkers for DKD progression based on the pathogenesis of the disease such as cytokines and growth factors. Serum markers include soluble tumor necrosis factor receptor α TNFα receptors, TNFα, interleukin 6 IL-6 neutrophil gelatinase-associated lipocalin, IL and L-type fatty acid-binding protein of tubular cell injury, serum endothelial nitric oxide synthase, von Willebrand factor and vascular endothelial growth factor, and kidney injury molecular 1 KIM So far, the best circulating biomarkers that could predict the progression of DKD are tumor necrosis factor receptor TNFR 1, TNFR2, and KIM Gohda et al.
Elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria [ 45 ].
TNFR but not hemoglobin A1c predicts that the progression of CKD may imply the possibility that DKD is an inflammatory disease, which could explain why hyperglycemic control is not enough to control the disease progression.
Fornoni et al. Further researches are in need to clarify how activation of circulating TNF pathway contributes to DKD. In addition, KIM-1 level at baseline was observed strongly predicted rate of eGFR loss and ESRD during 5—15 years of follow-up in a cohort of patients with type 1 diabetes and proteinuria [ 44 ].
This suggests that tubular cell injury occurred early at DKD and was associated with the progression. Coca et al. In the future, artificial intelligence could be applied to combine clinical parameters with the circulating biomarkers to enhance the predictive value for DKD progression.
Identification of such a diagnostic tool will help us to better manage the patients with the early stages of DKD. This includes lifestyle modification, resource allocation, and the use of medications. The progression and related biomarkers of DKD are seen in Figure 2.
Progression and biomarkers of DKD. KIM-1, kidney injury molecular 1; TNFR, tumor necrosis factor receptor; GBM, glomerular basement membrane; eGFR, estimated glomerular filtration rate; KW, Kimmelstiel-Wilson; ESRD, end-stage renal disease; MA, microalbuminuria.
DN is classically characterized by GBM thickening, mesangial expansion, nodular glomerular sclerosis, and tubulointerstitial fibrosis [ 48 ]. The traditional paradigm of glomerulus-centered pathophysiology has expanded to the tubule-interstitium and the immune response [ 49 ].
In type 1 diabetes patients, Mauer et al. In later stages, afferent and efferent arteriolar hyalinosis and Kimmelstiel-Wilson nodules are seen, both of which are considered specific findings of DN. Simultaneously, tubular basement thickening, parallel to GBM thickening, is also observed.
As for type 2 diabetes, the pathological changes are more complicated and often classified into 3 categories [ 53 ]: class I is the classic diabetic glomerulopathy as described above; class II has predominant vascular and interstitial changes, relatively normal glomerular structure.
This group of patients often has an early decline of GFR without significant albuminuria. Clinically, patients have an early decline of GFR without significant proteinuria. Mechanistically, these patients may have unrecognized AKI episodes during the disease progression.
It is unclear whether diabetes interacts with the primary glomerular disease to accelerate the progression of CKD. In type 1 diabetes, most patients could have a diagnosis of DKD based on clinical presentation. However, the diagnosis of DKD in type 2 diabetes often requires additional tests including kidney biopsy.
Diabetes is a common disease with high coincidence with other nondiabetic CKD. Another interesting observation is that clinical manifestation is not necessarily associated with histological findings in DKD, as suggested by an autopsy study [ 41 ]. In that research, of patients had histopathologic changes of DN in the kidney, but 20 of histologically proven DN cases did not present with DN-associated clinical manifestations within their lifetime.
At the most clinical practice, patients with atypical clinical features should prompt evaluation for non-DKD by performing kidney biopsy. These atypical presentations are constructed of rapidly decreasing renal function, rapidly increasing proteinuria, active urinary sediment, refractory hypertension, and nephrotic range of proteinuria with normal GFR.
Membranous diseases or minimal change disease should be ruled out from a nephrotic range of proteinuria with normal GFR because these patients could be treated with steroids and immunosuppressive therapy. Conventional therapy of DKD includes better hyperglycemic control, RAS blockers, and other managements such as lipid-lowering therapy and so on.
In humans, RAS inhibition has proved to be the single most effective therapy for slowing the progression of DN [ 54 ]. However, 3 randomized, placebo-controlled trials of —3, patients with type 1 diabetes and normoalbuminuria RASS [ 55 ], EUCLID [ 56 ], AND DIRECT [ 57 ] suggest that early therapy in patients, type 1 diabetes is ineffective in preventing the development of MA.
In addition, the combination therapy with an angiotensin-converting enzyme inhibitor plus an angiotensin II receptor blocker does not prevent renal disease progression or death, and it increases the rate of serious adverse events such as AKI, hyperkalemia, and hypotension, as shown by the Veterans Affairs Nephropathy in Diabetes study VA NEPHRON-D [ 58 ].
The continued increase in diabetic ESRD urgently requires additional innovative therapies. A better understanding of the pathogenesis of DKD could help us to identify new drug targets for DKD.
The recent success of SGLT2 inhibitors as a new therapy for DKD patients is exciting and encouraging news for the nephrologists. SGLT2 inhibitors have been shown to lower body weight, blood pressure, serum uric acid, and glomerular hyperfiltration through increased urinary excretion of glucose and sodium, osmotic diuresis, and improved tubule-glomerular feedback mechanism [ 60 ].
In patients with type 2 DM and high cardiovascular risks, empagliflozin is associated with slower progression of kidney disease and lower rates of clinically relevant renal events than placebo when added to standard care [ 62, 63 ].
Canagliflozin, another SGLT2 inhibitor, was shown in patients with type 2 diabetes and kidney disease CREDENCE ; the risk of kidney failure was significantly lower in the canagliflozin group than in the placebo group at a median follow-up of 2. In Dekkers research, they demonstrated that 6 weeks of dapagliflozin decreased albuminuria by In another study NCT , in patients with type 2 diabetes and CKD 3A, decreases from baseline in eGFR were greater with dapagliflozin than placebo at Week 24 —2.
However, attentions should be paid to side effects such as hypoglycemia, urinary and genital infections, elevated liver enzymes, bone fractures, or amputations. Glucagon-like peptide-1 GLP-1 is one of the incretins released from the intestine in response to food intake and it can stimulate insulin secretion.
Its level is decreased and its analogs e. liraglutide have been used in type 2 DM. According to the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcomes Results double-blind trial with 9, patients with type 2 DM and high cardiovascular risk, patients with liraglutide had lower rate of new onset of persistent macroalbuminuria and progression of DKD than placebo [ 68, 69 ].
In another randomized study of 3, patients with type 2 diabetes, patients using semaglutide another GLP-1 analog had lower rates of new or deteriorating nephropathy than those with placebo [ 70 ].
Dipeptidyl peptidase 4 inhibitors linagliptin and saxagliptin can reduce the amount of albuminuria, but the evidence is less clear than GLP-1 analog [ 71, 72 ]. Peroxisome proliferator activated receptor-γ agonist, rosiglitazone, can significantly decrease urinary albumin to creatinine ratio in type 2 diabetes patients after 3 months of therapy [ 73 ].
Avosentan, an endothelin-1 receptor A antagonist, can reduce urinary albumin excretion, but the study was terminated early because of excessive cardiovascular events during the treatment course due to the fluid overload [ 75 ].
A recent study in patients showed that atrasentan, a more selective endothelin receptor A antagonist, had a proteinuria-lowering effect without significant accumulation of body fluid [ 76 ]. However, this study was terminated early due to the recruitment issue.
Future studies are required to confirm whether atrasentan has additional renal protective effects on top of the RAS blockades and SGLT2 inhibitors, the new standard care for DKD patients.
Mineralocorticoid receptor antagonists MRA exert an antifibrotic and anti-inflammatory effect on the kidneys and other target organs like the heart and vessels [ 77 ].
Due to significant side effects associated with the first- spironolactone and second- eplerenone generation MRA, new MRA such as apararenone also called MT , esaxerenone, and finerenone have a relatively low risk of hyperkalemia.
A clinical trial of MT in patients with DKD NCT is ongoing in Japan clinicaltrials. Esaxerenone is also being studied in phase II and III randomized clinical trial RCT , but no results have been published yet [ 78 ]. Finerenone has been investigated in several phase II RCTs.
In the MRA tolerability study-heart failure ARTS-HF , finerenone reduced albuminuria in patients with CKD and heart failure and had a lower risk of hyperkalemia than spironolactone [ 79 ]. The risk of hyperkalemia leading to discontinuation was 2.
Two double-blind placebo-controlled phase III RCTs, FIDELIO NCT and FIGARO NCT are currently ongoing to examine the effects of finerenone on DKD and cardiovascular outcomes [ 81, 82 ]. Another phase III RCT NCT to determine the effect of pirfenidone on GFR and albuminuria in patients with DKD is still ongoing.
Pentoxifylline, another nonspecific antifibrotic agent, was shown to reduce albuminuria and slow progression of renal disease in patients with type 2 diabetes with stages 3—4 CKD on top of RAS blockade [ 83 ].
Two more clinical trials NCT and NCT are ongoing. Hyperglycemia-associated generation of advanced glycation end products AGE and engagement of the receptor for AGE with its ligands can induce oxidative stress and renal inflammation.
Pyridoxamine, a member of family of vitamin B6, can remove free radicals and carbonyl products and block synthesis of AGEs. Clinical studies showed that pyridoxamine did not provide a significant renal protection in DKD patients [ 84 ], but a significant beneficial effect was observed in a subgroup of DKD population.
Therefore, more clinical studies are required to further confirm this finding. Not only in immune cells, but JAK-signal transducer and activator of transcription also play critical roles in renal cells, including mesangial cells, podocytes, and tubular epithelial cells [ 85 ].
This pathway is activated by reactive oxygen species induced by the hyperglycemic state [ 86 ]. A phase II clinical trial using Baricitinib, a selective JAK-1 and JAK-2 inhibitor, showed a reduction of proteinuria and expression of several inflammatory markers in patients with DKD [ 85 ].
Nuclear factor-2 erythroid related factor Nrf2 -keep 1 pathway has been also shown to play a major role in the progression of DKD [ 87 ]. Pharmacological activation of Nrf2 decreases cytokine production, M1 macrophage accumulation, and the formation of an atherosclerotic plaque lipid core in the experimental model of streptozotocin-induced diabetic mice on an apolipoprotein E-deficient background [ 88 ].
In addition, its activation improves the pathological changes in the glomerulus of streptozotocin-induced diabetic mice through a reduction in oxidative stress, TGF-β expression, and extracellular matrix proteins [ 89 ]. Bardoxolone methyl reduces the generation of oxidative stress by the activation of Nrf2 and inhibition of NF-kB pathway.
The short-term study revealed that the use of bardoxolone methyl can increase the GFR in patients with type 2 DM and impaired renal function but have no influence of albuminuria [ 23 ].
However, the large phase III clinical study was terminated early because of more cardiovascular events [ 90 ]. Oxidative stress plays a critical role in the pathogenesis of DN [ 91 ].
NADPH oxidase NOX enzyme isoforms are involved in the production of reactive oxygen species that cause kidney cell injury in DKD [ 92 ]. However, the phase II trial in patients with T2DM and albuminuria failed to show any significant renal protection [ 93 ].
APX, a pan-NOX inhibitor, has been shown to have a renal protective effect in an experimental animal model of diabetes [ 94 ], but human studies have not been done yet.
The proinflammatory chemokine ligand 2, also known as MCP-1, has been implicated in the pathogenesis of DN and has become a novel treatment target. Mouse models treated with NOX-E36, a chemokine ligand 2 inhibitor, exhibited a reduction in albuminuria [ 95 ].
A phase II clinical trial demonstrated that treatment of NOX-E36 reduced albuminuria in patients with T2DM and DN [ 96 ]. Long-term effects of these medications on renal outcomes and mortality are still in need.
All drugs for DKD treatment are shown in Table 1. DKD remains the most common cause of ESRD in the world including the US and China. DM patients with CKD could have a variety of clinical presentations with or without albuminuria. We need to perform more kidney biopsy for DKD patients with albuminuria because a significant number of DM patients could have non-DKD glomerular disease.
The clinical presentation does not necessarily correlate with histological changes in DKD patients. Identification of biomarkers for early detection of DKD patients at high risk for progression could help us to better manage DKD patients and prevent their progression.
Identification of SGLT2 inhibitors as a new therapy for DKD has a huge impact, however, is not sufficient to halt the progression of DKD.
Therefore, there is an urgent need to better understand the pathogenesis of DKD and develop more drugs to treat these patients. is supported by VA Merit Award, NIH 1R01DK, NIH 1R01DK, NIH PDK; K. is supported by NIH R01 DK Sign In or Create an Account.
Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Kidney Diseases. Advanced Search. Skip Nav Destination Close navigation menu Article navigation. Volume 6, Issue 4. Good and Bad News in the DKD Epidemiology.
Albuminuria Is Not Necessarily Associated with a Decline in Glomerular Filtration Rate in DKD. Identification of High-Risk DKD Patients.
New Insights into DKD Pathology. Challenges and Opportunities in Developing New Therapies for DKD. Disclosure Statement. Funding Sources. Author Contributions. Article Navigation. Review Articles March 31 Diabetic Kidney Disease: Challenges, Advances, and Opportunities Subject Area: Nephrology.
Ya Chen ; Ya Chen. b Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
This Site. Google Scholar. Kyung Lee ; Kyung Lee. Zhaohui Ni ; Zhaohui Ni. John Cijiang He John Cijiang He. he mssm.
Kidney Dis 6 4 : — Article history Received:. Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest.
View large Download slide. Table 1. Review of drugs for DKD treatments. View large. View Large. There are no acknowledgments to declare. The authors have no conflicts of interest to declare. and J.
Received date: February 21, ; Nephroparhy date: Nephropatjy 14, ; Published date: March 17, Citation: Ti Avdancements, Xue Diabetic nephropathy research advancements, Yin Q, Shao S, Cai J, et al. J Clin Exp Nephrol doi: Copyright: © Ti M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Diabetic nephropathy research advancements -
Two double-blind placebo-controlled phase III RCTs, FIDELIO NCT and FIGARO NCT are currently ongoing to examine the effects of finerenone on DKD and cardiovascular outcomes [ 81, 82 ].
Another phase III RCT NCT to determine the effect of pirfenidone on GFR and albuminuria in patients with DKD is still ongoing. Pentoxifylline, another nonspecific antifibrotic agent, was shown to reduce albuminuria and slow progression of renal disease in patients with type 2 diabetes with stages 3—4 CKD on top of RAS blockade [ 83 ].
Two more clinical trials NCT and NCT are ongoing. Hyperglycemia-associated generation of advanced glycation end products AGE and engagement of the receptor for AGE with its ligands can induce oxidative stress and renal inflammation.
Pyridoxamine, a member of family of vitamin B6, can remove free radicals and carbonyl products and block synthesis of AGEs. Clinical studies showed that pyridoxamine did not provide a significant renal protection in DKD patients [ 84 ], but a significant beneficial effect was observed in a subgroup of DKD population.
Therefore, more clinical studies are required to further confirm this finding. Not only in immune cells, but JAK-signal transducer and activator of transcription also play critical roles in renal cells, including mesangial cells, podocytes, and tubular epithelial cells [ 85 ].
This pathway is activated by reactive oxygen species induced by the hyperglycemic state [ 86 ]. A phase II clinical trial using Baricitinib, a selective JAK-1 and JAK-2 inhibitor, showed a reduction of proteinuria and expression of several inflammatory markers in patients with DKD [ 85 ].
Nuclear factor-2 erythroid related factor Nrf2 -keep 1 pathway has been also shown to play a major role in the progression of DKD [ 87 ].
Pharmacological activation of Nrf2 decreases cytokine production, M1 macrophage accumulation, and the formation of an atherosclerotic plaque lipid core in the experimental model of streptozotocin-induced diabetic mice on an apolipoprotein E-deficient background [ 88 ].
In addition, its activation improves the pathological changes in the glomerulus of streptozotocin-induced diabetic mice through a reduction in oxidative stress, TGF-β expression, and extracellular matrix proteins [ 89 ]. Bardoxolone methyl reduces the generation of oxidative stress by the activation of Nrf2 and inhibition of NF-kB pathway.
The short-term study revealed that the use of bardoxolone methyl can increase the GFR in patients with type 2 DM and impaired renal function but have no influence of albuminuria [ 23 ].
However, the large phase III clinical study was terminated early because of more cardiovascular events [ 90 ]. Oxidative stress plays a critical role in the pathogenesis of DN [ 91 ].
NADPH oxidase NOX enzyme isoforms are involved in the production of reactive oxygen species that cause kidney cell injury in DKD [ 92 ]. However, the phase II trial in patients with T2DM and albuminuria failed to show any significant renal protection [ 93 ].
APX, a pan-NOX inhibitor, has been shown to have a renal protective effect in an experimental animal model of diabetes [ 94 ], but human studies have not been done yet. The proinflammatory chemokine ligand 2, also known as MCP-1, has been implicated in the pathogenesis of DN and has become a novel treatment target.
Mouse models treated with NOX-E36, a chemokine ligand 2 inhibitor, exhibited a reduction in albuminuria [ 95 ]. A phase II clinical trial demonstrated that treatment of NOX-E36 reduced albuminuria in patients with T2DM and DN [ 96 ]. Long-term effects of these medications on renal outcomes and mortality are still in need.
All drugs for DKD treatment are shown in Table 1. DKD remains the most common cause of ESRD in the world including the US and China. DM patients with CKD could have a variety of clinical presentations with or without albuminuria.
We need to perform more kidney biopsy for DKD patients with albuminuria because a significant number of DM patients could have non-DKD glomerular disease.
The clinical presentation does not necessarily correlate with histological changes in DKD patients. Identification of biomarkers for early detection of DKD patients at high risk for progression could help us to better manage DKD patients and prevent their progression. Identification of SGLT2 inhibitors as a new therapy for DKD has a huge impact, however, is not sufficient to halt the progression of DKD.
Therefore, there is an urgent need to better understand the pathogenesis of DKD and develop more drugs to treat these patients. is supported by VA Merit Award, NIH 1R01DK, NIH 1R01DK, NIH PDK; K. is supported by NIH R01 DK Sign In or Create an Account.
Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Kidney Diseases. Advanced Search. Skip Nav Destination Close navigation menu Article navigation.
Volume 6, Issue 4. Good and Bad News in the DKD Epidemiology. Albuminuria Is Not Necessarily Associated with a Decline in Glomerular Filtration Rate in DKD.
Identification of High-Risk DKD Patients. New Insights into DKD Pathology. Challenges and Opportunities in Developing New Therapies for DKD. Disclosure Statement. Funding Sources.
Author Contributions. Article Navigation. Review Articles March 31 Diabetic Kidney Disease: Challenges, Advances, and Opportunities Subject Area: Nephrology. Ya Chen ; Ya Chen. b Department of Nephrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
This Site. Google Scholar. Kyung Lee ; Kyung Lee. Zhaohui Ni ; Zhaohui Ni. John Cijiang He John Cijiang He. he mssm. Kidney Dis 6 4 : — Article history Received:.
Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide. Table 1. Review of drugs for DKD treatments. View large. View Large. There are no acknowledgments to declare.
The authors have no conflicts of interest to declare. and J. wrote the manuscript; K. and Z. revised manuscript. Karger Publishers [Internet]. Centers for Disease Control and Prevention: National Diabetes Statistics Report, Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in Search ADS.
Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. How to prevent the microvascular complications of type 2 diabetes beyond glucose control. Incidence of End-Stage Renal Disease Attributed to Diabetes Among Persons with Diagnosed Diabetes - United States and Puerto Rico, In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria.
Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes. The Presence and Consequence of Nonalbuminuric Chronic Kidney Disease in Patients With Type 1 Diabetes. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes.
Normoalbuminuric renal-insufficient diabetic patients: a lower-risk group. Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: the renal insufficiency and cardiovascular events RIACE Italian multicenter study.
Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes.
Rate and determinants of association between advanced retinopathy and chronic kidney disease in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events RIACE Italian multicenter study.
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The influence of multiple episodes of acute kidney injury on survival and progression to end stage kidney disease in patients with chronic kidney disease. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT.
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Cumulative Risk of End-Stage Renal Disease Among Patients With Type 2 Diabetes: A Nationwide Inception Cohort Study. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes.
Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds.
Structural Predictors of Loss of Renal Function in American Indians with Type 2 Diabetes. Insights to the genetics of diabetic nephropathy through a genome-wide association study of the GoKinD collection. Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease.
Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. The early natural history of nephropathy in type 1 diabetes: I.
Study design and baseline characteristics of the study participants. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria.
Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Combined angiotensin inhibition for the treatment of diabetic nephropathy.
Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. van Bommel. SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.
Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. UK Prospective Diabetes Study Group.
Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers.
Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment chronic kidney disease stage 3A : the DERIVE Study. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction.
A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. de Zeeuw. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.
Genomic and rapid effects of aldosterone: what we know and do not know thus far. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
Mineralocorticoid Receptor Antagonist Tolerability Study—Diabetic Nephropathy ARTS-DN Study Group. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial.
Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Blood pressure and sympathetic nervous system response to renal denervation. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial.
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Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy. C-C motif-ligand 2 inhibition with emapticap pegol NOX-E36 in type 2 diabetic patients with albuminuria.
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Citing articles via Web Of Science CrossRef Latest Most Read Most Cited From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective. Bakris; Diabetic Nephropathy: Update on Pillars of Therapy Slowing Progression.
Diabetes Care 1 September ; 46 9 : — Management of diabetic kidney disease DKD has evolved in parallel with our growing understanding of the multiple interrelated pathophysiological mechanisms that involve hemodynamic, metabolic, and inflammatory pathways.
These pathways and others play a vital role in the initiation and progression of DKD. Since its initial discovery, the blockade of the renin-angiotensin system has remained a cornerstone of DKD management, leaving a large component of residual risk to be dealt with.
The advent of sodium—glucose cotransporter 2 inhibitors followed by nonsteroidal mineralocorticoid receptor antagonists and, to some extent, glucagon-like peptide 1 receptor agonists GLP-1 RAs has ushered in a resounding paradigm shift that supports a pillared approach in maximizing treatment to reduce outcomes.
This pillared approach is like that derived from the approach to heart failure treatment. In this way, each drug class focuses on a specific aspect of the disease's pathophysiology.
In this article, we review the evolution of the pillar concept of therapy as it applies to DKD and discuss how it should be used based on the outcome evidence. We also discuss the exciting possibility that GLP-1 RAs may be an additional pillar in the quest to further slow kidney disease progression in diabetes.
Presently the leading cause of end-stage kidney disease ESKD worldwide, DKD affects million people, and it disproportionately affects those who are socially disadvantaged 2. The global percentage of prevalent ESKD patients with diabetes increased from In , half of all patients in the U.
with ESKD had diabetes reported as the primary etiologic cause 4. The current global prevalence of diabetes is million and is projected to grow to million by 5 , reaching million by 6. Further, the number of renal replacement treatment RRT recipients has steadily climbed from 2.
Albeit lifesaving, RRT expansion is not economically tenable, given the unhealthy aging trends of growing populations, and is often inaccessible to many low- and middle-income countries. Notably, a small subgroup of people progress to ESKD without significant albuminuria 9. The foremost goal of curtailing DKD progression is, therefore, to reduce CVD risk and then to avoid dialysis Compared with levels for the general population, DKD confers a threefold higher risk of all-cause mortality and a year loss in life expectancy.
Reduced eGFR and albuminuria independently predict increased CV morbidity and mortality, and the presence of both exerts multiplicative effects on CV mortality risk 11 , 14 , Recognition of the marked CV risk CKD portends is reflected in changes to clinical practice guidelines 8 , 16 that now include CKD among the highest-risk groups in screening and treatment recommendations Heat map representing CKD staging by GFR and albuminuria and risk of further CKD deterioration.
Adapted from Levey et al. Nothing beyond glycemic and blood pressure control was available to halt CKD progression until a trial of captopril in in people with type 1 diabetes The following 8 years of research on angiotensin receptor blockers ARBs further solidified RAS blockade in all patients with diabetes 18 — Thus, additional therapies were needed.
In , the serendipitous discovery of sodium—glucose cotransporter 2 SGLT2 inhibitors provided hope that DKD progression could be further slowed.
This has clearly been shown in multiple outcomes trials Around the same time as the discovery of SGLT2 inhibitors, trials were started on a novel class of agents, the nonsteroidal mineralocorticoid receptor antagonists NS-MRAs , specifically finerenone.
This compound was distinctly different from spironolactone and also slowed DKD, independent of SGLT2 inhibitor use We now have two evidence-based medications, which, when combined with RAS inhibition, are proven to slow DKD progression to approximately 2.
The purpose of this review is to provide an update on what we now have as pillars of therapy to slow DKD. We will also discuss the glucagon-like peptide 1 receptor agonists GLP-1 RAs , as they show promise and are currently being evaluated for modifying the downward trajectory of DKD.
A detailed review of the mechanisms implicated in DKD progression is beyond the scope of this article; however, the reader is referred to some comprehensive articles on this topic 23 , The mechanisms underlying DKD can be broadly conceptualized as stemming from an interplay of three key processes, each with variable contributions depending on the genetic makeup of an individual, which accounts for heterogeneity in the hemodynamic, metabolic, and inflammatory components Fig.
Metabolic, hemodynamic, and inflammatory pathways implicated in the underlying pathophysiology of DKD, underscoring the need for multitargeted therapies to halt disease progression.
MR is a pervasive ligand-activated transcription factor that exerts injury beyond the kidney to endothelial cells, adipocytes, smooth muscle cells, and immune cells 55 , Once released in local tissue, inflammatory cytokines exert pleiotropic effects, setting in motion inflammatory and profibrotic processes that affect adjacent compartments and contribute to increased adverse cross talk between glomeruli, which contributes further to increased scarring AA, afferent arteriole; AGE, advanced glycation end products; EA, efferent arteriole; GM-CSF, granulocyte macrophage colony-stimulating factor; IFNγ, γ-interferon; LPS, lipopolysaccharide; MD, macula densa; NO, nitric oxide; NF-κB, nuclear factor κ light-chain enhancer of activated β-cell; RAGE, receptor-bound advanced glycation end products.
Hemodynamic effects are central to the maintenance of nephron homeostasis and center around the renin-angiotensin-aldosterone system. The enzyme renin is key to the activation of the RAS.
Produced by the juxtaglomerular cells of the nephron, renin is found in the area adjacent to the afferent arterioles. Angiotensin II, which is generated by activation of the RAS, binds avidly to two specific receptors, designated AT1 and AT2, that exert pleiotropic effects 25 , AT1 activation mediates increased efferent arteriolar resistance of the nephron, which increases intraglomerular pressure to maintain the renal filtration rate AT2 receptor activation, in contrast, modulates renal vasodilating prostaglandin release, thereby exerting protective counterregulatory action on blood pressure regulation, which opposes AT1 receptor action High angiotensin II levels exert several nonhemodynamic effects that contribute to renal injury, including increased adrenal aldosterone secretion, induction of fibrogenic chemokines monocyte chemoattractant protein-1 [MCP-1] and transforming growth factor-β [TGF-β] , and macrophage activation, which creates an inflammatory milieu 29 — 31 Fig.
Angiotensin II and endothelin contribute to the earliest changes in glomeruli exposed to hyperglycemia, which results in a mesangial expansion 33 — These changes, along with inflammation, contribute to glomerulosclerosis over time Podocytes are critical for maintaining the permselectivity of the glomerular filtration barrier Podocyte injury leads to foot process effacement and podocyte loss, the unifying mechanism underlying albuminuria in diabetes Fig.
RAS blockade improves permselectivity, whereas dihydropyridine calcium blockers like nifedipine, when used alone, worsen permselectivity Local mechanisms underlying glomerular hypertension.
Endothelin 1, reactive oxygen species, and thromboxane A2 increase efferent vessel tone, whereas insulin resistance upregulates cyclooxygenase 2 COX-2 , prostanoids, and the kallikrein-kinin system, resulting in afferent arteriole dilatation RAS activation damages glomerular endothelial cells GEC , which increases fenestrations and induces apoptosis.
Hyperglycemia leads to advanced glycation end products AGEs , which bind to their receptors RAGEs , which decreases nitric oxide NO availability and stimulates transforming growth factor-β TGF-β , a profibrotic factor.
Diabetes further accelerates endothelial progenitor cell EPC aging, which reduces their reparative function. Vascular endothelial growth factor VEGF synthesis by podocytes is dysregulated. Podocyte injury leads to foot process effacement and podocyte loss, the unifying mechanism underlying albuminuria in diabetes 33 — Changes in tubular function can trigger glomerular hemodynamic changes via impaired tubuloglomerular feedback In diabetes, supraphysiologic levels of glucose delivered to the proximal tubule upregulate SGLT1 and SGLT2 to maximize the reabsorption of glucose and sodium 41 , Reduced sodium delivery to the distal nephron results in negative tubuloglomerular feedback Fig.
Studies of individuals with type 1 diabetes demonstrate that to increase glomerular perfusion, local angiotensin production is upregulated, which triggers afferent arteriole dilatation and efferent arteriole constriction 41 , This explains, in part, the renoprotective role of SGLT2 inhibitors under conditions of normal kidney function.
By blocking glucose reabsorption at the proximal tubule and diverting it into the urine, tubuloglomerular balance is restored, with the net effect of lowering intraglomerular pressure and reducing hyperfiltration 44 , Hence, the mechanism of renoprotection in advanced kidney disease is unclear.
Note that these mechanisms have not been studied in type 1 diabetes. Hyperglycemia, insulin resistance, and dyslipidemia commonly coexist, which sets in motion several dysregulated metabolic pathways inextricably related to oxidative stress and inflammatory processes, ultimately creating a vicious cycle where one process potentiates another 47 , Most notable are the polyol and protein kinase C PKC pathways, which augment oxidative stress and deplete endothelial nitric oxide synthase, respectively, leading to higher endothelin-1 and vascular endothelial growth factor levels.
Endothelial instability and nuclear factor-κB NF-κB —mediated cytokines tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6] favor an inflammatory response.
The hyperglycemic milieu also encourages the accumulation of advanced glycation end products AGEs. AGEs are a heterogeneous group of nonenzymatically glycated molecules. Upon engaging with their receptors RAGEs , which are found throughout the kidney, they trigger cellular function perturbations, including NF-κB upregulation, which induces a cascade of proinflammatory cytokines TNF-α and IL AGEs reduce the bioavailability of endothelium-derived nitric oxide and increase reactive oxygen species production, which is linked to impaired vasodilatation in diabetes 49 Fig.
Inflammation and fibrosis are major interrelated contributors to DKD progression. Mounting evidence implicates an intricate interaction between the mineralocorticoid receptor MR aldosterone and RAS-related C3 botulinum toxin substrate 1 Rac1 in driving the inflammatory processes that lead to the final common pathway of fibrosis in DKD.
The deleterious effects of MR activation in modulating inflammation and fibrosis were long recognized in animal studies of the heart and provide the therapeutic basis for MR antagonism 50 , Animal studies showed similar benefits of MR blockade on the kidneys 52 and vasculature MR activation occurs in the aldosterone-responsive distal nephron, causing sodium reabsorption and potassium excretion.
Aldosterone secretion is stimulated by RAS activation in response to decreased circulating plasma volume or significant increases in serum potassium levels. While critical for survival in states of low sodium intake, it becomes pathologic in the setting of persistently high sodium intake 54 , as exemplified by Western and many Asian diets.
Inappropriate aldosterone signaling combined with high sodium intake results in hypertension, a direct contributor to glomerular injury and fibrosis.
The MR possesses a binding affinity for cortisol and corticosterone similar to that of aldosterone. These cells typically coexpress 11B-dehydrogenase isoenzyme 2 11B-HSD2 , which neutralizes cortisol and thereby mitigates MR overactivation. Outside the distal nephron, MRs are expressed on other cell types, including podocytes, fibroblasts, vascular cells, and macrophages; these cells, however, do not uniformly coexpress the steroid-blunting effects of 11B-HSD2, which permits unbridled MR activation MR is upregulated in hyperglycemia, insulin resistance, dyslipidemia, and obesity.
This results in increased gene transcription of profibrotic factors plasminogen activator inhibitor-1 PAI-1 and TGF-β1, connective tissue growth factor, and extracellular matrix proteins, all of which contribute to progressive DKD 56 Fig. Innate immunity plays a critical role in the pathogenesis of DKD, but a detailed discussion is beyond the scope of this review.
Briefly, macrophage infiltration has been identified as one of the hallmarks of DKD, the burden of which is associated with worse disease Hyperglycemia, endothelial cell dysfunction, angiotensin II, AGEs, and oxidized LDL recruit macrophages Macrophage-MR activation polarizes macrophage differentiation toward the M1 phenotype, which promotes inflammation via a cascade of injurious cytokines 59 Figs.
Of note, however, is that MR inhibition favors macrophage switching toward an M2 anti-inflammatory phenotype with demonstrated beneficial effects in CKD The therapeutic effects of MR antagonism in curtailing DKD were first reported in using animal models There are no outcome trials with the steroidal MRAs due to tolerability issues.
However, they have been shown in people with early DKD to reduce albuminuria and blood pressure significantly. Other NS-MRAs, namely, finerenone, esaxerenone, and apararenone, also have demonstrated significant albuminuria reduction and a very low adverse effect profile in advanced DKD 64 , 65 , although esaxerenone is only available in Japan None of these agents have ever been tested in outcome trials.
The timeline of the major therapeutic outcome trials focused on delaying DKD in patients with type 2 diabetes and CKD following the publication of RENAAL and IDNT 73 — MoAs, mechanisms of action. DKD management has evolved over the last 50 years.
However, following the trials that showed a clear benefit of ARBs in slowing DKD progression, nothing was proven to further curtail advancing DKD until the advent of SGLT2 inhibitors.
Many trials using novel targeted therapies were attempted between and , all of which failed to show any benefit in changing the trajectory of DKD Fig. Since the approval of the first SGLT2 inhibitor, dapagliflozin, in January , the field has added other drugs to this class.
Additionally, approval of the NS-MRA finerenone, in July , has further advanced the field from one to three therapies in the tool kit. Questions remain concerning when and how to use these drugs.
Obesity reduces the production of adiponectin in favor of leptin. Gene transcription of inflammatory mediators such as IL-1, IL-6, IL-7, IL-8, and TNF-α is increased, which creates a proinflammatory state and oxidative stress.
Profibrotic factors plasminogen activator inhibitor-1 PAI-1 and TGF-β1, connective tissue growth factor, and extracellular matrix proteins are increased, all contributing to progressive diabetic nephropathy. IL, interleukin; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein Many trials have established that a reduction in albuminuria is associated with slowed DKD progression and reduced CV event rates 69 — Given the advent of many new therapies over the past decade, we put forth the concept of pillars of therapy, originally adopted by heart failure cardiologists.
The concept is akin to any building structure where no single beam alone can support its standing. Hence, we now have three established, proven therapies that, when used together, will maximally decelerate DKD progression.
This does not imply that those with high albuminuria, formerly called microalbuminuria, do not derive benefit from treatment—in fact, they do, and the benefits are predominantly CV. However, the slowing of the DKD trajectory in these cohorts was detected in post hoc analyses.
This ushered in two additional landmark trials conducted in patients with type 1 diabetes, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan RENAAL 20 and Irbesartan Diabetic Nephropathy Trial IDNT 19 , before RAS blockers became formally integrated into the standard of care The introduction of SGLT2 inhibitors in January created a resounding paradigm shift and renewed excitement in improving DKD management.
Although they were originally designed to lower glucose by promoting urinary glucose excretion, it was ultimately appreciated that SGLT2 inhibitors were, in effect, cardiorenal risk—reducing agents The renoprotective benefits of SGLT2 inhibitors were initially gleaned from secondary data analyses of trials with time to major adverse CV events as primary outcomes.
In a meta-analysis of six double-blinded randomized trials of SGLT2 inhibitors in patients with type 2 diabetes, a consistent reduction in hospitalization for heart failure and progression to ESKD was found However, in three landmark trials that followed, where kidney outcomes were the defined primary end points in a high-risk cohort, the benefits of SGLT2 inhibitors when combined with optimized RAS blockade became universally accepted.
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation CREDENCE trial was the first nephropathy outcome trial to specify its primary outcome as ESKD, doubling of creatinine level, or death from renal or CV causes with an SGLT2 inhibitor.
The unequivocal renal benefits prompted early trial termination The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease DAPA-CKD trial, which was published a year later than the CREDENCE trial, randomized a mixed cohort of participants, i. Most recently, The Study of Heart and Kidney Protection With Empagliflozin EMPA-KIDNEY outcome trial adds to the substantial body of evidence underscoring the robust salutary effects of SGLT2 inhibitors on renal outcomes.
Over 6, participants with and without diabetes, with a wide range of GFR declines, from mild to severe, and with normal or high albuminuria, were randomized to empagliflozin versus placebo in addition to standard-of-care therapies.
It should further be noted that there were many people with normal and high albuminuria in this trial. Hence, SGLT2 inhibitors serve as a solid second pillar to slow DKD progression The hazardous sequela of MR activation by aldosterone shifted attention to developing therapies downstream of the RAS target, which ultimately addresses the inflammatory and ensuing profibrotic processes that contribute to DKD progression and heart failure.
MR antagonism is not new. Steroid-based MRAs, including first- and second-generation spironolactone and eplerenone, respectively, continue to be used extensively in symptomatic heart failure patients This has been adopted by the U.
Food and Drug Administration as evidence of benefit and as a guideline by the American Diabetes Association. The exception is when a dual RAS blockade is used. Therefore, MRAs have been generally contraindicated in advanced kidney disease Finerenone, apararenone, esaxerenone, and ocedurenone are members of a new class of NS-MRAs with pharmacologic properties distinct from those of their distant cousins, the steroidal agents.
Finerenone is the only one developed and approved for cardiorenal risk reduction, whereas the others are approved only for blood pressure control, with no outcome data supporting use in DKD. Finerenone demonstrates superior anti-inflammatory and antifibrotic outcomes compared with its steroidal counterparts in preclinical studies 92 — Unlike the steroidal MRAs, the NS-MRAs achieve balanced tissue distribution between the heart and kidney rather than affecting the kidney alone Finerenone was studied in two complementary phase 3 randomized, double-blinded, placebo-controlled clinical trials that included over 13, participants with type 2 diabetes optimized on maximally tolerated RAS blockade before randomization to the NS-MRA or placebo 96 , These trials were developed with the same protocol but different inclusion criteria, which allowed for an individual pooled patient analysis in the Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis FIDELITY Despite the similar frequency of adverse effects in both groups, the incidence of trial discontinuation related to hyperkalemia was slightly higher with finerenone than with placebo 2.
The frequency of reported adverse effects was similar to that for placebo, and the incidence of trial discontinuation related to hyperkalemia was slightly higher with finerenone than with placebo 1. The FIDELITY individual pooled patient analysis included 13, patients with type 2 diabetes and a wide range of CKD stages, from 1 to 4, and high to very high albuminuria.
This is a very important finding given the notably higher risk of heart failure and premature death associated with having both diabetes and CKD 4 , 99 , Studies of finerenone in type 1 diabetes are currently underway. The incidence of clinically important adverse effects related to hyperkalemia was slightly higher for finerenone, with 1.
However, unlike many other trials, all participants were required to be on maximally tolerated RAS blockade. Differences in hyperkalemia risk between the NS-MRA finerenone and its steroidal counterpart, spironolactone, are exemplified by a comparative outcome of a subgroup with resistant hypertension from the FIDELITY analysis and the Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease AMBER trial In the FIDELITY study, the incidence of hyperkalemia was GLP-1 RAs are recommended for patients with DKD who have not met their glycemic targets despite optimization with metformin and SGLT2 inhibitors Post hoc analyses of these CVOT, like analyses of SGLT2 inhibitors, also demonstrated possible benefits in delaying DKD progression Additionally, a large analysis of more than 12, participants pooled from the earliest trials of GLP-1 RAs, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes SUSTAIN-6 and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER , evaluated changes in albuminuria, rate of annual eGFR change, and time to persistent eGFR declines.
Semaglutide and liraglutide were associated with significant slowing of annual eGFR decline, 0. This trial enrolled 4, patients with known type 2 diabetes and either current CKD eGFR Notably, there was a higher prevalence of CKD in the trial cohort than in the seven CVOT studies completed to date.
Additionally, Since Abdominal obesity is independently associated with albuminuria despite normoglycemia and normotension and addresses an important subgroup of patients who have obesity-related glomerulopathy and who, by conventional screening, may be classified as metabolically healthy yet are still at risk for developing ESKD This is not surprising given the inflammatory milieu engendered by excess adiposity Fig.
FLOW A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease is an ongoing randomized placebo-controlled trial that assesses the efficacy of semaglutide in type 2 diabetes and CKD and the first designed with primary renal end points The renoprotective properties associated with GLP-1 RAs reviewed here were drawn from post hoc analyses of major CVOT, the evidence of which has been compelling, nonetheless.
DKD management should start with maximally dosed RAS blockade; this is based on the doses used in the original RAS blocking trials, wherein dose reduction to avoid hyperkalemia resulted in markedly reduced protection against DKD decline. Each drug class that provided improved outcomes was coupled with RAS blockade and independently showed benefits on kidney and heart outcomes.
These findings provide impetus to adopt a pillared approach for reducing cardiorenal events similar to how heart failure cardiologists have approached heart failure management. Notably, there has never been a trial that evaluated the simultaneous use of all four agents in heart failure or that compared different drug combinations against each other.
Each trial was assessed on its merits within each drug class and then combined in retrospect to provide the best results. We currently have three agents with additive effects on albuminuria and heart failure outcomes when combined individually with RAS blockade.
An adequately statistically powered study that evaluates the three, or possibly soon-to-be four, different agents together would require well over , participants; therefore, extrapolation, which the cardiologists have done successfully, uses all three agents together over a short time.
Practice guidelines articulate that clinicians should start first by titrating to maximally tolerated RAS blockade before introducing these medications SGLT2 inhibitors, NS-MRAs, and GLP-1 RAs , as was done in pivotal clinical trials Initial changes in eGFR and associated long-term amelioration of renal function decline have also been reported with SGLT2 inhibitors and finerenone, albeit to a lesser degree than with RAS blockers 96 , , — The manifold pathophysiological mechanisms involved in end-organ damage argue for a pillared approach with targeted therapies that have distinct pharmacodynamic actions An elegant study that used an animal model of preclinical hypertension—induced cardiorenal disease with a low-dose combination therapy of finerenone and empagliflozin revealed additive cardiorenal benefit above that of the respective dose-dependent monotherapy, as measured by reductions in blood pressure, proteinuria, cardiac fibrosis, vasculopathy, and mortality These findings further argue strongly for distinct pharmacodynamic actions that counteract the manifold pathophysiological mechanisms involved in end-organ damage Fig.
Acute changes in GFR slopes with three distinct classes of drugs with unique mechanisms that slow kidney disease progression associated diabetes. B : Rate of eGFR decline between finerenone and placebo. Despite equivalent GFR at baseline, the finerenone group shows stabilization of slowed GFR declines 96 and higher GFR declines at 4 months, which are associated with better long-term outcomes.
C : Initial decline in GFR decline in the empagliflozin group compared with placebo at month 4 EMPA-REG Outcome, BI Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; LS, least squares.
Additionally, in a small open-label randomized crossover clinical study, the efficacy and safety of dapagliflozin and a low dose of the steroidal MRA eplerenone were evaluated in a cohort of patients with CKD.
The combination of the two drugs was associated with an additive effect on albuminuria reduction compared with the use of either drug alone. Importantly, the incidence of hyperkalemia was significantly less in the combination group than in the group that received eplerenone alone This is consistent with data from the larger FIDELIO-DKD trial that demonstrated greater protection from hyperkalemia when an SGLT2 inhibitor was combined with finerenone The use of combination therapies with NS-MRAs and SGLT2 inhibitors was further explored in the FIDELITY subgroup analysis, which revealed that, compared with placebo, cardiorenal benefits of finerenone were appreciably higher irrespective of concomitant GLP-1RA or SGLT2 inhibitor use at baseline or anytime during the trial.
Metrics Nephfopathy. Diabetic nephropathy DN or diabetic kidney disease refers to the deterioration of reseacrh function seen in chronic advanxements 1 and type 2 diabetes Detoxification Support for Balanced Hormones patients. The progression of the nfphropathy is known Diabetes and sleep disorders occur in Diabstic series of stages and Diabetic nephropathy research advancements linked nephropathg glycemic and blood pressure control. However, despite aggressive blood sugar control the prevalence of chronic kidney disease CKD in diabetic patients has not witnessed any decrease in the last two decades; which has lead to identification of additional factors in its progression. The nutritional status of patients is an important and modifiable factor that may influence CKD processes and outcome. It directly stems from the traditional dietary choices that patients make due to poor nutritional awareness. Dietary management of DN patients is challenging, as the twin factors of diet overload on kidney function needs to be balanced with malnutrition.
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