Whereas diabetes advocates a healthy and balanced diet, diet of a CKD or diabetic nephropathy patient is challenging and designed to delay progression of kidney damage and the associated secondary conditions such as hypertension, hyperlipidemia, uremia, etc. As food intake could be a burden on kidney function, a delicate balance between nutrition and sustainable physiological load is essential to maintain quality of life for the patient.

A common problem encountered in patients with renal failure and proteinuria is their lack of nutritional knowledge and continued adherence to traditional food choices that are rich in carbohydrate, proteins or minerals.

Since a majority of patients are dyslipidemic the only control they exercise is on limiting fat intake. Such a skewed diet places a tremendous burden on kidney function that causes further problems in disease management.

An ideal diet recommended for diabetic nephropathy patients with compromised kidney function includes a proper amount of fat to prevent malnutrition. More so when total calories coming from protein and carbohydrate intake needs to be restricted.

A total fat reduction as advised by earlier studies can be a very unhealthy practice. Thus, to achieve these goals nutritionists advice limiting saturated fatty acid consumption while taking vegetable oils and omega-rich fatty acid containing oils in moderation. Many clinical studies have highlighted the renoprotective effects of a low protein diet on DN, although protein restriction alone does not result in a positive outcome for patients [ 35 ].

Moreover, a protein-deficient diet 0. Interestingly, in animal type 2 DM models a very low protein diet VLPD improved tubulo-interstitial damage, inflammation and fibrosis, through restoration of autophagy via reduction of a mammalian target of rapamycin complex 1 mTORC1 activity [ 37 ].

Although a low protein diet slows progression of renal dysfunction in human subjects with chronic glomerular nephritis, VLPD has not been clinically validated. A low-salt diet that is devoid of salted and pickled foods is highly recommended for DN patients. Restricted sodium intake allows better blood pressure control in such patients.

High salt intake and urinary protein excretion were associated with annual creatinine clearance decline in type 2 DKD patients as reported by Kanauchi et al. Potassium is an essential electrolyte involved in the contraction and relaxation of muscles. During a deficit in kidney function potassium excretion is reduced leading to an accumulation in body tissues.

Therefore, potassium intake specifically from foods such as grains, potatoes, corn, soybean, nuts, tomatoes, banana, melons, kiwi etc.

must be restricted. Like potassium, phosphorus excretion is also reduced during chronic kidney damage leading to increased blood phosphorus levels. Since phosphate is in homeostatic equilibrium with the skeletal muscle calcium levels, an imbalance leads to a significant calcium loss and debilitating bone disease.

In summary, excessive carbohydrate and protein intake is managed with a target of kcal of energy per day in which 60 percent comes from carbohydrate and 40 percent from proteins.

In a recent study, such a regimen achieved a commendable control in blood lipid and glucose values in a patient with stage 4 chronic kidney disease [ 39 ]. However, patient adherence to the recommended diet seems to be gender-specific. For example, Ahola et al. Therefore, effective adherence through patient education may be a crucial factor in the management of DN through diet.

In conclusion, this review summarizes the recent advances in the pathophysiology of diabetic nephropathy and the importance of dietary factors in modifying treatment outcomes for patients.

A critical analysis of studies that emphasize the importance of patient-centered dietary intervention in successful management of advanced CKD patients has been presented. Large-scale cohort studies are necessary to evaluate the efficiency of diet as a new therapeutic paradigm.

Notably, in newly diagnosed DN patients these dietary interventions may no longer be regarded as complementary measures but significant factors that delay progression of the disease. International Diabetes Federation IDF Diabetes Atlas.

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N Engl J Med. American Diabetes Association. Nephropathy in diabetes Position Statement. Diabetes Care. Google Scholar. Ballantyne FC, Gibbons J, O-Reilly DS. Urine albumin should replace total protein for the assessment of glomerular proteinuria. Ann Clin Biochem. Kim SS, Song SH, Kim IJ, Jeon YK, Kim BH, et al.

Nonalbuminuric proteinuria as a biomarker for tubular damage in early development of nephropathy with type 2 diabetic patients. Diabetes Metab Res Rev.

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BMC Nephrol. Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. Mogensen CE. The natural history of type 2 diabetic nephropathy. Am J Kidney Dis.

Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol. Klemens R, Angela G, Sabine H, et al. Diabetic nephropathy in 27, children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset and sex.

Eberhard R. Diabetic nephropathy. Saudi J Kidney Dis Transplant. Hameed I, Masoodi SR, Malik PA, Mir SA, Ghazanfar K, Ganai BA. Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.

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Kawanami D, Matoba K, Utsunomiya K. Signaling pathways in diabetic nephropathy. Histol Histopathol. CAS PubMed Google Scholar. Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?

Parving HH, Oenboll B, Syendsen PA, Christiansen JS, Andersen AR. Early detection of patients at risk of developing diabetic nephropathy: a longitudinal study of urinary albumin excretion.

Acta Endocrinol Copenh. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. de Boer IH, Afkarian M, Rue TC, Cleary PA, Lachin JM, Molitch ME, et al. Renal outcomes in patients with type 1 diabetes and macroalbuminuria.

Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, et al. Predictors for the developmental of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR.

Risk factors for renal dysfunction in type 2 diabetes: UK prospective diabetes study Pavkov ME, Knowler WC, Bennett PH, Looker HC, Krakoff J, Nelson RG. Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians. Kidney Int. MacIssac RJ, Ekinci EI, Jerums G.

Markers of and risk factors for the development of diabetic kidney disease. Motawi TK, Shehata NI, ElNokeety MM, El-Emady YF. Potential serum biomarkers for early detection of diabetic nephropathy. Diabetes Res Clin Pract. Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, Chrousos GP, Papassotiriou I.

Biomarkers of diabetic nephropathy: a update. Crit Rev Clin Lab Sci. Oltean S, Coward R, Collino M, Baelde H. Diabetic nephropathy: novel molecular mechanisms and therapeutic avenues. Biomed Res Intl. Montero RM, Covic A, Gnudi L, Goldsmith D.

Diabetic nephropathy: what does the future hold? Int Urol Nephrol. Lytvyn Y, Bjornstad P, Pun N, Cherney DZ. New and old agents in the management of diabetic nephropathy.

Curr Opin Nephrol Hypertens. Meloni C, Tatangelo P, Cipriani S, Rossi V, Suraci C, Tozzo C, et al. Adequate protein dietary restriction in diabetic and nondiabetic patients with chronic renal failure. J Ren Nutr. Otoda T, Kanasaki K, Koya D. Low-protein diet for diabetic nephropathy.

Curr Diab Rep. Trimeche A, Selmi Y, Ben Slama F, Ben Amara H, Hazar I, Ben Mami F, et al. Effect of protein restriction on renal function and nutritional status of type 1 diabetes at the stage of renal impairment.

Tunis Med. Kitada M, Ogura Y, Monno I, Koya D. A low-protein diet for diabetic kidney disease: its effect and molecular mechanism, an approach from animal studies. Kanauchi N, Ookawara S, Ito K, Mogi S, Yoshida I, Kakei M, et al.

Factors affecting the progression of renal dysfunction and the importance of salt restriction in patients with type 2 diabetic kidney disease. Clin Exp Nephrol. Kim HY. Nutritional intervention for a patient with diabetic nephropathy.

Clin Nutr Res. Ahola KAJ, Forsblom C, Groop PH. 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.

An important caveat is that GLP-1 RA and SGLT2 inhibitor users comprised 6. More importantly, there was no sign that drug coadministration with finerenone increased any risk of kidney injury When combined with finerenone, SGLT2 inhibitors reduced hyperkalemic events compared with levels found in nonusers 8.

These are separate retrospective analyses of renal outcome trials clearly showing a protective effect of SGLT2 inhibitors from hyperkalemia in the setting of NS-MRA and MRA use 98 , Since the institution of the RAS blockade in the s, we have witnessed significant strides in addressing the unmitigated risk associated with DKD progression.

We now have two additional drug classes to add to the RAS blockers, SGLT2 inhibitors and NS-MRAs, bolstered by a robust body of outcome data, and a possible third class.

The efficacy of GLP-1 RAs is supported by retrospective analyses but needs to be proven in the ongoing FLOW randomized clinical trial. The safety and tolerability of these two drug classes, when given together against a backdrop of maximal RAS blockade, are very encouraging and reflect the complexity of the underlying pathophysiology that drives DKD progression.

Moreover, the protective role of SGLT2 inhibitors in preventing hyperkalemia with finerenone use is very heartening. This article is featured in a podcast available at diabetesjournals. was supported in part by a National Institutes of Health T32 award. Duality of Interest. reports being a consultant to and on steering committees of several outcome trials of companies, including KBP Biosciences, Janssen, Novo Nordisk, Ionis, Alnylam, ESTAR, Bayer, and AstraZeneca.

No other potential conflicts of interest relevant to this article were reported. Author Contributions. and G. researched the data and shared writing and editing responsibilities for the manuscript.

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The Additive Value of Drug Combination. Article Information. Article Navigation. Review August 25 Diabetic Nephropathy: Update on Pillars of Therapy Slowing Progression Sandra C. Naaman ; Sandra C. Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, IL.

This Site. Google Scholar. George L. Bakris Corresponding author: George L. Bakris, gbakris uchicago. Diabetes Care ;46 9 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Graphical Abstract View large Download slide.

View large Download slide. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III.

Search ADS. Worldwide epidemiology of diabetes-related end-stage renal disease, National Institute of Diabetes and Digestive and Kidney Diseases. Accessed 14 May NCD Risk Factor Collaboration NCD-RisC. Worldwide trends in diabetes since a pooled analysis of population-based studies with 4.

In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing.

Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia.

Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights. Keywords : Diabetic nephropathies ; Epigenomics ; Glycation end products, advanced ; Hypoxia-inducible factor 1 ; NF-E2-related factor 2 ; Sodium-glucose transporter 2.

The concept of diabetic kidney disease and diabetic nephropathy. GFR, glomerular filtration rate. The time course of current treatments. The time course of future treatments. Citations Citations to this article as recorded by. PubReader ePub Link Cite CITE. export Copy Format NLM AMA APA MLA.

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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. 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.

de Boer. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Acute Kidney Injury Predicts Major Adverse Outcomes in Diabetes: Synergic Impact With Low Glomerular Filtration Rate and Albuminuria.

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.

Multiple Risk Factor Intervention Trial. The growing volume of diabetes-related dialysis: a population based study. Heterogeneity of diabetes outcomes among asians and pacific islanders in the US: the diabetes study of northern california DISTANCE.

Rates of complications and mortality in older patients with diabetes mellitus: the diabetes and aging study. 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.

Some of the biomedical technologies which support omics analyses are outlined in Figure 1. In many cases, the application of multiple technologies to characterize a particular molecular domain often provides complementary rather than redundant information.

Moreover, integration of data from several molecular domains is key to characterizing the molecular heterogeneity of DKD, although integrative multi-omic analyses are not trivial owing to the complexity of the multiple high-dimensional datasets involved [ 17, 56 ]. It is also worth noting that changes in different molecular domains such as the transcriptome, the proteome, and the metabolome may not necessarily directly correlate [ 16, 57, 58 ].

For example, factors impacting translational efficiency will diminish mRNA-protein correlations for a given target, as will modalities of protein regulation other than gene transcription, such as post-translational modifications [ 57 ].

Furthermore, differences in the coverage of molecular domains by omics technologies may result in difficulties mapping insights from one to the other [ 16, 58 ].

Techniques that allow for integration of not only two data domains at a time such as the transcriptome and the proteome but also allow for simultaneous integration of clinical phenotypic data, imaging data, and histopathological data along with multiple molecular omics data domains are essential to gain more holistic insights into cellular function and interaction in a complex organ system such as the diabetic kidney [ 17, 56 ].

The current one-size-fits-all approach to DKD care ignores the clinically apparent heterogeneity in disease prognosis and treatment-responsiveness [ 10 ]. It is hoped that a systems biology approach to DKD research will pave the way for a precision medicine approach to routine DKD care by unravelling individual-level molecular mechanisms which underlie progressive DKD and which are amenable to targeting by existing or novel therapeutic strategies [ 15, 16 ].

Certain priorities for translational DKD research which may be advanced by a systems nephrology approach include: 1. The development of model systems in vitro or animal which reliably recapitulate progressive and advanced human DKD characterized by single-cell and spatially resolved transcriptomics, thereby enhancing the translational relevance of preclinical DKD studies;.

The identification of biomarkers which predict response to RAAS blockade, SGLT2is, and other emerging disease-modifying treatments for DKD in light of the inter-individual variability in treatment response; and. The delineation of mechanisms of DKD progression in the face of combined therapy with RAAS blockade and an SGLT2i, the current backbone of treatment, which may help define targets for novel therapies which minimise the significant residual risk of progressive renal functional decline.

However, the efficacy of appropriately targeted novel therapeutics may still be impacted by inter-individual pharmacokinetic differences.

Thus, pharmacogenomic profiling will play an important role in optimising outcomes for individuals with DKD. While a comprehensive systems nephrology approach is now technically feasible in research studies, this must be balanced with plans for eventual implementation of elements of this paradigm in clinical practice.

The value of biological insights derived from the refined techniques currently available must be balanced against their clinical translatability; researchers and clinicians alike should grapple with this compromise from the outset in an effort to prioritize which elements of the systems nephrology paradigm offer benefit to the largest number of patients in clinical practice.

This will help to ensure that implementation of a systems nephrology approach in routine DKD care will not perpetuate, or indeed exacerbate, inequity in healthcare delivery. This manuscript was invited following a presentation at the European Renal Association Diabesity Working Group Annual CME in Maribor, Slovenia on September 16th—17th Figure 1 was created with BioRender.

This work was performed within the Irish Clinical Academic Training ICAT Programme, supported by the Wellcome Trust and the Health Research Board Grant No. This research was funded in whole, or in part, by the Wellcome Trust Grant No. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Martin wrote the manuscript and Neil G. Docherty provided proof-reading and critical review. Martin and Neil G. Docherty reviewed and approved the final manuscript. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Nephron.

Advanced Search. Skip Nav Destination Close navigation menu Article navigation. The Promise of Personalised Diabetic Kidney Disease Care. Model Systems and Data Sources. Non-Omics Data. Molecular Omics Data. Conflict of Interest Statement. Funding Sources. Author Contributions. Article Navigation.

Review Articles September 11 Early Publication. A Systems Nephrology Approach to Diabetic Kidney Disease Research and Practice Subject Area: Nephrology. Martin Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

liampvmartin gmail. This Site. Google Scholar. Neil G. Docherty Neil G. Nephron 1— Article history Received:. Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Journal Section:.

View large Download slide. Table 1. An essential toolkit for a systems nephrology approach to diabetic kidney disease a. View Large. The development of model systems in vitro or animal which reliably recapitulate progressive and advanced human DKD characterized by single-cell and spatially resolved transcriptomics, thereby enhancing the translational relevance of preclinical DKD studies; 2.

The identification of biomarkers which predict response to RAAS blockade, SGLT2is, and other emerging disease-modifying treatments for DKD in light of the inter-individual variability in treatment response; and 3. The authors have no conflicts of interest to declare.

Oshima M, Shimizu M, Yamanouchi M, Toyama T, Hara A, Furuichi K, et al. Trajectories of kidney function in diabetes: a clinicopathological update. Nat Rev Nephrol.

Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease.

Shaman AM, Bain SC, Bakris GL, Buse JB, Idorn T, Mahaffey KW, et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER.

Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial.

Lancet Diabetes Endocrinol. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. Martin WP, Docherty NG, Le Roux CW. Impact of bariatric surgery on cardiovascular and renal complications of diabetes: a focus on clinical outcomes and putative mechanisms.

Expert Rev Endocrinol Metab. Martin WP, White J, Lopez-Hernandez FJ, Docherty NG, le Roux CW. Metabolic surgery to treat obesity in diabetic kidney disease, chronic kidney disease, and end-stage kidney disease; what are the unanswered questions? Front Endocrinol. Tye SC, Denig P, Heerspink HJL.

Precision medicine approaches for diabetic kidney disease: opportunities and challenges. Nephrol Dial Transplant. Luyckx VA, Rule AD, Tuttle KR, Delanaye P, Liapis H, Gandjour A, et al. Nephron overload as a therapeutic target to maximize kidney lifespan. Rossing P, Caramori ML, Chan JCN, Heerspink HJL, Hurst C, Khunti K, et al.

KDIGO clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. Krolewski AS. Progressive renal decline: the new paradigm of diabetic nephropathy in type 1 diabetes.

Diabetes Care. de Boer IH, Alpers CE, Azeloglu EU, Balis UGJ, Barasch JM, Barisoni L, et al. Rationale and design of the kidney precision medicine project.

Mariani LH, Pendergraft WFIII, Kretzler M. Defining glomerular disease in mechanistic terms: implementing an integrative biology approach in nephrology.

Clin J Am Soc Nephrol. Lindenmeyer MT, Alakwaa F, Rose M, Kretzler M. Perspectives in systems nephrology. Cell Tissue Res. Eddy S, Mariani LH, Kretzler M. Integrated multi-omics approaches to improve classification of chronic kidney disease.

Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. Tuttle KR, Brosius FCIII, Adler SG, Kretzler M, Mehta RL, Tumlin JA, et al. 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.

An important caveat is that GLP-1 RA and SGLT2 inhibitor users comprised 6. More importantly, there was no sign that drug coadministration with finerenone increased any risk of kidney injury When combined with finerenone, SGLT2 inhibitors reduced hyperkalemic events compared with levels found in nonusers 8.

The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose.

Temporary hyperglycemia causes advanced glycation end product AGE accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing.

Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD.

Future studies are expected to provide new insights. Keywords : Diabetic nephropathies ; Epigenomics ; Glycation end products, advanced ; Hypoxia-inducible factor 1 ; NF-E2-related factor 2 ; Sodium-glucose transporter 2. The concept of diabetic kidney disease and diabetic nephropathy.

GFR, glomerular filtration rate. The time course of current treatments. The time course of future treatments.