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Diabetic nephropathy treatment options

Diabetic nephropathy treatment options

Appetite suppressants for hunger control T. Optiosn of pentoxifylline on renal Diagetic and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. The effect of lipid reduction by antilipemic agents on progression of diabetic nephropathy is still unknown.

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Diabetic nephropathy treatment options -

This renoprotective effect is independent of blood pressure reduction , and may be related to decreased intraglomerular pressure and passage of proteins into the proximal tubule These drugs decrease UAE and the rate of progression from microalbuminuria to more advanced stages of diabetic nephropathy.

ARBs were also effective in reducing the development of macroalbuminuria in microalbuminuric type 2 diabetic patients. It is also interesting to note that UAE was still reduced 1 month after the withdrawal of irbesartan These data reinforce the idea that the antiproteinuric effect of ARBs is blood pressure independent.

Although there is no long-term study comparing the effects of ACE inhibitors and ARBs on the progression from microalbuminuria to overt diabetic nephropathy, both agents led to a similar reduction in albuminuria in a week study and a 1-year study Therefore, the use of either ACE inhibitors or ARBs is recommended as a first-line therapy for type 1 and type 2 diabetic patients with microalbuminuria, even if they are normotensive In proteinuric patients, Mogensen was the first to demonstrate, almost 30 years ago, that treatment of hypertension reduced albuminuria and the rate of GFR decline in type 1 diabetic patients.

Subsequently, other studies have clearly demonstrated that aggressive treatment of hypertension has a strong beneficial effect in reducing GFR decline in proteinuric type 1 diabetic patients This reduction in GFR decline was predicted by reduction in albuminuria According to the MDRD Modification of Diet in Renal Disease trial, the lower the blood pressure, the greater the preservation of renal function in nondiabetic patients Although this study included mainly nondiabetic patients, this goal also has been recommended for proteinuric diabetic patients Addition of ACE inhibitors in proteinuric type 1 diabetic patients or ARBs in macroalbuminuric type 2 diabetic patients , decreased proteinuria and renal function decline.

Although there was no difference in the cardiovascular event rate, a significantly lower incidence of congestive heart failure was observed among patients receiving ARBs The antiproteinuric effect of ARBs has certain characteristics. It occurs early within 7 days after treatment is started and persists stable thereafter , and it is independent of blood pressure reduction and has a dose-response effect beyond the doses needed to control blood pressure This raise in creatinine is associated with long-term preservation of renal function, and therefore ACE inhibitors should not be stopped Greater increases should raise the suspicion of renal-artery stenosis.

Inhibition of the RAS, especially with ACE inhibitors, might raise serum potassium levels, particularly in patients with renal insufficiency For these reasons, albuminuria, serum creatinine, and potassium should be checked monthly during the first 2—3 months after starting treatment with ACE inhibitors or ARBs.

Recently, Mogensen et al. ACE inhibitors and ARBs interrupt the RAS at different levels, and the combination of these classes of drugs may have an additive effect on renoprotection.

Other studies have also demonstrated that the combination of ACE inhibitors and ARBs had a synergistic effect in blood pressure and UAE reduction in patients with type 1 and type 2 diabetes with diabetic nephropathy. RAS dual blockade is more effective in reducing UAE than maximal recommended doses of ACE inhibitors alone Even though no long-term trials analyzing the benefit of RAS dual blockade in diabetic nephropathy are available, in nondiabetic proteinuric patients the COOPERATE Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Nondiabetic Renal Disease trial has shown that dual therapy was superior to monotherapy at its maximal doses in retarding the progression of renal disease in a 3-year follow-up The combination of spironolactone, an aldosterone antagonist, with an ACE inhibitor was also more effective in reducing UAE and blood pressure in micro- and macroalbuminuric type 2 diabetic patients than the ACE inhibitor alone A detailed discussion of the agents used to treat hypertension in patients with diabetic nephropathy is beyond the scope of this article, and recent guidelines , and reviews on this subject are available , , Therefore, only general guidelines will be discussed here, taking into account the special characteristics of these patients.

It is more important to reach the blood pressure goals than to use a particular agent, since most patients will require several agents. However, due to the known renoprotective effect of ACE inhibitors and ARBs, treatment should start with either of these agents.

Patients with systolic blood pressure 20 mmHg or diastolic blood pressure 10 mmHg above the goal should start treatment with two agents. An ACE inhibitor or ARB and a low-dose thiazide diuretic ARBs and ACE inhibitors can be combined if there is no reduction in albuminuria or if blood pressure target levels are not reached, even before maximizing the dose of each agent.

Additional agents should be added as needed. Calcium channel blockers have an additional effect on reducing blood pressure levels.

These agents should only be used in combination with an ACE inhibitor and should not be used in patients with a recent coronary event. Possibly, a metabolic neutral compound, carvedilol, should be used. The combination of β-blockers and nondihydropyridine calcium channel blockers should be used with caution, since both agents have negative chronotropic effects.

Blood pressure treatment could be assessed by h ambulatory monitoring in the following situations: in patients with treatment-resistant hypertension, when there is a suspicion of white coat hypertension, or to detect drug-induced or autonomic neuropathy—related hypotensive episodes This was probably related to the lower amount of saturated fat and the higher proportion of polyunsaturated fatty acids found in chicken meat than in red meat.

The beneficial effect of polyunsaturated fatty acids on endothelial function could also reduce UAE. A normal protein diet with chicken as the only source of meat may represent an additive strategy for the treatment of microalbuminuric type 2 diabetic patients. However, long-term studies are necessary.

According to a meta-analysis of five studies including a total of patients, dietary protein restriction slowed the progression of diabetic nephropathy in patients with type 1 diabetes. More recently, a 4-year randomized controlled trial in 82 patients with type 1 diabetes with progressive diabetic nephropathy showed that a moderately low—protein diet 0.

The effect of lipid reduction by antilipemic agents on progression of diabetic nephropathy is still unknown. So far, there have been no large trials analyzing whether the treatment of dyslipidemia could prevent the development of diabetic nephropathy or the decline of renal function.

However, there is some evidence that lipid reduction by antilipemic agents might preserve GFR and decrease proteinuria in diabetic patients Moreover, the results of the recently presented CARDS Collaborative Atorvastatin Diabetes Study , which showed a marked reduction of cardiovascular events in patients with diabetes and at least one additional risk factor for coronary artery disease, suggest that all diabetic patients should be taking statins www.

Furthermore, anemia has been considered a risk factor for progression of renal disease and retinopathy Low-dose aspirin has been recommended for primary and secondary prevention of cardiovascular events in adults with diabetes. This therapy did not have a negative impact on renal function UAE or GFR in type 1 and type 2 diabetic patients with micro- or macroalbuminuria , Although this study was underpowered to analyze the effect on the development of cardiovascular events, these data raise the issue that diabetic patients could be less responsive to aspirin therapy aspirin resistance.

This phenomenon was associated with higher levels of A1c, lower concentration of HDL cholesterol, and higher concentration of total cholesterol Patients with microalbuminuria frequently have other cardiovascular risk factors, such as hypertension and dyslipidemia.

In the Steno-2 study, multifactorial intervention was compared with conventional treatment in microalbuminuric type 2 diabetic patients The multifactorial intervention consisted of a stepwise implementation of lifestyle changes and pharmacological therapy, including a low-fat diet, a three to five times a week light-to-moderate exercise program, a smoking cessation program, and prescription of ACE inhibitors or ARBs and aspirin.

The measures described above might not be effective in some patients with diabetes, and novel therapeutic strategies are warranted. High doses of thiamine and its derivate benfotiamine have been shown to retard the development of microalbuminuria in experimental diabetic nephropathy, probably due to decreased activation of protein kinase C, decreased protein glycation, and oxidative stress Treatment with ALT, a cross-link breaker of the advanced glycation end products, has been shown to result in a significant reduction in UAE, blood pressure, and renal lesions in experimental diabetes Treatment with a protein kinase C β inhibitor ruboxistaurin normalized GFR, decreased albumin excretion rate, and ameliorated glomerular lesions in diabetic rodents In a rat model of diabetes-induced glomerulosclerosis, administration of a modified heparin glycosaminoglycan prevented albuminuria, glomerular, and tubular matrix accumulation and transforming growth factor β1 mRNA overexpression Very few studies have been conducted in humans.

Sulodexide, a glycosaminoglycan, significantly reduced albuminuria in micro- or macroalbuminuric type 1 and type 2 diabetic patients Pimagedine, a second-generation inhibitor of advanced glycation end products, reduced urinary protein excretion and the decline in GFR in proteinuric type 1 diabetic patients in a randomized, placebo-controlled study In the last few years, we have witnessed enormous progress in the understanding of the risk factors and mechanisms of diabetic nephropathy, the stages of renal involvement in diabetes, and the treatment strategies to prevent or interrupt the progression of diabetic nephropathy.

Treatment of hypertension is a priority. Attention to these procedures will also ensure the reduction of cardiovascular mortality. In a 5-year prospective study, Barnett et al. Diabetic nephropathy stages: cutoff values of urine albumin for diagnosis and main clinical characteristics.

This study was partially supported by Projeto de Núcleos de Excelência do Ministério de Ciência e Tecnologia, Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq , and Hospital de Clínicas de Porto Alegre. A table elsewhere in this issue shows conventional and Système International SI units and conversion factors for many substances.

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Volume 28, Issue 1. Previous Article Next Article. STAGES, CLINICAL FEATURES, AND CLINICAL COURSE. SCREENING AND DIAGNOSIS. Article Information.

Article Navigation. Diabetic Nephropathy: Diagnosis, Prevention, and Treatment Jorge L. Gross, MD ; Jorge L. Gross, MD.

From the Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. This Site. Google Scholar. Mirela J. de Azevedo, MD ; Mirela J. de Azevedo, MD.

Sandra P. Silveiro, MD ; Sandra P. Silveiro, MD. Luís Henrique Canani, MD ; Luís Henrique Canani, MD. Maria Luiza Caramori, MD ; Maria Luiza Caramori, MD. Themis Zelmanovitz, MD Themis Zelmanovitz, MD. Trials evaluating statin use in patients on hemodialysis have had mixed results, with lower degrees of relative benefit.

Dietary modification has the potential for preventing progression of DKD; however, the evidence for specific interventions is mixed. The American Diabetes Association recommends a protein-restricted diet 0. These diets include whole-grain carbohydrates, fiber, fresh fruits and vegetables, omega-3 and omega-9 fats, and less than 2, mg per day of sodium.

Foods that are high in sugar, saturated fats, and processed carbohydrates should be avoided. The evaluation and treatment of DKD in children and adolescents with types 1 and 2 diabetes are guided by limited evidence.

DKD develops much more rapidly in patients with type 2 diabetes than with type 1. Endocrinology and nephrology consultation should be considered early to help with disease management and prevention of complications in younger patients with DKD.

Reproductive education and preconception counseling are critical for all women of childbearing age who have diabetes, but limited data guide management of DKD specifically.

Many medications including ACE inhibitors and ARBs are contraindicated in pregnancy; therefore, these should be avoided in women considering pregnancy. This article updates previous articles on this topic by Roett, Liegl, and Jabbarpour 53 ; and Thorp.

Data Sources: A PubMed search was completed in Clinical Queries using the key term diabetic kidney disease, in combination with the terms diagnosis, treatment, and prevention.

The search included meta-analyses, randomized controlled trials, clinical trials, and reviews, with particular attention to recently published manuscripts. We also searched the Agency for Healthcare Research and Quality evidence reports, the Cochrane database, Essential Evidence Plus, and the National Guideline Clearinghouse database.

Search dates: May 16, , and February 15, Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE.

Global estimates of diabetes prevalence for and projections for Diabetes Res Clin Pract. Menke A, Casagrande S, Geiss L, Cowie CC.

Prevalence of and trends in diabetes among adults in the United States, — Murphy D, McCulloch CE, Lin F, et al. Trends in prevalence of chronic kidney disease in the United States.

Ann Intern Med. Saran R, Robinson B, Abbott KC, et al. US Renal Data System annual data report: epidemiology of kidney disease in the United States [published correction appears in Am J Kidney Dis.

Am J Kidney Dis. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR UKPDS Group.

Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study UKPDS Kidney Int. Macisaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Dunkler D, Kohl M, Heinze G, et al.

Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus. American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes— Diabetes Care. Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease.

J Clin Invest. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Levin A, Stevens PE, Bilous RW, et al.

KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes [published correction appears in N Engl J Med.

N Engl J Med. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

Glycemic targets: standards of medical care in diabetes— Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA Clinical Guidelines Committee of the American College of Physicians. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians.

Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial [published correction appears in Lancet. Groop PH, Cooper ME, Perkovic V, Emser A, Woerle HJ, von Eynatten M.

Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction.

Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial.

Diabetes Obes Metab. Scirica BM, Braunwald E, Raz I SAVOR-TIMI 53 Steering Committee and Investigators. Heart failure, saxagliptin and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial [published correction appears in Circulation.

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. Fujita H, Morii T, Fujishima H, et al.

The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.

Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. UK Prospective Diabetes Study UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34 [published correction appears in Lancet.

Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. The CREDENCE trial was the first landmark placebo control trial for an SGLT2 inhibitor where the primary outcome being evaluated were the renal outcomes.

The DAPA—CKD trial in was the first kidney disease outcome trial to include a substantial proportion of participants with and without type 2 diabetes. Dapagliflozin was the first drug in the nephrology world that was given fast-track, breakthrough, and priority approval by the US Food and Drug Administration FDA in April due to its profound benefit on kidney outcomes and all-cause mortality.

This suggests that the effect of SGLT2 inhibition can be seen across the entire cohort of CKD patients, however, the benefit was more pronounced in patients with proteinuria. This trial was also stopped early because of clear positive efficacy. As a result of this trial the European Medicines Agency EMA , and most recently the FDA approved empagliflozine for the treatment of adult patients with chronic kidney disease with or without diabetes.

Glucagon-like peptide-1 receptor agonists have been used to treat type 2 diabetes since GLP-1 increases insulin sensitivity and secretion from pancreatic beta cells and increases its proliferation. It also slows gastric emptying and promotes satiety Exenatide was the first GLP-1 receptor agonist on the market and was manufactured from a salivary hormone exendin 4 Since that time, multiple medications of this drug class have been released, including lixisenatide, liraglutide, dulaglutide, and semaglutide.

Tirazepatide is a new medication that, in addition to being a GLP-1 receptor agonist, also activates the receptors of glucose-dependent insulin tropic polypeptide GIP which improves insulin sensitivity and secretion in a way similar to GLP-1 Kidney protection is one of the numerous beneficial effects of some GLP-1 receptor agonists.

Suggested mechanisms include blocking angiotensin II inflammatory effects and oxidative stress and decreasing glomeruli hyperfiltration in animal models 4. Other favorable benefits include weight loss, cardiovascular benefits, and cerebrovascular benefits 55 , which make this drug class the first line of recommended anti-hyperglycemic medications by the ADA, particularly in patients with overweight or obesity, and in patients who have non-proteinuric kidney disease 39 Figure 2.

It is important that clinicians familiarize themselves with the different medications in this class, since not all of them share the same degree of benefits. When looking at their utilities from a kidney standpoint, only liraglutide, dulaglutide, and subcutaneous semaglutide have demonstrated kidney benefits and effects on major cardiovascular events 56 — Importantly, no dosage adjustment is needed in patients with kidney disease.

Tirazepatide has demonstrated the maximum benefits on weight loss among all weight loss-promoting medications up to When patients on insulin treatment begin taking a GLP-1 receptor agonist, it is crucial to monitor their insulin dosage closely. Increasing the dose of the GLP-1 receptor agonist may require a decrease in insulin dosage and adjustment or discontinuation of insulin secretagogues if hypoglycemia is a concern.

Glucagon-like peptide-1 receptor agonists can be used as a combination therapy with insulin and other oral medications except for other incretin therapies such as DPP-4 inhibitors; this combination is unlikely to provide additional benefits on glycemic targets.

Providing patients with dietary consultation, including eating small meals with low-fat content and avoiding spicy food, might help reduce their symptoms. Patients with underlying gastroparesis might benefit from a slower titration.

In patients with severe forms of gastroparesis, GLP-1 receptor agonist should be avoided. Another consideration is to evaluate patients for gallbladder disease before initiating the medication in patients with symptoms suggestive of cholelithiasis.

Pancreatitis has been reported in association with GLP-1 receptor agonist use; however, causality has not been established. If patients develop symptoms suggestive of pancreatitis, the medication should be discontinued.

Medications of this class are contraindicated in patients with a personal or family history of medullary thyroid cancer c-cell tumors. Although the risk was only seen in animal models, human prevalence is not determined. None of the other more common thyroid cancers have been associated with an increased risk.

Clinicians should reassure patients with a personal or family history of non-c-cell thyroid tumors. Studies using data from cardiovascular outcome trials suggested an association between retinopathy progression and GLP-1 receptor agonist use.

However, one could argue that retinopathy can worsen with any treatment that causes rapid hemoglobin A1c reduction. Furthermore, an analysis of the FDA Adverse Event Reporting System showed no evidence that GLP-1 receptor agonists are associated with adverse effects related to retinopathy progression.

More studies showed no effect of GLP-1 receptor agonists on angiogenesis and no association between GLP-1 agonist exposure and severe diabetic retinopathy. In clinical practice, we suggest close follow-up in patients with a history of moderate to severe retinopathy, particularly in patients who experience a rapid reduction of hemoglobin A1c levels with GLP-1 receptor agonist treatment Table 3.

An analysis of data presented in the ELIXA trial, which compared lixisenatide to placebo, showed that lixisenatide reduced the urinary albumin-to-creatinine ratio UACR and it was only statistically significant in participants with stage A3 albuminuria A post hoc analysis of EXSCEL trial data compared exenatide to placebo which showed decreased onset of severe albuminuria in the exenatide group, but the difference was not statistically significant The LEADER trial, which studied liraglutide vs.

SUSTAIN-6 studied semaglutide vs. placebo with nephropathy as a secondary outcome; new or worsening nephropathy occurred in 3. The AWARD-7 trial compared dulaglutide to insulin glargine in patients with moderate to severe kidney disease and type 2 diabetes; a decrease in UACR was seen in patients receiving dulaglutide 1.

The REWIND trial studied dulaglutide vs. placebo, showing less new-onset stage A3 albuminuria in the dulaglutide group Of note, kidney disease outcomes were secondary in all mentioned trials.

However, there is an ongoing dedicated kidney outcomes trial designed to determine the kidney-protective effects of semaglutide in participants with CKD and T2D the FLOW trial. This study was just stopped early due to an interim analysis suggesting a very high likelihood of study success.

Full results are now expected in early A meta-analysis published by Kristensen et al. Multiple studies have highlighted the potential benefit of MRAs in managing hypertension and reducing proteinuria.

In addition to blocking the epithelial sodium channel in the principal cell and decreasing sodium reabsorption, MRAs have been demonstrated to decrease inflammation, oxidative stress, and scarring 67 , While steroidal MRAs like spironolactone and eplerenone have been available for some time, their use is limited by their side effects The newest addition to our repertoire is non-steroidal MRAs ns-MRAs , with the prototype, finerenone.

These newer medications have demonstrated protective cardiorenal effects with a more favorable risk-to-benefit ratio compared to their steroidal counterparts 70 Figure 3. Figure 3. Visual representation of the renin—angiotensin—aldosterone system RAAS and the mechanism of ACEi, angiotensin receptor blockers ARB , and mineralocorticoid receptor blockers.

Medications used in diabetic kidney disease are depicted in green. Prior to initiating treatment with MRAs, it is essential to consider several factors. Firstly, the patient should already be receiving maximal tolerated doses of RAAS and SGLT2 inhibition.

Secondly, when faced with uncontrolled hypertension and hyperaldosteronism, it is preferable to add a steroidal MRA such as spironolactone and eplerenone rather than finerenone due to the limited blood pressure effect of the latter.

However, the use of spironolactone is limited by hyperkalemia and gynecomastia. It has been shown that the addition of a potassium binder in conjunction with spironolactone decreased the rate of drug discontinuation, particularly in advanced CKD Eplerenone has less binding affinity at androgen receptors and is a viable alternative in patients who experience enlargement of breast tissue with spironolactone The trials evaluating the effectiveness of ns-MRA in patients with DKD were conducted before the benefits of SGLT2 inhibitors were well established.

In fact, only a small percentage of patients 4. Currently, it is recommended that providers initiate and prioritize maximally tolerated RAAS and SGLT2 inhibition as the standard of care before considering additional treatment like finerenone, despite limited data on the efficacy of ns-MRA in patients receiving both RAAS and SGLT2 inhibition.

The concomitant use of SGLT2 inhibitors with their potential kaliuretic effect might help mitigate the hyperkalemia challenge. During treatment, potassium levels should be followed regularly.

If hyperkalemia was the limiting factor preventing dose up-titration, it is recommended to resume the medication at a lower dose after the achievement of normokalaemia on follow-up labs.

It is also worth mentioning that, although these medications are not primarily used as antihypertensives as mentioned above, they still have considerable impact on lowering blood pressure. Lastly, it should be noted that concomitant use of both steroidal and ns-MRAs is not recommended Table 4.

Spironolactone has demonstrated promising efficacy in managing DKD, particularly in reducing proteinuria and slowing the progression of kidney damage. Several reviews including a Chocrane systematic review confirmed the additional benefit of steroidal MRAs for kidney and cardiac protection when used with an ACEior ARB 75 , A study by Mehdi et al.

Multiple phase II randomized clinical trials investigated the efficacy and safety of finerenone. Fewer side effects were seen with the ns-MRA as highlighted in the Mineralocorticoid Receptor Agonist Tolerability Trial ARTS showing significantly less hyperkalemia compared to spironolactone A dose-dependent decrease in albuminuria was seen in the subsequent ARTS-DN trial further paving the path for further investigations In more recent years, phase III trials namely the finerenone in reducing kidney failure and decreasing progression of diabetic kidney disease FIDELIO-DKD and the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease FIGARO-DKD provided the biggest evidence of cardiorenal protection.

The composite kidney outcome occurred in 5. Once again, finerenone proved to reduce the risk of cardiovascular and kidney outcomes in diabetics on maximal dose ACE inhibitor or ARB, with lower rates of hyperkalemia compared to placebo across stages of kidney disease Endothelins were first discovered in with the first endothelin aptly named endothelin 1.

Endothelin 1 has simultaneously been implicated in inflammation, vasoconstriction, and mesangial proliferative effects mediated by endothelin receptor A. There is also evidence for overexpression of endothelin receptors in diabetics.

Antagonism of the endothelin receptor was shown to aid with microcirculation in animal models, however, similar effects have yet to be shown in human trials Endothelin A receptor blockade has multiple effects including a reduction in glomerular vasodilation which can also alter permeability for proteins including albumin leading to a lower tubular load of protein excretion Though sparsentan has been granted accelerated FDA approval for the treatment of IgA nephropathy in adults, there are currently no medications approved for treatment of DKD in this class.

Volume overload and heart failure exacerbations remain a concern when for treatments using endothelin receptor antagonists. Combining endothelin receptor antagonists with SGLT2 inhibitors may reduce fluid retention similar to thiazides or loop diuretics This can potentially be explained by a synergistic effect between medication classes and their effect This hypothesis is being evaluated in the ZENITH trial.

This trial randomized groups CKD patients with and without diabetes to receive zibotentan combined with dapagliflozin. Recruitment for this study has been completed at the time of writing but results are pending Hemoglobin was noted to stabilize after that period Finally, current FDA guidelines recommend monthly monitoring of liver enzymes since elevation and liver injury were reported in several ERAs 88 , Discontinuation of the medication is advised if liver enzymes increase more than five times the upper limit of normal, or if bilirubin increases more than twice the upper limit of normal, or if clinical signs of liver toxicity or failure are seen although no serious liver injury was noted in ASCEND or SONAR trials 89 Table 5.

The ASCEND trial evaluated kidney composite outcomes in patients receiving either avosentan or placebo. Due to safety concerns relating to volume overload and heart failure exacerbations, the trial was terminated early.

Despite having a statistically significant reduction in albuminuria in patients on avosentan, there were no differences in kidney composite outcomes The SONAR trial evaluated whether endothelin antagonism could be of benefit in certain groups of patients with diabetic kidney disease.

The study followed a pragmatic trial design in which patients with diabetic kidney disease and proteinuria despite maximal tolerated RAAS blockade were treated with atrasentan during an enrichment period. Patients who did not develop significant volume retention were then randomized to receive atrasentan vs.

Results showed improved kidney outcomes in patients who tolerated the endothelin antagonist. Other pharmacological options targeting several inflammatory pathways have been the subject of interest. Other herbal supplements with antioxidant properties have also been investigated such as silymarin, but more research is needed before adding these agents to our growing list of management options Preliminary findings suggest that DDP-4 inhibitors such as saxagliptin and linagliptin, may offer potential advantages for patients with DKD Several new agents have made a significant impact in the field of DKD with clear protective advantages not only in terms of kidney disease progression but also in cardiovascular risk mitigation.

While RAAS inhibitors continue to be essential for managing these patients, we now have the option of offering additional medications that can complement the benefit of blocking RAAS including SGLT2 inhibitors, GLP-1 receptor agonists, and MRA.

In summary, borrowing the terminology from our heart failure colleagues, the guideline-directed medical therapy for DKD is here and for the time being includes ACEi or ARB, SGLT2 inhibitors, GLP-1 receptor agonist, and an MRA.

The expansion of therapeutic options has marked the beginning of a new era in DKD management where we can hopefully be more impactful in the care of these patients Table 6. YB: Writing — original draft. AA: Writing — original draft.

KA: Writing — original draft. OO: Writing — original draft. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Globally, more treatmrnt million people have diabetes teeatment and almost Fiber optic network capacity may be Low-carb and blood sugar regulation by Prevention hephropathy diabetes in the general population is the most effective Appetite suppressants for hunger control of minimizing the impact of DKD; understanding risk factors Appetite suppressants for hunger control DKD development can help with early identification and intervention. Effectively using screening guidelines, treatment strategies, and subspecialty referral can help prevent progression of DKD. The role of primary care physicians in the management of patients with DKD secondary to type 2 diabetes is reviewed. DKD has multiple pathophysiologic mechanisms involving microvascular and macrovascular changes. These changes lead to albuminuria, decreased glomerular filtration, or both. For patients who develop macroalbuminuria, in any given year the risk of mortality 4. Diabetic nephropathy treatment options

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