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Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries, including the United States. As a microvascular complication, it affects individuals with both type 1 and type 2 diabetes. Significant progress has been made in recent years in understanding the mechanisms of diabetes mellitus, and recent studies have led to updates in treatment guidelines. Staying informed about these latest developments is crucial for providing optimal care to patients with diabetes and kidney disease. The primary pathological features of diabetic kidney disease (DKD) include glomerular hypertrophy, glomerular basement membrane thickening, effacement of podocyte foot processes, and mesangial matrix expansion. Traditional markers of DKD, such as albuminuria and creatinine, are relatively insensitive and have limited utility due to delayed detection. Several new medication classes have improved the prognosis for patients with diabetes mellitus, with supporting data highlighting their benefits. Lifestyle factors, particularly dietary choices, also play a significant role in the progression of kidney disease and should be carefully evaluated. Early detection and treatment are critical to delaying progression. Diagnosis involves albuminuria assessment, with thresholds for moderate and severe stages. Management emphasizes cardiovascular risk reduction, glycemic and blood pressure control, and renin-angiotensin system inhibition. Recent advances include improved treatment guidelines, novel biomarkers, and a focus on tubulointerstitial injury. This activity explores the causes, pathophysiology, and treatment of diabetic nephropathy, emphasizing recent advancements in therapeutic approaches and lifestyle modifications to improve patient outcomes. This activity also underscores the critical role of the interprofessional healthcare team in optimizing care through coordinated management strategies. Objectives: Identify the early signs and risk factors of diabetic nephropathy in patients with type 1 and type 2 diabetes. Implement evidence-based management strategies for diabetic nephropathy, including glycemic control, blood pressure management, and cardiovascular risk reduction. Select appropriate biomarkers for monitoring disease progression and assessing treatment efficacy in patients with diabetic nephropathy.

Identify the early signs and risk factors of diabetic nephropathy in patients with type 1 and type 2 diabetes. Implement evidence-based management strategies for diabetic nephropathy, including glycemic control, blood pressure management, and cardiovascular risk reduction. Select appropriate biomarkers for monitoring disease progression and assessing treatment efficacy in patients with diabetic nephropathy. Collaborate with interdisciplinary healthcare teams, including nephrologists, dietitians, and cardiologists, to provide comprehensive care for patients with diabetic nephropathy. Access free multiple choice questions on this topic.

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in many developed countries, including the United States.[1] As a microvascular complication, diabetic nephropathy affects individuals with both type 1 diabetes (T1D) and type 2 diabetes (T2D). The condition presents with persistent albuminuria and a progressive decline in the glomerular filtration rate (GFR). Substantial evidence indicates that early, aggressive treatment can delay or prevent the progression of the disorder. While diabetic nephropathy can develop in both T1D and T2D, the majority of diabetes cases (>90%) are T2D, which is primarily insulin-resistant. Please see StatPearls' companion resource, "Type 2 Diabetes," for more information. Recent studies have led to updates in treatment guidelines, making it essential to review this extensive topic for providing optimal care to patients with diabetes and kidney disease. Recent guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) and several renal organizations recommend using the terms "diabetes and chronic kidney disease (CKD)" or "diabetic kidney disease (DKD)" instead of "diabetic nephropathy." However, all these terms are currently used in the literature. Additionally, the Kidney Disease Outcomes Quality Initiative (KDOQI) work group emphasizes the need for long-term multidisciplinary teams to address the widespread impact of diabetes and highlights the importance of holistic care and lifestyle modifications for effective management.[2]

Hyperglycemia triggers the production of reactive oxygen species and activates several molecular pathways. These include the formation of advanced glycemic end products, increased oxidation, activation of nuclear factor kappa B (NF-κB) and protein kinase C, upregulation of transforming growth factor-beta (TGF-β)/SMAD, and heightened lipotoxicity. At the cellular level, hyperglycemia stimulates abnormal cell signaling, enhances matrix formation, and thickens the glomerular basement membrane (GBM). A significant feature is marked inflammation, driven by elevated levels of cytokines and chemokines, leading to fibrosis and increased vascular permeability. These interconnected pathways drive the onset and progression of diabetic nephropathy by promoting inflammation, fibrosis, endothelial dysfunction, and podocyte damage. Gaining insight into these mechanisms can lead to the development of novel therapeutic strategies. Macrophage Activation Hyperglycemia leads to the production of glucose degradation products and glycation end products, intensifying inflammation and promoting macrophage infiltration in the kidneys, a key factor in diabetic nephropathy. Immune complexes and cytokines, such as TGF-β1 (secreted by macrophages) and intracellular cell adhesion molecule-1 (ICAM-1, produced by renal tubular cells), are critical in this process.[3] An autopsy series identified a correlation between the presence of CD163+ macrophages in renal tissue and the severity of diabetic nephropathy, interstitial fibrosis, tubular atrophy, and glomerulosclerosis.[4] Macrophages contribute to renal fibrosis by attracting fibroblasts and can themselves transform into myofibroblasts, further driving fibrotic progression.[3][5] Macrophages also activate the renin-angiotensin-aldosterone system (RAAS), leading to alterations in renal hemodynamics. RAAS activation further recruits macrophages through the actions of monocyte chemoattractant protein-1 (MCP-1), osteopontin, and various adhesion molecules, including selections, ICAM-1, PCAM-1, and VCAM.

Macrophages also activate the renin-angiotensin-aldosterone system (RAAS), leading to alterations in renal hemodynamics. RAAS activation further recruits macrophages through the actions of monocyte chemoattractant protein-1 (MCP-1), osteopontin, and various adhesion molecules, including selections, ICAM-1, PCAM-1, and VCAM. Interest has increasingly shifted from the well-established glomerular mechanisms of diabetic nephropathy to the lesser-known mechanisms of tubulointerstitial disease in DKD. Some biopsy studies have found that macrophage infiltration in the tubulointerstitium correlates more strongly with declining GFR and renal fibrosis than glomerular macrophage infiltration. Additionally, tubular epithelial cells can undergo a transformation into mesenchymal cells, contributing to the secretion of extracellular matrix and the proliferation of fibroblasts.[6] Several medications have been shown to reduce macrophage activity through the following mechanisms: RAAS inhibitors: These inhibitors decrease the expression of MCP-1. Pioglitazone: This drug decreases the expression of NF-κB. Vitamin D-25(OH): This vitamin decreases macrophage adhesion.[3] Endothelial Cell Damage Endothelial cell damage is one of the earliest pathological changes in diabetic nephropathy. This damage generates reactive oxygen species, which are major contributors to the progression of diabetic nephropathy. Hyperglycemia and hemodynamic changes trigger the release of cell adhesion molecules (as noted earlier), glycosaminoglycans, and chemokines, which further amplify the immune response. This response involves direct endothelial damage and is further exacerbated by the transition of endothelial cells into mesenchymal cells.[7] Podocyte Damage Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. Contributing factors to podocyte damage include lipotoxicity (ie, increased lipid synthesis and decreased degradation), oxidative stress, mitochondrial dysfunction, vascular dysfunction (eg, shear stress from hyperfiltration), and impaired autophagy.[8][9] Additionally, podocyte damage is associated with reduced nephrin expression and inhibition of insulin-like growth factor-1 (IGF-1)/insulin receptor signaling pathways.[9][10]

Podocytes are essential components of the glomerular filtration barrier, and their injury leads to proteinuria. Podocyte injury may involve hypertrophy, reduced density, and apoptosis. Contributing factors to podocyte damage include lipotoxicity (ie, increased lipid synthesis and decreased degradation), oxidative stress, mitochondrial dysfunction, vascular dysfunction (eg, shear stress from hyperfiltration), and impaired autophagy.[8][9] Additionally, podocyte damage is associated with reduced nephrin expression and inhibition of insulin-like growth factor-1 (IGF-1)/insulin receptor signaling pathways.[9][10] Key therapeutic interventions targeting factors that damage podocytes, as tested in clinical and preclinical trials, involve the following mechanisms: Lipid-lowering agents: Statins and resveratrol decrease lipid accumulation. Atrasentan (with losartan): This drug may increase podocyte number. Spironolactone: This drug decreases RAAS activation and may reduce autophagy. Sacubitril (with losartan): This drug may decrease inflammation, oxidative stress, and blood sugar levels. Glucagon-like peptide-1 inhibitors: These inhibitors (GLP1) help decrease oxidative stress and apoptosis. Sodium-glucose cotransporter-2 inhibitors: These inhibitors (SGLT2Is) may reduce oxidative stress and apoptosis.[9] Polyol Pathway and Uric Acid The polyol pathway contributes to diabetic nephropathy through the accumulation of fructose and sorbitol, glucose byproducts that increase osmotic pressure, leading to edema and cell membrane rupture.[5] Structurally similar to glucose, fructose is metabolized by the liver, and under normal physiological conditions, only small amounts of dietary fructose appear in the plasma. However, fructose metabolism produces urate as a byproduct, which can contribute to insulin resistance, endothelial dysfunction, and renal tubular injury. Hyperuricemia also activates the RAAS and may be a risk factor for cardiovascular disease.[11][12] In addition, fructose also contributes to oxidative stress, which is a key contributor to diabetic nephropathy. Aldolase reductase, which catalyzes the rate-limiting step of the polyol pathway, has been targeted in studies, which show that aldolase reductase inhibitors can reverse diabetic nephropathy lesions in animal models.[13][14] Genetics

Hyperuricemia also activates the RAAS and may be a risk factor for cardiovascular disease.[11][12] In addition, fructose also contributes to oxidative stress, which is a key contributor to diabetic nephropathy. Aldolase reductase, which catalyzes the rate-limiting step of the polyol pathway, has been targeted in studies, which show that aldolase reductase inhibitors can reverse diabetic nephropathy lesions in animal models.[13][14] Genetics Genetics is crucial for the development of diabetic nephropathy, with both genetic and environmental factors contributing to its onset. Individuals with a family history of diabetes or kidney disease are at higher risk of developing diabetic nephropathy. Certain genes have been associated with the development of diabetic nephropathy, which include variations in the following genes: APOL1: Variants in this gene are strongly associated with hypertension and various renal diseases, such as focal and segmental glomerulosclerosis. These gene variants are predominantly found in individuals of African ancestry. While APOL1 mutations are not typically linked to the initial development of diabetic nephropathy, they appear to accelerate its progression.[15] ACE: Polymorphisms in the angiotensin-converting enzyme (ACE) gene have been linked to diabetic nephropathy and may have a role in the renoprotective effects of ACE inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapies.[16][17] COL4A3, COL4A4, and COL4A5: These genes encode for collagen type IV, which is a critical structural component of the GBM. Mutations in these genes have been associated with increased susceptibility to diabetic nephropathy.[18][19] Another aspect of the gene-environment interaction is gene regulation. Prolonged hyperglycemia can influence epigenetic mechanisms, including DNA methylation, posttranslational histone modifications, and noncoding RNA regulation.[20]

In the United States, the Centers for Disease Control and Prevention (CDC) reports that 14% of individuals aged 20 or older are affected by CKD, with 30% of those also having diabetes.[3] Approximately 30% to 40% of patients with diabetes mellitus develop diabetic nephropathy.[21][22] By 2045, the global incidence of diabetes is projected to exceed 783 million, and by 2030, diabetic complications are expected to become the seventh leading cause of mortality.[5][21]

Patients with T2D may present with albuminuria at the time of diabetes diagnosis, whereas diabetic nephropathy typically develops 15 to 20 years after the onset of T1D. Approximately 30% of patients with T1D and 40% of those with T2D develop diabetic nephropathy, primarily because the exact onset of T2D is often unclear. Structural and functional changes occur in the kidney on account of diabetes and result in proteinuria, hypertension, and progressive reduction of kidney function, which are hallmarks of diabetic nephropathy.[23] The 3 main pathological lesions of diabetic nephropathy include diffuse mesangial cell expansion, GBM thickening, and arteriolar hyalinization. However, almost all kidney compartments, including the glomerular capillary wall, podocytes, mesangium, tubulointerstitium, and renal vasculature, are affected. Diabetic nephropathy typically aligns with the progression of albuminuria, advancing from normal albumin levels to microalbuminuria (moderately increased albuminuria) and eventually to macroalbuminuria (severely increased albuminuria). Aggressive treatment can partially reverse this progression.[24][25][23] The glomerular filtration barrier is a highly regulated structure consisting of capillary endothelial cells, GBM, and podocytes. The GBM is 3 to 6 times thicker than capillaries in other parts of the body and is highly fenestrated, with fenestrations covering up to 50% of the endothelial surface. Primarily composed of type IV collagen and negatively charged proteoglycans, the GBM functions as a selective filter, permitting the passage of water and small solutes while excluding large proteins, such as albumin, when intact.[5] Nephrin is a key component of the GBM that helps maintain the integrity of the slit diaphragms, the primary barrier preventing protein loss in urine. Reduced nephrin expression is an early event in the development of diabetic nephropathy. Synaptopodin, another protein localized to podocyte foot processes, is also downregulated in diabetic nephropathy. MCP-1 further reduces the expression of both nephrin and synaptopodin and is associated with albuminuria.[26]

Nephrin is a key component of the GBM that helps maintain the integrity of the slit diaphragms, the primary barrier preventing protein loss in urine. Reduced nephrin expression is an early event in the development of diabetic nephropathy. Synaptopodin, another protein localized to podocyte foot processes, is also downregulated in diabetic nephropathy. MCP-1 further reduces the expression of both nephrin and synaptopodin and is associated with albuminuria.[26] Hyperfiltration is one of the earliest pathological changes observed in diabetic nephropathy, involving both the glomeruli and renal tubules. This phenomenon is partially mediated by hyperglycemia-induced upregulation of apical sodium-glucose cotransporter-1 (SGLT1) and -2 (SGLT2) and basolateral glucose transporters, along with decreased vascular resistance.[23][27] Under normoglycemic conditions, approximately 160 g/d of glucose is filtered by the kidneys, with nearly all reabsorbed in the proximal tubule via SGLT2. SGLT1 has a minor role in urinary glucose absorption and primarily facilitates intestinal glucose absorption. Hyperfiltration reduces sodium concentration at the macula densa, increasing dietary salt sensitivity, which worsens hypertension. Increased tubular hyperfiltration contributes to nephron enlargement. This process is accompanied by glomerular and intracellular hypertrophy, which occur through distinct mechanisms.[23][27][28] Evidence suggests that animal protein promotes hyperfiltration and insulin resistance, while plant protein enhances insulin sensitivity. Therefore, diabetic patients should prioritize plant protein in their diet.[29] Hyperfiltration is also mediated by vascular regulation. Prostaglandins and atrial natriuretic peptides are 2 potential mediators that reduce arteriolar resistance, further contributing to hyperfiltration. Both are elevated in patients with diabetic nephropathy, particularly those with severe albuminuria (>3.0 g/d).[27][30] Endothelial dysfunction is another factor linked to glomerular hyperfiltration, with increased endothelin-1 levels observed in patients with T2D and proteinuria. Although endothelin receptor blockers have not shown efficacy to date, ongoing research continues in this area.[27][31]

Abnormal renal pathology is evident even before the onset of microalbuminuria. Characteristic lesions observed on light microscopy include thickened glomerular and tubular basement membranes, diffuse mesangial expansion, and arteriolar hyalinosis. The pathological classification includes: Class I: GBM thickening Class IIa: Mild mesangial expansion Class IIb: Severe mesangial expansion Class III: Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) Class IV: Advanced diabetic nephropathy with over 50% glomerulosclerosis and associated lesions Tubulointerstitial inflammation or atrophy and vascular lesions are scored on scales from 0 to 3. Additional findings include arteriosclerosis, exudative lesions, and interstitial fibrosis. Mesangial expansion limits capillary filtration capacity, contributing to a decline in GFR.[24]

A longer duration of diabetes mellitus, poor glycemic control, and uncontrolled hypertension are significant risk factors for developing diabetic nephropathy. Additional risk factors include obesity, smoking, hyperlipidemia, and a family history of diabetes or kidney disease. Patients may also present with associated conditions such as peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy. Notably, diabetic retinopathy has a particularly strong correlation with diabetic nephropathy, as previously highlighted.[5] Patients with diabetic nephropathy often exhibit similar physical characteristics to other individuals with diabetes. In the early stages, patients are typically asymptomatic, with the condition often identified through screening that reveals proteinuria levels between 30 and 300 mg/g creatinine. As the disease progresses, patients may present with symptoms such as fatigue, foamy urine (indicative of urine protein (>3.5 g/d), and pedal edema due to hypoalbuminemia and nephrotic syndrome. Other generalized findings associated with diabetes mellitus include the following: Fatigue Dizziness Polydipsia and polyuria Polyphagia Blurred vision or vision loss [32] Tingling or numbness Peripheral neuropathy Foot ulcers [33][34] Delayed wound healing Frequent infections Nausea, vomiting, and abdominal pain Acanthosis Nigricans (commonly seen in T2D) [35] Unexplained weight loss (commonly seen in T1D) Please see StatPearls' companion resource, "Type 2 Diabetes," for more information.

Proteinuria Proteinuria is the hallmark of diabetic nephropathy. Diagnosing DKD is more challenging in T2D than in T1D, as the exact onset of T2D is often unclear. History and physical exam are crucial in diagnosing diabetic nephropathy in T2D. Patients diagnosed with T1D should have proteinuria checked within 5 years of diagnosis, while those diagnosed with T2D should be screened at the time of diagnosis and annually thereafter. Increased proteinuria is an indicator of declining kidney function and should be treated aggressively.[25][23] Diabetic nephropathy is diagnosed by persistent albuminuria on 2 or more occasions, separated by at least 3 months, using early morning urine samples. Persistent albuminuria is defined as 300 mg/d or greater. Moderately increased albuminuria, a marker of early diabetic nephropathy, is between 30 and 300 mg over 24 hours. Severe albuminuria is classified as greater than 300 mg of albuminuria per day. Moderately increased albuminuria can also be defined as a spot urine-to-creatinine ratio of 20 to 200 mg/g or 20 to 200 µg/min.[36][37] Urinary Biomarkers Given the relative nonspecificity and delayed utility of creatinine change and albuminuria as markers of diabetic nephropathy, other molecules are being explored as potential markers. In recent years, there has been growing interest in studying markers of tubulointerstitial injury rather than focusing solely on the glomerulus. Additionally, non-albuminuric proteinuria, which indicates tubulointerstitial injury, is strongly associated with DKD. Some evidence even suggests that proximal tubular damage may occur earlier than glomerular damage.[23][38][39] Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are elevated in early diabetic nephropathy, even before the onset of albuminuria, and correlate with a decline in decreased GFR.[23][38] Urinary KIM-1 is associated with proximal tubule damage, while NGAL is associated with damage to the loop of Henle and distal tubule. NGAL is also an early marker of acute kidney injury (AKI), with serum elevations detectable within hours of the causative insult and up to 24 to 72 hours before creatinine levels.[40] Urinary NGAL also appears before albuminuria.[23][38][39]

Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are elevated in early diabetic nephropathy, even before the onset of albuminuria, and correlate with a decline in decreased GFR.[23][38] Urinary KIM-1 is associated with proximal tubule damage, while NGAL is associated with damage to the loop of Henle and distal tubule. NGAL is also an early marker of acute kidney injury (AKI), with serum elevations detectable within hours of the causative insult and up to 24 to 72 hours before creatinine levels.[40] Urinary NGAL also appears before albuminuria.[23][38][39] The most studied biomarkers for diabetic nephropathy include NGAL, KIM-1, and periostin. One study found that NGAL had a sensitivity of 76% and specificity of 55%, KIM-1 had a sensitivity of 63% and specificity of 90%, and periostin had a sensitivity of 80% and specificity of 66%.[39][41] Although many of these biomarkers are not yet widely available outside research settings, their use is becoming more established, and combining them may enhance early detection of diabetic nephropathy. Some of the potential biomarkers for diabetic nephropathy that have been studied over the last decade are listed in the Table below. Table Table. Potential Biomarkers for Diabetic Nephropathy. Table reference [42]

The management of diabetic nephropathy focuses on 4 key areas, including cardiovascular risk reduction, glycemic control, blood pressure (BP) control, and inhibition of the renin-angiotensin system (RAS). Modifying risk factors, such as tobacco cessation and implementing optimal lipid control strategies, is essential for reducing cardiovascular risk.[43][44][45] Glycemic Control Intensive glycemic control is most effective when initiated before the onset of diabetic complications, with reduced efficacy when started later. Therefore, early intensive glycemic control is highly recommended.[46] The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that T2D patients who achieved early glycemic control with a hemoglobin A1c (HbA1c) of 7.0% maintained improved microvascular outcomes and lower mortality even after the study ended, despite HbA1c values converging between the 2 groups.[47][48] The Diabetes Control and Complications Trial (DCCT) showed comparable results in T1D patients.[49] The long-term benefits of early glucose-lowering therapy, particularly when HbA1c is kept below 6.5% during the first year of diagnosis, have been referred to as the "legacy effect" or "metabolic memory." However, long-term intensive glucose control is not always beneficial, as some studies have shown worse all-cause and cardiovascular outcomes in T2D patients due to hypoglycemic events associated with aggressive glycemic control. The KDOQI and KDIGO guidelines recommend an HbA1c goal of approximately 7.0% to help mitigate the development of microvascular complications.[5] Other less commonly used methods for evaluating glycemic control include glycated albumin and fructosamine; however, these measurements are not well-validated. While HbA1c is the most accurate measure of long-term glycemic control, it may not accurately reflect episodes of hypoglycemia or severe hyperglycemia, both of which are more prevalent in CKD. Although the National Kidney Foundation (NKF)-KDOQI guidelines suggest an HbA1c goal of around 7.0%, individualized targets based on the patient's overall clinical condition are recommended.[3][50] Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Other less commonly used methods for evaluating glycemic control include glycated albumin and fructosamine; however, these measurements are not well-validated. While HbA1c is the most accurate measure of long-term glycemic control, it may not accurately reflect episodes of hypoglycemia or severe hyperglycemia, both of which are more prevalent in CKD. Although the National Kidney Foundation (NKF)-KDOQI guidelines suggest an HbA1c goal of around 7.0%, individualized targets based on the patient's overall clinical condition are recommended.[3][50] Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers The KDIGO guidelines recommend a BP target of less than 120/80 mm Hg for individuals with diabetes, allowing for individualization based on patient-specific factors. ACEIs or ARBs are advised for all diabetic patients with hypertension unless contraindicated.[5] In addition, these medications should be titrated to the highest tolerated dose. The use of ACEIs or ARBs in cases of albuminuria without hypertension remains insufficiently studied and should be considered on an individual basis. Kidney transplant recipients with diabetes and hypertension should also receive RAAS inhibition as part of their management. Evidence supports the use of these medications in hypertensive dialysis patients, as discontinuing ACEIs or ARBs has been associated with higher rates of cardiovascular death, myocardial infarction, and ischemic stroke. KDIGO guidelines recommend strict dietary compliance and the use of potassium binders, if necessary, to manage ACEI/ARB-associated hyperkalemia.[2] Studies demonstrate the benefits of ARBs in delaying the progression of kidney disease, as evidenced by the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study) and IDNT (Irbesartan Diabetic Nephropathy Trial) trials.[51][52] The UKPDS highlighted the positive impact of BP control on diabetes-related complications, including mortality, cardiovascular events, and microvascular outcomes. However, aggressive systolic BP control (<120 mm Hg) compared to standard therapy (<140 mm Hg) showed no significant differences in cardiovascular outcomes or progression to ESRD.[53]

Studies demonstrate the benefits of ARBs in delaying the progression of kidney disease, as evidenced by the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study) and IDNT (Irbesartan Diabetic Nephropathy Trial) trials.[51][52] The UKPDS highlighted the positive impact of BP control on diabetes-related complications, including mortality, cardiovascular events, and microvascular outcomes. However, aggressive systolic BP control (<120 mm Hg) compared to standard therapy (<140 mm Hg) showed no significant differences in cardiovascular outcomes or progression to ESRD.[53] The HOPE, LIFE, and ALLHAT trials confirmed the benefit of ACEIs in slowing CKD for individuals with an estimated GFR (eGFR) of more than 60 mL/min/1.73m2. In addition, studies such as IRMA2 (Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial) have shown the benefit of ARBs in preventing proteinuria in patients with microalbuminuria. Studies in patients with T1D and overt proteinuria have shown that ACEIs can slow the progression of diabetic nephropathy. The IDNT and RENAAL studies demonstrated similar benefits in T2D patients. These studies provide strong evidence that RAAS-blocking medications help slow the progression of diabetic nephropathy, independent of their effect on BP. However, the use of multiple RAS-blocking agents can lead to adverse outcomes, including acute renal failure, and is no longer recommended. Additionally, the treatment of diabetic patients with RAAS inhibition who do not have hypertension or albuminuria is discouraged.[2][54] A post hoc analysis of the RENAAL trial demonstrated that uric acid levels were reduced in the losartan group, suggesting another potential mechanism by which ARBs provide renoprotection. While small studies have investigated the effects of uric acid–lowering agents, the results have been mixed.[12] In cases of AKI, it is common practice to temporarily discontinue ACEI/ARB therapy until creatinine levels return to baseline. However, a retrospective study indicated that patients who continued ACEI/ARB therapy had lower mortality after 2 years, despite higher rates of renal-related hospitalizations.[55]

A post hoc analysis of the RENAAL trial demonstrated that uric acid levels were reduced in the losartan group, suggesting another potential mechanism by which ARBs provide renoprotection. While small studies have investigated the effects of uric acid–lowering agents, the results have been mixed.[12] In cases of AKI, it is common practice to temporarily discontinue ACEI/ARB therapy until creatinine levels return to baseline. However, a retrospective study indicated that patients who continued ACEI/ARB therapy had lower mortality after 2 years, despite higher rates of renal-related hospitalizations.[55] Additionally, the benefits of continuing ACEI/ARB therapy in patients with advanced CKD remain unclear. The STOP-ACEI (Study on the Effect of Angiotensin-Converting Enzyme Inhibitors) trial, a large multicenter randomized controlled study, investigated the impact of ACEI therapy on CKD progression in patients with diabetic nephropathy and an eGFR below 30 mL/min/1.73m2. The results revealed no significant difference in outcomes between those who continued ACEI/ARB therapy and those who discontinued it.[56] Metformin and Glucagon-Like Peptide-1 Receptor Agonists The KDIGO guidelines and the American Diabetes Association (ADA) suggest using metformin alongside dietary modifications as first-line treatment for T2D patients with CKD and an eGFR greater than 30 mL/min/1.73m2. Metformin has demonstrated significant benefits in CKD progression, cardiovascular outcomes, and all-cause mortality. However, metformin should not be initiated in individuals with an eGFR of less than 45 mL/min/1.73m2, as they are at risk of progressing to an eGFR of less than 30 mL/min/1.73m2 and developing lactic acidosis. The metformin dosage should be halved for eGFR between 45 and 60 mL/min/1.73m2. Metformin should also be withheld during inpatient admissions to prevent complications from potential renal insults. Additionally, metformin may reduce vitamin B12 and folate levels, necessitating regular monitoring and supplementation as needed.[2][57]

The KDIGO guidelines and the American Diabetes Association (ADA) suggest using metformin alongside dietary modifications as first-line treatment for T2D patients with CKD and an eGFR greater than 30 mL/min/1.73m2. Metformin has demonstrated significant benefits in CKD progression, cardiovascular outcomes, and all-cause mortality. However, metformin should not be initiated in individuals with an eGFR of less than 45 mL/min/1.73m2, as they are at risk of progressing to an eGFR of less than 30 mL/min/1.73m2 and developing lactic acidosis. The metformin dosage should be halved for eGFR between 45 and 60 mL/min/1.73m2. Metformin should also be withheld during inpatient admissions to prevent complications from potential renal insults. Additionally, metformin may reduce vitamin B12 and folate levels, necessitating regular monitoring and supplementation as needed.[2][57] The European Society of Cardiology recommends glucagon-like peptide-1 receptor agonists (GLP1RAs) or SGLT2 inhibitors (SGLT2Is) as first-line agents for patients with high cardiovascular risk. The KDIGO guidelines advise using GLP1RAs when glycemic control is not achieved with metformin or SGLT2Is. GLP1RAs should be titrated gradually and avoided in combination with dipeptidyl peptidase-4 inhibitors. Robust evidence supports the use of GLP1RAs and SGLT2Is to improve outcomes across diverse patient populations.[2][58] Mineralocorticoid Antagonists

The European Society of Cardiology recommends glucagon-like peptide-1 receptor agonists (GLP1RAs) or SGLT2 inhibitors (SGLT2Is) as first-line agents for patients with high cardiovascular risk. The KDIGO guidelines advise using GLP1RAs when glycemic control is not achieved with metformin or SGLT2Is. GLP1RAs should be titrated gradually and avoided in combination with dipeptidyl peptidase-4 inhibitors. Robust evidence supports the use of GLP1RAs and SGLT2Is to improve outcomes across diverse patient populations.[2][58] Mineralocorticoid Antagonists Mineralocorticoid receptor activation has been strongly associated with inflammation, fibrosis, and adverse hemodynamic remodeling in cardiac and renal diseases. Spironolactone and eplerenone, steroidal mineralocorticoid antagonists, have demonstrated efficacy, particularly in patients with heart failure and reduced ejection fraction. Additionally, these agents have been shown to effectively reduce proteinuria in CKD, with comparable benefits in proteinuria caused by diabetes mellitus and other conditions.[59][60] Spironolactone is associated with a high incidence of hyperkalemia, gynecomastia, and other adverse effects, limiting its widespread use. Eplerenone, while associated with a lower risk of hyperkalemia and fewer adverse effects, has a less pronounced BP-lowering effect.[61] Historically, the use of spironolactone and eplerenone in ESRD has been avoided. However, several randomized controlled trials have demonstrated improved cardiac outcomes with low-dose spironolactone in this population.[62]

Mineralocorticoid receptor activation has been strongly associated with inflammation, fibrosis, and adverse hemodynamic remodeling in cardiac and renal diseases. Spironolactone and eplerenone, steroidal mineralocorticoid antagonists, have demonstrated efficacy, particularly in patients with heart failure and reduced ejection fraction. Additionally, these agents have been shown to effectively reduce proteinuria in CKD, with comparable benefits in proteinuria caused by diabetes mellitus and other conditions.[59][60] Spironolactone is associated with a high incidence of hyperkalemia, gynecomastia, and other adverse effects, limiting its widespread use. Eplerenone, while associated with a lower risk of hyperkalemia and fewer adverse effects, has a less pronounced BP-lowering effect.[61] Historically, the use of spironolactone and eplerenone in ESRD has been avoided. However, several randomized controlled trials have demonstrated improved cardiac outcomes with low-dose spironolactone in this population.[62] Finerenone is a selective, nonsteroidal mineralocorticoid antagonist approved for managing CKD associated with T2D. Finerenone functions as a bulky, passive antagonist of the mineralocorticoid receptor. The medication has been shown to reduce albuminuria and improve renal and cardiovascular outcomes in patients with CKD and T2D, as demonstrated in multiple studies, including FIDELITY-DKD, FIGARO-DKD, and FINEARTS-HF.[62][63][64] Finerenone has demonstrated effectiveness in patients with and without reduced ejection fraction. Additionally, evidence suggests it may help prevent or delay the onset of heart failure in individuals with T2D and CKD.[65] The ARTS trial demonstrated that finerenone is at least as effective as spironolactone, with lower rates of hyperkalemia and other adverse effects. Additionally, data analysis indicates that finerenone improves albuminuria independently of changes in BP or GFR.[59][65] Esaxerenone, which has a mechanism of action similar to finerenone, is not approved by the Food and Drug Administration (FDA); however, it is used in Japan and other countries, where it has been shown to reduce albuminuria in patients with T2D.[59] Sodium-Glucose Cotransporter-2 Inhibitors

Finerenone is a selective, nonsteroidal mineralocorticoid antagonist approved for managing CKD associated with T2D. Finerenone functions as a bulky, passive antagonist of the mineralocorticoid receptor. The medication has been shown to reduce albuminuria and improve renal and cardiovascular outcomes in patients with CKD and T2D, as demonstrated in multiple studies, including FIDELITY-DKD, FIGARO-DKD, and FINEARTS-HF.[62][63][64] Finerenone has demonstrated effectiveness in patients with and without reduced ejection fraction. Additionally, evidence suggests it may help prevent or delay the onset of heart failure in individuals with T2D and CKD.[65] The ARTS trial demonstrated that finerenone is at least as effective as spironolactone, with lower rates of hyperkalemia and other adverse effects. Additionally, data analysis indicates that finerenone improves albuminuria independently of changes in BP or GFR.[59][65] Esaxerenone, which has a mechanism of action similar to finerenone, is not approved by the Food and Drug Administration (FDA); however, it is used in Japan and other countries, where it has been shown to reduce albuminuria in patients with T2D.[59] Sodium-Glucose Cotransporter-2 Inhibitors SGLT2Is reduce glucose reabsorption in the proximal tubule, leading to increased glucosuria, decreased capillary hypertension, and reduced albuminuria, GFR loss, and metabolic demand on nephrons. They also mitigate macula densa sodium hypersensitivity, decreasing glomerular hypertension and energy expenditure. Another key mechanism is the stimulation of hypoxia-inducible factors (HIFs), which enhance erythropoietin production.[27] This class of medications has demonstrated effectiveness in both patients with and without T2D through glucose-dependent and glucose-independent mechanisms.[28] Unlike many diabetic agents, SGLT2Is generally do not cause hypoglycemia, as their glucose-lowering effect halts when filtered glucose levels approach 80 g/d. Additionally, SGLT2Is increase glucagon secretion, stimulating hepatic gluconeogenesis.[66]

SGLT2Is reduce glucose reabsorption in the proximal tubule, leading to increased glucosuria, decreased capillary hypertension, and reduced albuminuria, GFR loss, and metabolic demand on nephrons. They also mitigate macula densa sodium hypersensitivity, decreasing glomerular hypertension and energy expenditure. Another key mechanism is the stimulation of hypoxia-inducible factors (HIFs), which enhance erythropoietin production.[27] This class of medications has demonstrated effectiveness in both patients with and without T2D through glucose-dependent and glucose-independent mechanisms.[28] Unlike many diabetic agents, SGLT2Is generally do not cause hypoglycemia, as their glucose-lowering effect halts when filtered glucose levels approach 80 g/d. Additionally, SGLT2Is increase glucagon secretion, stimulating hepatic gluconeogenesis.[66] The beneficial effects of SGLT2Is extend beyond glucose control. These medications promote a metabolic shift from carbohydrate to lipid utilization, resulting in visceral and subcutaneous fat reduction, as well as overall weight loss. The free fatty acids released during this process are converted into ketone bodies, which serve as an energy source for renal and cardiac cells. Another renoprotective mechanism of SGLT2Is is the blockade of glucose reabsorption, which also reduces the accompanying absorption of sodium, chloride, and free water. This reduction helps mitigate the glomerular hyperfiltration commonly observed in diabetes, thereby preserving GFR. These mechanisms collectively contribute to renoprotection in both diabetic and nondiabetic patients.[27][28] Several cardiovascular outcome trials have demonstrated the positive effects of SGLT2Is on kidney outcomes, including reductions in albuminuria and other adverse renal events. These findings have generated interest in using primary renal outcomes as a dedicated endpoint. Notable randomized controlled trials include EMPA-REG, CANVAS, and DECLARE-TIMI.[67][68] Additionally, the DAPA-CKD trial highlighted the benefits of SGLT2Is on renal and cardiovascular outcomes in patients without T2D. The CREDENCE trial, which compared SGLT2Is to placebo in patients with T2D and albuminuric CKD, was terminated early due to a 30% relative risk reduction in renal and cardiovascular events observed in the treatment group.[69][70] Additional Treatments

Several cardiovascular outcome trials have demonstrated the positive effects of SGLT2Is on kidney outcomes, including reductions in albuminuria and other adverse renal events. These findings have generated interest in using primary renal outcomes as a dedicated endpoint. Notable randomized controlled trials include EMPA-REG, CANVAS, and DECLARE-TIMI.[67][68] Additionally, the DAPA-CKD trial highlighted the benefits of SGLT2Is on renal and cardiovascular outcomes in patients without T2D. The CREDENCE trial, which compared SGLT2Is to placebo in patients with T2D and albuminuric CKD, was terminated early due to a 30% relative risk reduction in renal and cardiovascular events observed in the treatment group.[69][70] Additional Treatments Shenkang, a traditional Chinese medicine, is an injectable mixture containing 4 extracts—rhubarb (Rheum officinale Baill), astragalus (Astragalus membranaceus Bunge), salvia miltiorrhiza (Salvia miltiorrhiza Bunge), and safflower (Carthamus tinctorius L.). Animal studies have demonstrated that Shenkang injections can reduce fibrosis and increase nephrin expression.[21][71] Isoquercitrin, a natural compound found in various plants, has demonstrated potential as an antidiabetic agent due to its physiological properties. Studies have shown that it inhibits the SGLT2 pathway and reduces blood sugar levels in animal models, suggesting its promise as a therapeutic agent.[72][73] Renal Replacement Once ESRD develops with an eGFR of 10 to 15 mL/min/1.73m2, renal replacement therapy may be required. Dialysis options include peritoneal dialysis, hemodialysis, and renal transplantation. Renal transplant is generally preferred for patients with good functional status, and patients should be referred to a transplant center when their GFR declines to approximately 20 mL/min/1.73m2. A study found that 47% of patients on the renal transplant list also have diabetes—a percentage that is expected to increase.[74] Simultaneous pancreas and kidney transplants are becoming more common and have shown excellent outcomes. Studies indicate better outcomes for diabetic patients who receive both organs compared to those who receive only a kidney transplant.[75][76] However, DKD can recur in the transplanted kidney in about 7% of cases, with the use of tacrolimus being particularly associated with this recurrence.[77][78]

Several conditions can mimic diabetic nephropathy, but they are usually differentiated from diabetic nephropathy based on patient history and laboratory parameters. Some of these include: Multiple myeloma Amyloidosis Membranous nephropathy Renal artery stenosis Tubulointerstitial nephritis Hypertensive nephropathy Focal segmental glomerulosclerosis Infection-related glomerulonephritis

Diabetic nephropathy is associated with high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality, and the majority of patients ultimately die from ESRD. Additionally, diabetic retinopathy is commonly associated with diabetic nephropathy.

Protein intake should be around 0.8 g/kg of body weight in patients with diabetes and CKD.[3] A higher recommendation of 1.0 to 1.2 g/kg may apply to diabetic patients on dialysis.[3] Significant evidence suggests that consuming plant protein is associated with a lower risk of CKD and proteinuria progression compared to animal protein.[79][80] HbA1c should be maintained at less than 7.0%, but treatment plans should be individualized. BP should be kept at less than 120/80 mm Hg. Sodium intake should be limited to less than 2.3 g/d in patients with diabetes and an eGFR of less than 30 mL/min/1.73m2.[2] Nephrotoxic agents and drugs should be avoided. Urine albumin levels should be regularly monitored. Patients who consistently monitor blood glucose levels at home tend to experience a delay in the progression of renal dysfunction.[81]

The rapidly evolving field of diabetic nephropathy offers hope for future treatments, with ongoing research into newly discovered mechanisms, biomarkers, and therapeutic interventions. Promising future areas for intervention include polyol pathway inhibitors, antioxidants, vasoprotective agents, new anti-inflammatory drugs, and microRNA regulation. MicroRNAs are noncoding RNAs implicated in the pathogenesis of diabetic nephropathy, influencing processes such as inflammation, oxidative stress, apoptosis, and vascular cell function.[20] Another medication class under investigation is the HIF prolyl hydroxylase inhibitors, currently used to treat anemia of CKD. These drugs work by prolonging the activity of HIF—a transcription factor that boosts erythropoietin gene expression and enhances cellular adaptations to hypoxia. This class of medications may also have a role in preventing tubulointerstitial injury and renal fibrosis.[82]

Diabetic nephropathy is a severe condition with lifelong consequences, marked by high morbidity and mortality rates. While there is no cure, and treatment options have limitations, prevention and early intervention remain crucial. The care of patients with diabetic nephropathy involves a multidisciplinary healthcare team, including internal medicine specialists, hospitalists, endocrinologists, nephrologists, cardiologists, and pathologists. Patient-centered care requires a collaborative approach, with contributions from physicians, advanced practice providers, nurses, pharmacists, and other healthcare professionals. Dietitians play a vital role in helping patients plan diets that ensure adequate protein intake and help maintain optimal blood sugar levels. First and foremost, healthcare providers must have the clinical skills and expertise required to diagnose, evaluate, and treat this condition effectively. This includes proficiency in interpreting laboratory results, recognizing potential complications, and understanding the nuances of managing medications appropriately. Ethical considerations are crucial when determining treatment options and respecting patient autonomy in decision-making. Responsibilities within the interprofessional team should be clearly defined, ensuring each member contributes their specialized knowledge and skills to optimize patient care. Effective interprofessional communication fosters a collaborative environment where information is shared, questions are welcomed, and concerns are addressed promptly. Lastly, care coordination is essential for ensuring seamless and efficient patient care. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must collaborate to streamline the patient's journey from diagnosis to treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of individuals affected by diabetic nephropathy.