Diabetic Nephropathy Diagnosis: An In-Depth Guide for Clinicians

Introduction

Diabetic nephropathy, currently also referred to as diabetes and chronic kidney disease (CKD) or diabetic kidney disease (DKD), stands as the primary culprit behind end-stage renal disease (ESRD) within developed nations, notably including the United States.[1] This microvascular complication is a significant concern for individuals diagnosed with both type 1 diabetes (T1D) and type 2 diabetes (T2D). Characterized by persistent albuminuria and a progressive decline in glomerular filtration rate (GFR), diabetic nephropathy’s trajectory can be significantly altered with timely and aggressive intervention. While it can manifest in both T1D and T2D, the latter, primarily driven by insulin resistance, accounts for the vast majority of diabetes cases (>90%). For a deeper understanding of T2D, StatPearls offers a comprehensive resource on “Type 2 Diabetes.”

Recent advancements and studies have prompted updates in treatment guidelines, making it essential for healthcare providers to have a current understanding of diabetic nephropathy, especially regarding diagnosis, to ensure optimal patient care. Leading organizations such as Kidney Disease: Improving Global Outcomes (KDIGO) and the Kidney Disease Outcomes Quality Initiative (KDOQI) emphasize using terms like “diabetes and CKD” or “diabetic kidney disease (DKD)” alongside “diabetic nephropathy,” all of which are currently prevalent in medical literature. Furthermore, KDOQI stresses the importance of multidisciplinary healthcare teams and holistic, lifestyle-focused management approaches in addressing the widespread impact of diabetes on kidney health.[2] This updated terminology and holistic approach underscore the evolving understanding and management strategies for diabetic kidney disease, highlighting the necessity for precise and early Diabetic Nephropathy Diagnosis.

Etiology of Diabetic Nephropathy

Hyperglycemia is the central trigger in the pathogenesis of diabetic nephropathy, initiating a cascade of events that lead to renal damage. Elevated glucose levels induce the production of reactive oxygen species and activate several detrimental molecular pathways. These pathways include the formation of advanced glycemic end products (AGEs), increased oxidative stress, activation of nuclear factor kappa B (NF-κB) and protein kinase C (PKC), upregulation of transforming growth factor-beta (TGF-β)/SMAD signaling, and heightened lipotoxicity.

At a cellular level, hyperglycemia disrupts normal cell signaling, promotes excessive matrix formation, and thickens the glomerular basement membrane (GBM). A hallmark of diabetic nephropathy is significant inflammation, characterized by elevated levels of cytokines and chemokines, which contributes to fibrosis and increased vascular permeability. These interconnected pathways drive the onset and progression of diabetic nephropathy by fostering inflammation, fibrosis, endothelial dysfunction, and podocyte damage. Understanding these intricate mechanisms is crucial for developing targeted diagnostic and therapeutic strategies for diabetic nephropathy diagnosis and management.

Macrophage Activation in Diabetic Nephropathy

Hyperglycemia leads to the formation of glucose degradation products and glycation end products, which significantly amplify inflammation and encourage macrophage infiltration in the kidneys. This macrophage infiltration is a pivotal factor in the development and progression of 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), play critical roles in this inflammatory process.[3] Autopsy studies have revealed a direct correlation between the presence of CD163+ macrophages in renal tissue and the severity of diabetic nephropathy, including interstitial fibrosis, tubular atrophy, and glomerulosclerosis.[4] Macrophages contribute to renal fibrosis not only by attracting fibroblasts but also by their capacity to transform into myofibroblasts, further accelerating fibrotic progression.[3, 5]

Macrophages also stimulate the renin-angiotensin-aldosterone system (RAAS), resulting in alterations in renal hemodynamics. RAAS activation further recruits macrophages through the actions of monocyte chemoattractant protein-1 (MCP-1), osteopontin, and various adhesion molecules, such as selections, ICAM-1, PCAM-1, and VCAM.

Recent research has increasingly focused on the tubulointerstitial mechanisms in DKD, moving beyond the well-established glomerular mechanisms of diabetic nephropathy. Biopsy studies have indicated that macrophage infiltration in the tubulointerstitium shows a stronger correlation 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 demonstrated efficacy in reducing macrophage activity through various mechanisms, offering potential therapeutic avenues for diabetic nephropathy diagnosis and treatment:

RAAS inhibitors: These agents reduce the expression of MCP-1, thereby mitigating macrophage recruitment and activation.
Pioglitazone: This drug decreases the expression of NF-κB, a key regulator of inflammatory responses in macrophages.
Vitamin D-25(OH): This vitamin has been shown to decrease macrophage adhesion, potentially reducing their infiltration into renal tissues.[3]

Endothelial Cell Damage in Diabetic Nephropathy

Endothelial cell damage is recognized as one of the earliest pathological changes in diabetic nephropathy. This damage leads to the generation of reactive oxygen species, which are significant contributors to the progression of diabetic nephropathy. Hyperglycemia and hemodynamic changes trigger the release of cell adhesion molecules, glycosaminoglycans, and chemokines, further amplifying the immune response. This response involves direct endothelial damage and is exacerbated by the endothelial-to-mesenchymal transition.[7]

Podocyte Damage in Diabetic Nephropathy

Podocytes, essential components of the glomerular filtration barrier, are highly susceptible to injury in diabetic nephropathy, leading to proteinuria. Podocyte injury can manifest as hypertrophy, reduced density, and apoptosis. Factors contributing to podocyte damage include lipotoxicity (increased lipid synthesis and decreased degradation), oxidative stress, mitochondrial dysfunction, vascular dysfunction (shear stress from hyperfiltration), and impaired autophagy.[8, 9] Furthermore, podocyte damage is associated with reduced nephrin expression and inhibition of insulin-like growth factor-1 (IGF-1)/insulin receptor signaling pathways.[9, 10]

Therapeutic interventions targeting podocyte damage are under investigation in clinical and preclinical trials, focusing on mechanisms such as:

Lipid-lowering agents: Statins and resveratrol aim to decrease lipid accumulation within podocytes.
Atrasentan (with losartan): This combination therapy may increase podocyte number, promoting glomerular health.
Spironolactone: This drug decreases RAAS activation and may reduce autophagy, potentially protecting podocytes.
Sacubitril (with losartan): This combination may reduce inflammation, oxidative stress, and blood sugar levels, indirectly benefiting podocytes.
Glucagon-like peptide-1 inhibitors (GLP1RAs): These agents help decrease oxidative stress and apoptosis in podocytes.
Sodium-glucose cotransporter-2 inhibitors (SGLT2Is): These inhibitors may reduce oxidative stress and apoptosis, offering podocyte protection.[9]

Polyol Pathway and Uric Acid in Diabetic Nephropathy

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] 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 is recognized as a potential risk factor for cardiovascular disease.[11, 12] Fructose also contributes to oxidative stress, a key factor in diabetic nephropathy. Aldolase reductase, which catalyzes the rate-limiting step of the polyol pathway, has been targeted in studies, demonstrating that aldolase reductase inhibitors can reverse diabetic nephropathy lesions in animal models.[13, 14]

Genetic Factors in Diabetic Nephropathy

Genetics plays a crucial role in the susceptibility and development of diabetic nephropathy, with both genetic predisposition and environmental factors contributing to its onset. Individuals with a family history of diabetes or kidney disease are at a significantly higher risk of developing diabetic nephropathy. Several genes have been associated with increased risk, including variations in:

ACE: Polymorphisms in the angiotensin-converting enzyme (ACE) gene have been linked to diabetic nephropathy and may influence the renoprotective effects of ACE inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapies.[16, 17]

Gene-environment interactions are also critical, with prolonged hyperglycemia influencing epigenetic mechanisms such as DNA methylation, posttranslational histone modifications, and noncoding RNA regulation.[20] Understanding these genetic and epigenetic factors is becoming increasingly important in personalized diabetic nephropathy diagnosis and management.

Epidemiology of Diabetic Nephropathy

Data from the Centers for Disease Control and Prevention (CDC) in the United States indicates that CKD affects 14% of adults aged 20 or older, with 30% of these individuals also having diabetes.[3] Approximately 30% to 40% of patients with diabetes mellitus will develop diabetic nephropathy.[21, 22] Globally, the incidence of diabetes is projected to exceed 783 million by 2045, and diabetic complications are expected to become the seventh leading cause of mortality by 2030.[5, 21] These statistics underscore the growing public health burden of diabetic nephropathy and the urgent need for improved diagnostic and preventative strategies.

Pathophysiology of Diabetic Nephropathy

In T2D, albuminuria may be present at the time of diabetes diagnosis, while diabetic nephropathy typically develops 15 to 20 years after the onset of T1D. Approximately 30% of patients with T1D and 40% with T2D will develop diabetic nephropathy, partly because the onset of T2D is often insidious and unclear. Diabetes-related structural and functional changes in the kidney result in proteinuria, hypertension, and a progressive reduction in kidney function, which are hallmarks of diabetic nephropathy.[23]

The primary pathological lesions of diabetic nephropathy include diffuse mesangial cell expansion, GBM thickening, and arteriolar hyalinization. However, virtually all kidney compartments, including the glomerular capillary wall, podocytes, mesangium, tubulointerstitium, and renal vasculature, are affected. Diabetic nephropathy progression typically correlates with increasing albuminuria, advancing from normal albumin levels to microalbuminuria (moderately increased albuminuria) and eventually to macroalbuminuria (severely increased albuminuria). Aggressive treatment interventions can partially reverse this progression.[24, 25, 23]

The glomerular filtration barrier, a highly specialized structure comprising capillary endothelial cells, the GBM, and podocytes, is critically affected in diabetic nephropathy. The GBM, significantly thicker than capillaries elsewhere in the body, 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 acts as a selective filter, allowing the passage of water and small solutes while excluding large proteins like albumin when intact.[5]

Nephrin, a key component of the GBM, is essential for maintaining the integrity of slit diaphragms, the primary barrier preventing protein loss in urine. Reduced nephrin expression is an early event in diabetic nephropathy development. Synaptopodin, another protein localized to podocyte foot processes, is also downregulated in diabetic nephropathy. MCP-1 further diminishes the expression of both nephrin and synaptopodin and is associated with albuminuria.[26]

Hyperfiltration, one of the earliest pathological changes in diabetic nephropathy, affects both glomeruli and renal tubules. This phenomenon is partly 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 plays a minor role in urinary glucose absorption, primarily facilitating intestinal glucose absorption. Hyperfiltration reduces sodium concentration at the macula densa, increasing dietary salt sensitivity and worsening hypertension. Increased tubular hyperfiltration contributes to nephron enlargement, 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, suggesting dietary protein source is a modifiable risk factor for diabetic nephropathy progression.[29]

Hyperfiltration is also mediated by vascular regulation. Prostaglandins and atrial natriuretic peptides are 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. While endothelin receptor blockers have not yet shown efficacy, research in this area continues.[27, 31]

Histopathology of Diabetic Nephropathy

Abnormal renal pathology is detectable even before the onset of microalbuminuria. Characteristic lesions observed under light microscopy include thickened glomerular and tubular basement membranes, diffuse mesangial expansion, and arteriolar hyalinosis.

The pathological classification of diabetic nephropathy 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 may include arteriosclerosis, exudative lesions, and interstitial fibrosis. Mesangial expansion limits capillary filtration capacity, contributing to a decline in GFR.[24] These histopathological classifications are critical for understanding disease severity and guiding management strategies following a diabetic nephropathy diagnosis.

History and Physical Examination in Diabetic Nephropathy Diagnosis

A prolonged 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 comorbid conditions such as peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy. Notably, diabetic retinopathy exhibits a particularly strong correlation with diabetic nephropathy.[5]

In the early stages of diabetic nephropathy, patients are often asymptomatic, with the condition typically identified through routine screening revealing proteinuria levels between 30 and 300 mg/g creatinine. As the disease progresses, patients may develop 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 may include:

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)

For more comprehensive information on diabetes, refer to StatPearls’ resource, “Type 2 Diabetes.” A thorough history and physical examination are crucial components in the diagnostic process of diabetic nephropathy.

Evaluation and Diabetic Nephropathy Diagnosis

Proteinuria Assessment for Diabetic Nephropathy Diagnosis

Proteinuria is a hallmark indicator of diabetic nephropathy. The diagnostic approach for DKD is more complex in T2D than in T1D due to the often-uncertain onset of T2D. History and physical examination are critical in diagnosing diabetic nephropathy, especially in T2D. Patients with T1D should undergo proteinuria screening within 5 years of diagnosis, while those with T2D should be screened at the time of diagnosis and annually thereafter. Increased proteinuria signifies declining kidney function and requires prompt and aggressive management.[25, 23]

Diabetic nephropathy diagnosis is established by persistent albuminuria detected 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, an early marker of diabetic nephropathy, ranges 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 albumin-to-creatinine ratio of 20 to 200 mg/g or 20 to 200 µg/min.[36, 37]

Urinary Biomarkers in Diabetic Nephropathy Diagnosis

Given the limitations of creatinine and albuminuria as late and nonspecific markers of diabetic nephropathy, there is growing interest in exploring novel urinary biomarkers for earlier and more accurate diabetic nephropathy diagnosis. Recent research emphasizes markers of tubulointerstitial injury, moving beyond a sole focus on glomerular damage. Non-albuminuric proteinuria, indicative of tubulointerstitial injury, is strongly associated with DKD, and some evidence suggests that proximal tubular damage may precede 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 GFR.[23, 38] Urinary KIM-1 is associated with proximal tubule damage, while NGAL is linked to damage in 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, making it a potentially valuable tool in early diabetic nephropathy diagnosis.[23, 38, 39]

The most extensively studied biomarkers for diabetic nephropathy include NGAL, KIM-1, and periostin. A study evaluating these biomarkers 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] While many of these biomarkers are not yet widely available outside research settings, their clinical use is becoming increasingly established, and combining biomarkers may enhance early diabetic nephropathy diagnosis. The table below lists potential biomarkers for diabetic nephropathy studied over the last decade.

Table

Table. Potential Biomarkers for Diabetic Nephropathy.

Table reference [42]

Treatment and Management of Diabetic Nephropathy

The management of diabetic nephropathy is multifaceted, focusing on four key areas: cardiovascular risk reduction, glycemic control, blood pressure (BP) control, and renin-angiotensin system (RAS) inhibition. Modifying lifestyle risk factors, such as smoking cessation and optimal lipid control, is crucial for reducing cardiovascular risk.[43, 44, 45]

Glycemic Control in Diabetic Nephropathy Management

Intensive glycemic control is most effective when initiated early, before the onset of diabetic complications, with diminishing benefits when started later. Therefore, early intensive glycemic control is strongly recommended in diabetic nephropathy management.[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 concluded, despite HbA1c values converging between the two groups.[47, 48]

The Diabetes Control and Complications Trial (DCCT) showed similar 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, are known 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 target of approximately 7.0% to mitigate the development of microvascular complications.[5]

While HbA1c is the most accurate measure of long-term glycemic control, it may not fully reflect episodes of hypoglycemia or severe hyperglycemia, both 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 for optimal diabetic nephropathy management.[3, 50]

Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs)

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] These medications should be titrated to the highest tolerated dose. The use of ACEIs or ARBs in cases of albuminuria without hypertension requires individualized consideration and further study. Kidney transplant recipients with diabetes and hypertension should also receive RAAS inhibition. 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 kidney disease progression, as shown in 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) has not shown additional benefit and may be harmful.[53]

The HOPE, LIFE, and ALLHAT trials confirmed the benefit of ACEIs in slowing CKD progression for individuals with an estimated GFR (eGFR) of more than 60 mL/min/1.73m2. Additionally, studies like IRMA2 (Irbesartan in Microalbuminuria, Type 2 Diabetic Nephropathy Trial) have demonstrated 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 diabetic nephropathy progression. The IDNT and RENAAL studies demonstrated similar benefits in T2D patients. This evidence strongly supports the use of RAAS-blocking medications to slow diabetic nephropathy progression, independent of their BP-lowering effect. However, the use of multiple RAS-blocking agents can lead to adverse outcomes, including acute renal failure, and is no longer recommended. Furthermore, RAAS inhibition in diabetic patients without hypertension or albuminuria is discouraged.[2, 54]

A post hoc analysis of the RENAAL trial indicated that uric acid levels were reduced in the losartan group, suggesting another potential renoprotective mechanism of ARBs. While small studies have explored the effects of uric acid–lowering agents, results have been mixed.[12] In AKI cases, temporary discontinuation of ACEI/ARB therapy until creatinine levels return to baseline is common practice. However, a retrospective study suggested that patients who continued ACEI/ARB therapy had lower mortality after 2 years, despite higher rates of renal-related hospitalizations.[55]

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 showed 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 (GLP1RAs)

KDIGO guidelines and the American Diabetes Association (ADA) recommend 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 shown significant benefits in CKD progression, cardiovascular outcomes, and all-cause mortality. However, metformin initiation is not recommended in individuals with an eGFR less than 45 mL/min/1.73m2 due to the risk of progressing to an eGFR 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, requiring regular monitoring and supplementation.[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. 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 is strongly linked to 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. These agents have also effectively reduced proteinuria in CKD, with comparable benefits in proteinuria caused by diabetes mellitus and other conditions.[59, 60] Spironolactone is associated with a higher 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, spironolactone and eplerenone use in ESRD has been avoided. However, several randomized controlled trials have demonstrated improved cardiac outcomes with low-dose spironolactone in this population.[62]

Finerenone, a selective, nonsteroidal mineralocorticoid antagonist, is approved for managing CKD associated with T2D. Finerenone acts as a bulky, passive antagonist of the mineralocorticoid receptor. It has been shown to reduce albuminuria and improve renal and cardiovascular outcomes in patients with CKD and T2D, as demonstrated in studies including FIDELITY-DKD, FIGARO-DKD, and FINEARTS-HF.[62, 63, 64] Finerenone has demonstrated effectiveness in patients with and without reduced ejection fraction and may help prevent or delay heart failure onset in individuals with T2D and CKD.[65] The ARTS trial showed finerenone is at least as effective as spironolactone, with lower rates of hyperkalemia and other adverse effects. Data analysis indicates that finerenone improves albuminuria independently of BP or GFR changes.[59, 65]

Esaxerenone, with a similar mechanism to finerenone, is not FDA-approved but is used in Japan and other countries, where it has been shown to reduce albuminuria in T2D patients.[59]

Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2Is)

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), enhancing erythropoietin production.[27] This medication class has demonstrated effectiveness in 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 ceases when filtered glucose levels approach 80 g/d. Additionally, SGLT2Is increase glucagon secretion, stimulating hepatic gluconeogenesis.[66]

SGLT2Is’ beneficial effects extend beyond glucose control. They promote a metabolic shift from carbohydrate to lipid utilization, resulting in visceral and subcutaneous fat reduction and overall weight loss. The free fatty acids released are converted into ketone bodies, serving as an energy source for renal and cardiac cells. Another renoprotective mechanism is the blockade of glucose reabsorption, which also reduces the absorption of sodium, chloride, and free water, mitigating glomerular hyperfiltration commonly seen in diabetes, thus preserving GFR. These mechanisms collectively contribute to renoprotection in both diabetic and nondiabetic patients.[27, 28]

Several cardiovascular outcome trials have demonstrated SGLT2Is’ positive effects on kidney outcomes, including reductions in albuminuria and other adverse renal events. These findings have increased interest in using primary renal outcomes as a dedicated endpoint. Notable trials include EMPA-REG, CANVAS, and DECLARE-TIMI.[67, 68] The DAPA-CKD trial highlighted SGLT2Is’ benefits on renal and cardiovascular outcomes in patients without T2D. The CREDENCE trial, comparing 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 in the treatment group.[69, 70]

Additional and Emerging Treatments

Shenkang, a traditional Chinese medicine, is an injectable mixture containing extracts of rhubarb (Rheum officinale Baill), astragalus (Astragalus membranaceus Bunge), salvia miltiorrhiza (Salvia miltiorrhiza Bunge), and safflower (Carthamus tinctorius L.). Animal studies suggest Shenkang injections can reduce fibrosis and increase nephrin expression.[21, 71] Isoquercitrin, a natural plant compound, shows antidiabetic potential by inhibiting the SGLT2 pathway and reducing blood sugar levels in animal models, suggesting therapeutic promise.[72, 73]

Renal Replacement Therapy

Once ESRD develops with an eGFR of 10 to 15 mL/min/1.73m2, renal replacement therapy becomes necessary. Dialysis options include peritoneal dialysis, hemodialysis, and renal transplantation. Renal transplant is generally preferred for patients with good functional status, and referral to a transplant center is recommended when 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 expected to rise.[74] Simultaneous pancreas and kidney transplants are increasingly common and show excellent outcomes, with studies indicating better outcomes for diabetic patients receiving both organs compared to kidney transplant alone.[75, 76] However, DKD recurrence can occur in the transplanted kidney in about 7% of cases, with tacrolimus use particularly associated with recurrence.[77, 78]

Differential Diagnosis of Diabetic Nephropathy

Several conditions can mimic diabetic nephropathy, but they are usually differentiated based on patient history and laboratory parameters. These include:

Multiple myeloma
Amyloidosis
Membranous nephropathy
Renal artery stenosis
Tubulointerstitial nephritis
Hypertensive nephropathy
Focal segmental glomerulosclerosis
Infection-related glomerulonephritis

Toxicity and Adverse Effect Management in Diabetic Nephropathy

Effect of Chronic Kidney Disease on Diabetes Medications

The kidneys play a crucial role in insulin clearance. In CKD, reduced GFR prolongs insulin half-life, necessitating dose adjustments to prevent hypoglycemia. This principle also applies to most oral antidiabetic medications, which are also cleared by the kidneys.

Metformin is contraindicated in patients with an eGFR less than 30 mL/min/1.73m2 due to the increased risk of lactic acidosis. Caution is advised for most oral antidiabetic medications when eGFR is less than 45 mL/min/1.73m2.

Patients with diabetic nephropathy are at increased AKI risk and should be closely monitored when using nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs) and intravenous contrast.

Prognosis of Diabetic Nephropathy

Diabetic nephropathy is associated with high morbidity and mortality. Microalbuminuria is an independent risk factor for cardiovascular mortality, and most patients ultimately die from ESRD. Diabetic retinopathy is also commonly associated with diabetic nephropathy, further worsening the prognosis.

Deterrence and Patient Education for Diabetic Nephropathy

Protein intake should be around 0.8 g/kg of body weight in patients with diabetes and CKD.[3]
A higher protein intake of 1.0 to 1.2 g/kg may be appropriate for diabetic patients on dialysis.[3]
Plant protein consumption is associated with a lower risk of CKD and proteinuria progression compared to animal protein.[79, 80]
HbA1c should be maintained below 7.0%, with individualized treatment plans.
BP should be kept below 120/80 mm Hg.
Sodium intake should be limited to less than 2.3 g/d in patients with diabetes and an eGFR less than 30 mL/min/1.73m2.[2]
Nephrotoxic agents and drugs should be avoided.
Regular monitoring of urine albumin levels is essential.
Consistent home blood glucose monitoring may delay renal dysfunction progression.[81]

Pearls and Future Directions in Diabetic Nephropathy

The field of diabetic nephropathy is rapidly evolving, offering hope for future treatments through ongoing research into newly discovered mechanisms, biomarkers, and therapeutic interventions. Promising future areas include polyol pathway inhibitors, antioxidants, vasoprotective agents, new anti-inflammatory drugs, and microRNA regulation. MicroRNAs, noncoding RNAs, are implicated in diabetic nephropathy pathogenesis, influencing inflammation, oxidative stress, apoptosis, and vascular cell function.[20]

HIF prolyl hydroxylase inhibitors, currently used for anemia of CKD, are also under investigation. These drugs prolong HIF activity, a transcription factor that boosts erythropoietin gene expression and enhances cellular adaptations to hypoxia, potentially preventing tubulointerstitial injury and renal fibrosis.[82] These emerging therapies, along with advancements in diabetic nephropathy diagnosis, hold the promise of significantly improving patient outcomes.

Enhancing Healthcare Team Outcomes in Diabetic Nephropathy Management

Diabetic nephropathy is a severe condition with lifelong consequences, high morbidity, and mortality. While a cure remains elusive and treatment options have limitations, prevention and early intervention are critical. The care of patients with diabetic nephropathy necessitates a multidisciplinary healthcare team, including internal medicine specialists, hospitalists, endocrinologists, nephrologists, cardiologists, and pathologists. Patient-centered care requires collaboration from physicians, advanced practice providers, nurses, pharmacists, and other healthcare professionals. Dietitians are crucial in helping patients plan diets that ensure adequate protein intake and optimal blood sugar levels.

Effective management requires healthcare providers to possess the clinical skills and expertise to diagnose, evaluate, and treat diabetic nephropathy effectively. This includes proficiency in interpreting laboratory results, recognizing potential complications, and understanding medication management. Ethical considerations are paramount in determining treatment options and respecting patient autonomy in decision-making. Clearly defined responsibilities within the interprofessional team ensure each member contributes specialized knowledge and skills to optimize patient care. Effective interprofessional communication fosters a collaborative environment for information sharing and prompt issue resolution.

Care coordination is essential for 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.

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References

1.Rabkin R. Diabetic nephropathy. Clin Cornerstone. 2003;5(2):1-11. [PubMed: 12800476]

2.Mottl AK, Alicic R, Argyropoulos C, Brosius FC, Mauer M, Molitch M, Nelson RG, Perreault L, Nicholas SB. KDOQI US Commentary on the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD. Am J Kidney Dis. 2022 Apr;79(4):457-479. [PMC free article: PMC9740752] [PubMed: 35144840]

3.Lin DW, Yang TM, Ho C, Shih YH, Lin CL, Hsu YC. Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease. Int J Mol Sci. 2024 Apr 15;25(8) [PMC free article: PMC11050450] [PubMed: 38673935]

4.Klessens CQF, Zandbergen M, Wolterbeek R, Bruijn JA, Rabelink TJ, Bajema IM, IJpelaar DHT. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2017 Aug 01;32(8):1322-1329. [PubMed: 27416772]

5.Yang J, Liu Z. Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy. Front Endocrinol (Lausanne). 2022;13:816400. [PMC free article: PMC9174994] [PubMed: 35692405]

6.Xu C, Ha X, Yang S, Tian X, Jiang H. Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms. Front Endocrinol (Lausanne). 2023;14:1232790. [PMC free article: PMC10583558] [PubMed: 37859992]

7.Rayego-Mateos S, Morgado-Pascual JL, Opazo-Ríos L, Guerrero-Hue M, García-Caballero C, Vázquez-Carballo C, Mas S, Sanz AB, Herencia C, Mezzano S, Gómez-Guerrero C, Moreno JA, Egido J. Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy. Int J Mol Sci. 2020 May 27;21(11) [PMC free article: PMC7312633] [PubMed: 32471207]

8.Li X, Zhang Y, Xing X, Li M, Liu Y, Xu A, Zhang J. Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects. Biomed Pharmacother. 2023 Dec;168:115670. [PubMed: 37837883]

9.Barutta F, Bellini S, Gruden G. Mechanisms of podocyte injury and implications for diabetic nephropathy. Clin Sci (Lond). 2022 Apr 14;136(7):493-520. [PMC free article: PMC9008595] [PubMed: 35415751]

10.Ising C, Koehler S, Brähler S, Merkwirth C, Höhne M, Baris OR, Hagmann H, Kann M, Fabretti F, Dafinger C, Bloch W, Schermer B, Linkermann A, Brüning JC, Kurschat CE, Müller RU, Wiesner RJ, Langer T, Benzing T, Brinkkoetter PT. Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med. 2015 Mar;7(3):275-87. [PMC free article: PMC4364945] [PubMed: 25643582]

11.Vallon V, Nakagawa T. Renal Tubular Handling of Glucose and Fructose in Health and Disease. Compr Physiol. 2021 Dec 29;12(1):2995-3044. [PMC free article: PMC9832976] [PubMed: 34964123]

12.Jalal DI, Maahs DM, Hovind P, Nakagawa T. Uric acid as a mediator of diabetic nephropathy. Semin Nephrol. 2011 Sep;31(5):459-65. [PMC free article: PMC3197214] [PubMed: 22000654]

13.Ma X, Ma J, Leng T, Yuan Z, Hu T, Liu Q, Shen T. Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention. Ren Fail. 2023 Dec;45(1):2146512. [PMC free article: PMC9930779] [PubMed: 36762989]

14.Zhou X, Liu Z, Ying K, Wang H, Liu P, Ji X, Chi T, Zou L, Wang S, He Z. WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling. Oxid Med Cell Longev. 2020;2020:7950457. [PMC free article: PMC7277034] [PubMed: 32566101]

15.Daneshpajouhnejad P, Kopp JB, Winkler CA, Rosenberg AZ. The evolving story of apolipoprotein L1 nephropathy: the end of the beginning. Nat Rev Nephrol. 2022 May;18(5):307-320. [PMC free article: PMC8877744] [PubMed: 35217848]

16.Ha SK. ACE insertion/deletion polymorphism and diabetic nephropathy: clinical implications of genetic information. J Diabetes Res. 2014;2014:846068. [PMC free article: PMC4284953] [PubMed: 25587546]

17.Bertoncello N, Moreira RP, Arita DY, Aragão DS, Watanabe IK, Dantas PS, Santos R, Mattar-Rosa R, Yokota R, Cunha TS, Casarini DE. Diabetic Nephropathy Induced by Increased Ace Gene Dosage Is Associated with High Renal Levels of Angiotensin (1-7) and Bradykinin. J Diabetes Res. 2015;2015:674047. [PMC free article: PMC4579315] [PubMed: 26442284]

18.Wang Y, Zhang J, Zhao Y, Wang S, Zhang J, Han Q, Zhang R, Guo R, Li H, Li L, Wang T, Tang X, He C, Teng G, Gu W, Liu F. COL4A3 Gene Variants and Diabetic Kidney Disease in MODY. Clin J Am Soc Nephrol. 2018 Aug 07;13(8):1162-1171. [PMC free article: PMC6086715] [PubMed: 30012629]

19.Gui H, Chen X, Ye L, Ma H. Seven basement membrane-specific expressed genes are considered potential biomarkers for the diagnosis and treatment of diabetic nephropathy. Acta Diabetol. 2023 Apr;60(4):493-505. [PubMed: 36627452]

20.Li X, Lu L, Hou W, Huang T, Chen X, Qi J, Zhao Y, Zhu M. Epigenetics in the pathogenesis of diabetic nephropathy. Acta Biochim Biophys Sin (Shanghai). 2022 Jan 25;54(2):163-172. [PMC free article: PMC9909329] [PubMed: 35130617]

21.Qu Z, Wang B, Jin Y, Xiao Q, Zhao Y, Zhao D, Yang L. Shenkang protects renal function in diabetic rats by preserving nephrin expression. BMC Complement Med Ther. 2023 Jul 17;23(1):244. [PMC free article: PMC10353195] [PubMed: 37460931]

22.Umanath K, Lewis JB. Update on Diabetic Nephropathy: Core Curriculum 2018. Am J Kidney Dis. 2018 Jun;71(6):884-895. [PubMed: 29398179]

23.Młynarska E, Buławska D, Czarnik W, Hajdys J, Majchrowicz G, Prusinowski F, Stabrawa M, Rysz J, Franczyk B. Novel Insights into Diabetic Kidney Disease. Int J Mol Sci. 2024 Sep 23;25(18) [PMC free article: PMC11432709] [PubMed: 39337706]

24.Satirapoj B, Adler SG. Comprehensive approach to diabetic nephropathy. Kidney Res Clin Pract. 2014 Sep;33(3):121-31. [PMC free article: PMC4714158] [PubMed: 26894033]

25.Clos-Garcia M, Ahluwalia TS, Winther SA, Henriksen P, Ali M, Fan Y, Stankevic E, Lyu L, Vogt JK, Hansen T, Legido-Quigley C, Rossing P, Pedersen O. Multiomics signatures of type 1 diabetes with and without albuminuria. Front Endocrinol (Lausanne). 2022;13:1015557. [PMC free article: PMC9755599] [PubMed: 36531462]

26.Tarabra E, Giunti S, Barutta F, Salvidio G, Burt D, Deferrari G, Gambino R, Vergola D, Pinach S, Perin PC, Camussi G, Gruden G. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes. 2009 Sep;58(9):2109-18. [PMC free article: PMC2731530] [PubMed: 19587356]

27.Yang Y, Xu G. Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease. Front Endocrinol (Lausanne). 2022;13:872918. [PMC free article: PMC9161673] [PubMed: 35663316]

28.Vallon V, Verma S. Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function. Annu Rev Physiol. 2021 Feb 10;83:503-528. [PMC free article: PMC8017904] [PubMed: 33197224]

29.Adeva-Andany MM, Fernández-Fernández C, Carneiro-Freire N, Vila-Altesor M, Ameneiros-Rodríguez E. The differential effect of animal versus vegetable dietary protein on the clinical manifestations of diabetic kidney disease in humans. Clin Nutr ESPEN. 2022 Apr;48:21-35. [PubMed: 35331493]

30.Liu C, Li Q, Feng X, Zhu J, Li Q. Deterioration of diabetic nephropathy via stimulating secretion of cytokines by atrial natriuretic peptide. BMC Endocr Disord. 2021 Oct 18;21(1):204. [PMC free article: PMC8525036] [PubMed: 34663293]

31.Jung C, Rafnsson A, Brismar K, Pernow J. Endothelial progenitor cells in relation to endothelin-1 and endothelin receptor blockade: a randomized, controlled trial. Int J Cardiol. 2013 Sep 30;168(2):1017-22. [PubMed: 23168014]

32.Goldney J, Sargeant JA, Davies MJ. Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy. Diabetologia. 2023 Oct;66(10):1832-1845. [PMC free article: PMC10474214] [PubMed: 37597048]

33.Wang Y, Shao T, Wang J, Huang X, Deng X, Cao Y, Zhou M, Zhao C. An update on potential biomarkers for diagnosing diabetic foot ulcer at early stage. Biomed Pharmacother. 2021 Jan;133:110991. [PubMed: 33227713]

34.Rehman ZU, Khan J, Noordin S. Diabetic Foot Ulcers: Contemporary Assessment And Management. J Pak Med Assoc. 2023 Jul;73(7):1480-1487. [PubMed: 37469062]

35.Radu AM, Carsote M, Dumitrascu MC, Sandru F. Acanthosis Nigricans: Pointer of Endocrine Entities. Diagnostics (Basel). 2022 Oct 17;12(10) [PMC free article: PMC9600076] [PubMed: 36292208]

36.Szabóová E, Lisovszki A, Fatľová E, Kolarčik P, Szabó P, Molnár T. Prevalence of Microalbuminuria and Its Association with Subclinical Carotid Atherosclerosis in Middle Aged, Nondiabetic, Low to Moderate Cardiovascular Risk Individuals with or without Hypertension. Diagnostics (Basel). 2021 Sep 19;11(9) [PMC free article: PMC8464680] [PubMed: 34574057]

37.Singh A, Satchell SC. Microalbuminuria: causes and implications. Pediatr Nephrol. 2011 Nov;26(11):1957-65. [PMC free article: PMC3178015] [PubMed: 21301888]

38.Hwang S, Park J, Kim J, Jang HR, Kwon GY, Huh W, Kim YG, Kim DJ, Oh HY, Lee JE. Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy. J Diabetes Complications. 2017 Dec;31(12):1704-1709. [PubMed: 29037450]

39.Zhou Y, Zhang Y, Chen J, Wang T, Li H, Wu F, Shang J, Zhao Z. Diagnostic value of α1-MG and URBP in early diabetic renal impairment. Front Physiol. 2023;14:1173982. [PMC free article: PMC10621041] [PubMed: 37929213]

40.Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, Krawczeski CD, Koyner JL, Murray P, Zappitelli M, Goldstein SL, Makris K, Ronco C, Martensson J, Martling CR, Venge P, Siew E, Ware LB, Ikizler TA, Mertens PR. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011 Apr 26;57(17):1752-61. [PMC free article: PMC4866647] [PubMed: 21511111]

41.Varatharajan S, Jain V, Pyati AK, Neeradi C, Reddy KS, Pallavali JR, Pandiyaraj IP, Gaur A. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and periostin: Novel urinary biomarkers in diabetic nephropathy. World J Nephrol. 2024 Dec 25;13(4):98880. [PMC free article: PMC11572651] [PubMed: 39723350]

42.Khanijou V, Zafari N, Coughlan MT, MacIsaac RJ, Ekinci EI. Review of potential biomarkers of inflammation and kidney injury in diabetic kidney disease. Diabetes Metab Res Rev. 2022 Sep;38(6):e3556. [PMC free article: PMC9541229] [PubMed: 35708187]

43.Zhu H, Li L, Liu S, Li J. Smoking and diabetic nephropathy: An updated systematic review and meta-analysis. J Diabetes Investig. 2024 Dec 27; [PubMed: 39728025]

44.Altunkaynak HO, Karaismailoglu E, Massy ZA. The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis. Toxins (Basel). 2024 Dec 16;16(12) [PMC free article: PMC11679735] [PubMed: 39728802]

45.Han YZ, Du BX, Zhu XY, Wang YZ, Zheng HJ, Liu WJ. Lipid metabolism disorder in diabetic kidney disease. Front Endocrinol (Lausanne). 2024;15:1336402. [PMC free article: PMC11089115] [PubMed: 38742197]

46.Laiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY, Huang ES, Karter AJ. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care. 2019 Mar;42(3):416-426. [PMC free article: PMC6385699] [PubMed: 30104301]

47.Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 09;359(15):1577-89. [PubMed: 18784090]

48.Genuth S, Eastman R, Kahn R, Klein R, Lachin J, Lebovitz H, Nathan D, Vinicor F., American Diabetes Association. Implications of the United kingdom prospective diabetes study. Diabetes Care. 2003 Jan;26 Suppl 1:S28-32. [PubMed: 12502617]

49.de Boer IH, Rue TC, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Sun W, Zinman B, Brunzell JD, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. White NH, Danis RP, Davis MD, Hainsworth D, Hubbard LD, Nathan DM. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med. 2011 Mar 14;171(5):412-20. [PMC free article: PMC3085024] [PubMed: 21403038]

50.Galindo RJ, Beck RW, Scioscia MF, Umpierrez GE, Tuttle KR. Glycemic Monitoring and Management in Advanced Chronic Kidney Disease. Endocr Rev. 2020 Oct 01;41(5):756-74. [PMC free article: PMC7366347] [PubMed: 32455432]

51.Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S., RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9. [PubMed: 11565518]

52.Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I., Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. [PubMed: 11565517]

53.Armstrong C., Joint National Committee. JNC8 guidelines for the management of hypertension in adults. Am Fam Physician. 2014 Oct 01;90(7):503-4. [PubMed: 25369633]

54.Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P., Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):870-8. [PubMed: 11565519]

55.Brar S, Ye F, James MT, Hemmelgarn B, Klarenbach S, Pannu N., Interdisciplinary Chronic Disease Collaboration. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury. JAMA Intern Med. 2018 Dec 01;178(12):1681-1690. [PMC free article: PMC6583606] [PubMed: 30422153]

56.Bhandari S, Mehta S, Khwaja A, Cleland JGF, Ives N, Brettell E, Chadburn M, Cockwell P., STOP ACEi Trial Investigators. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease. N Engl J Med. 2022 Dec 01;387(22):2021-2032. [PubMed: 36326117]

57.de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. [PMC free article: PMC2874129] [PubMed: 20488910]

58.Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC., ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 07;41(2):255-323. [PubMed: 31497854]

59.Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharmacol. 2022 Jul;179(13):3220-3234. [PubMed: 34811750]

60.Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014 Apr 29;(4):CD007004. [PubMed: 24782282]

61.Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T, Zannad F. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021 Jan 07;42(2):152-161. [PMC free article: PMC7813624] [PubMed: 33099609]

62.Agarwal A, Cheung AK. Mineralocorticoid Receptor Antagonists in ESKD. Clin J Am Soc Nephrol. 2020 Jul 01;15(7):1047-1049. [PMC free article: PMC7341785] [PubMed: 32269029]

63.Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-Kirschbaum N, Ruilope LM., Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA. 2015 Sep 01;314(9):884-94. [PubMed: 26325557]

64.Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G., FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 03;383(23):2219-2229. [PubMed: 33264825]

65.Filippatos G, Anker SD, Agarwal R, Ruilope LM, Rossing P, Bakris GL, Tasto C, Joseph A, Kolkhof P, Lage A, Pitt B., FIGARO-DKD Investigators. Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial. Circulation. 2022 Feb 08;145(6):437-447. [PMC free article: PMC8812430] [PubMed: 34775784]

66.Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017 Feb;60(2):215-225. [PMC free article: PMC5884445] [PubMed: 27878313]

67.Rastogi A, Bhansali A. SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS Trials: A Review. Diabetes Ther. 2017 Dec;8(6):1245-1251. [PMC free article: PMC5688986] [PubMed: 29076040]

68.Kluger AY, Tecson KM, Barbin CM, Lee AY, Lerma EV, Rosol ZP, Rangaswami J, Lepor NE, Cobble ME, McCullough PA. Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review. Rev Cardiovasc Med. 2018 Jun 30;19(2):41-49. [PubMed: 31032602]

69.Chaudhry K, Karalliedde J. Chronic kidney disease in type 2 diabetes: The size of the problem, addressing residual renal risk and what we have learned from the CREDENCE trial. Diabetes Obes Metab. 2024 Oct;26 Suppl 5:25-34. [PubMed: 39044385]

70.Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW., CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. [PubMed: 30990260]

71.Wang WW, Liu YL, Wang MZ, Li H, Liu BH, Tu Y, Yuan CC, Fang QJ, Chen JX, Wang J, Fu Y, Wan ZY, Wan YG, Wu W. Inhibition of Renal Tubular Epithelial Mesenchymal Transition and Endoplasmic Reticulum Stress-Induced Apoptosis with Shenkang Injection Attenuates Diabetic Tubulopathy. Front Pharmacol. 2021;12:662706. [PMC free article: PMC8367077] [PubMed: 34408650]

72.Zhang W, Zhang Y, Lv W, Kong Z, Wang F, Wang Y. Isoquercitrin improves diabetes nephropathy by inhibiting the sodium-glucose co-transporter-2 pathway. Biochem Biophys Res Commun. 2025 Jan;744:151142. [PubMed: 39708395]

73.Tao Y, Bao J, Zhu F, Pan M, Liu Q, Wang P. Ethnopharmacology of Rubus idaeus Linnaeus: A critical review on ethnobotany, processing methods, phytochemicals, pharmacology and quality control. J Ethnopharmacol. 2023 Feb 10;302(Pt A):115870. [PubMed: 36341819]

74.Valencia-Morales ND, Rodríguez-Cubillo B, Loayza-López RK, Moreno de la Higuera MÁ, Sánchez-Fructuoso AI. Novel Drugs for the Management of Diabetes Kidney Transplant Patients: A Literature Review. Life (Basel). 2023 May 26;13(6) [PMC free article: PMC10304316] [PubMed: 37374048]

75.Augustine T. Simultaneous pancreas and kidney transplantation in diabetes with renal failure: the gold standard? J Ren Care. 2012 Feb;38 Suppl 1:115-24. [PubMed: 22348371]

76.Nagendra L, Fernandez CJ, Pappachan JM. Simultaneous pancreas-kidney transplantation for end-stage renal failure in type 1 diabetes mellitus: Current perspectives. World J Transplant. 2023 Sep 18;13(5):208-220. [PMC free article: PMC10514751] [PubMed: 37746036]

77.Rodriguez Cubillo B, Rodriguez B, Calvo M, de la Manzanara V, Bautista J, Perez-Flores I, Calvo N, Moreno A, Shabaka A, Delgado J, Sanchez-Fructuoso AI. Risk Factors of Recurrence of Diabetic Nephropathy in Renal Transplants. Transplant Proc. 2016 Nov;48(9):2956-2958. [PubMed: 27932117]

78.Hariharan S, Peddi VR, Savin VJ, Johnson CP, First MR, Roza AM, Adams MB. Recurrent and de novo renal diseases after renal transplantation: a report from the renal allograft disease registry. Am J Kidney Dis. 1998 Jun;31(6):928-31. [PubMed: 9631835]

79.Jhee JH, Kee YK, Park JT, Chang TI, Kang EW, Yoo TH, Kang SW, Han SH. A Diet Rich in Vegetables and Fruit and Incident CKD: A Community-Based Prospective Cohort Study. Am J Kidney Dis. 2019 Oct;74(4):491-500. [PubMed: 31040089]

80.Cai Q, Dekker LH, Bakker SJL, de Borst MH, Navis GJ. Dietary Patterns Based on Estimated Glomerular Filtration Rate and Kidney Function Decline in the General Population: The Lifelines Cohort Study. Nutrients. 2020 Apr 16;12(4) [PMC free article: PMC7230954] [PubMed: 32316088]

81.Mahnensmith RL, Zorzanello M, Hsu YH, Williams ME. A quality improvement model for optimizing care of the diabetic end-stage renal disease patient. Semin Dial. 2010 Mar-Apr;23(2):206-13. [PubMed: 20525109]

82.Wang N, Zhang C. Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. Int J Mol Sci. 2024 Mar 07;25(6) [PMC free article: PMC10970506] [PubMed: 38542060]

Disclosure: Preeti Rout declares no relevant financial relationships with ineligible companies.

Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.