Diabetes-related renal complications: Insights on the impact of diabetic kidney disease on mortality

Abstract

Diabetes mellitus (DM) is a major contributor to disability and mortality, accounting for nearly 10% of all deaths in people aged 20 to 79 years. In addition, the increasing prevalence of diabetes has significantly increased the burden of disease across multiple facets of the disease spectrum. Diabetic kidney disease (DKD) is an important factor affecting morbidity and mortality in people with diabetes. DKD is characterized by a gradual deterioration of kidney function leading to end-stage renal disease (ESRD) in up to 50% of cases in certain populations and increased susceptibility to cardiovascular events. DKD is generally characterized by chronic kidney disease (CKD) defined by persistently (at least 3 months) elevated urinary albumin excretion (albumin-to-creatinine ratio ≥ 30 mg/g) and/or decreased estimated glomerular filtration rate (estimated glomerular filtration rate < 60 mL/minute/1.73 m²) in people with diabetes. As glomerular filtration rate decreases and albuminuria increases, the likelihood of adverse outcomes such as mortality and ESRD increases. People with a GFR ≤ 30 mL/minute/1.73 m² have a significantly increased risk in all categories of albuminuria. It is of pivotal importance to understand the pathophysiology of DKD, its gradual progression and the significant impact on mortality in diabetic patients. Early detection and optimal glycemic and blood pressure control are crucial to counteract the progression of the disease. Another important aspect is to identify the population group at greatest risk of diabetic-related deterioration of kidney function and prevent disease progression. There is an urgent need for thorough treatment strategies that address both renal and cardiovascular risk factors to reduce the strikingly high mortality rate closely associated with DKD in diabetics.

Key Words: Kidney diseases; Mortality; Chronic disease; Diabetic kidney disease; Diabetes mellitus

Core Tip: Diabetic kidney disease (DKD) is a major microvascular consequence of diabetes mellitus and a major factor in the progression of chronic kidney disease worldwide. In addition to its contribution to end-stage kidney disease, DKD significantly associated with increased all-cause and cardiovascular mortality. Epidemiological studies have consistently shown that even the early stages of DKD, characterized by microalbuminuria or a slight reduction in estimated glomerular filtration rate, are associated with an increased risk of mortality. The results of the current literature highlight the significance of early detection and vigilant oversight and management of DKD patients.

INTRODUCTION

Diabetes mellitus (DM) is a pathological condition, affecting 9.2% of the world's population and more than 463 million people worldwide[1]. It is characterized by an elevated blood glucose level, which manifests itself in the early stages as polydipsia and polyuria.

DM is a chronic disease that leads to various complications, which can be divided into macroangiopathic and microangiopathic. A microangiopathic complication, which is due to a multifactorial pathogenesis, is diabetic kidney disease (DKD), which is a common cause of chronic kidney disease (CKD) and affects about 30%-40% of patients with diabetes[2].

It is estimated that the number of DM patients will rise to 578 million by 2030 and 700 million by 2045, which will be accompanied by increased mortality due to DM-related complications[3]. DM care, lifestyle, food choices, socioeconomic status and genetic background all have a significant impact on the occurrence of DKD. Individual susceptibility to type 2 diabetes is partly determined by a genetic predisposition, but obesity, poor diet and a sedentary lifestyle are also major contributors to the current rise in the disease[4].

The aim of our editorial is to emphasize the need to take appropriate action to address the pandemic impact of DM globally and the problem of inequalities in the most vulnerable populations. This concept was highlighted in the recent retrospective study “Epidemiological trends in diabetic renal complications in United States adults: A centre for disease control and prevention wide-ranging online data for epidemiologic research analysis (1999-2020)”[5]. Muhammad et al[5] point out the significant inequalities that exist between racial and ethnic groups and between genders, drawing attention to the alarming situation that the world will face in the coming decades. It is imperative that the healthcare system keeps attention on this difficult situation.

PATHOPHYSIOLOGY

The pathophysiology of DM is multifactorial. DM type 1 is characterized by the absence of insulin secretion caused by the action of autoantibodies, such as pancreatic insula antibodies, glutamic acid antidecarboxylase antibodies, insulin antibodies, zinc transporter antibody 8, against the beta cells of the pancreas. Treatment is exclusively with insulin. In contrast, type 2 DM (T2DM) develops in people who have risk factors such as: Smoking, obesity, a diet rich in simple and complex carbohydrates, sedentary lifestyle, genetic predisposition. It is associated with insulin resistance, which, as a result of the constant stimulation of insulin production, leads in a second phase to the exhaustion of the beta cells of the pancreas and thus to a reduced production of this hormone. Several molecules are used in therapy (e.g. oral hypoglycemic drugs such as biguanides, alpha-glucosidase inhibitors, GLP1-RA, SGLT2i, gliptin), and insulin therapy is used in the most advanced stages. The first players in DKD treatment are angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs), whose benefits are related to the reduction in systemic and intraglomerular blood pressure and proteinuria and also to the reduction of aldosterone, that is known to over activate mineralcorticoid receptors in kidney and in heart, resulting in inflammation and fibrosis. Aldosterone breakthrough may increase cardiovascular and renal mortality, as it’s shown in AMADEO study (losArtan vs telMisArtan in hyperten sive type-2 DiabEtic patients with Overt nephropathy), where it is emphasized that this pathological condition is a relative frequent occurrence. So non-steroid mineralocorticoid receptor antagonists such as Finerenone were studied (FIDELIO-DKD trial)[6], this molecule achieved the primary outcome (kidney failure, a sustained decrease of at least 40% of epidermal growth factor receptor (eGFR) from baseline or death from renal causes) in 17.8% patients as compared to 21.1% in placebo. It showed to lower secondary cardiovascular outcomes and CKD progression; in FIGARO-DKD study, finerenone improved cardiovascular outcomes as compared to placebo in patients with T2DM, CKD stages 2-4 with elevated albuminuria. On the other hand, SGLT2i drugs are the cornerstone of DKD therapy: They promote glycosuria, reducing plasma glucose and inducing weight loss. The CREDENCE study[7] used canagliflozin vs placebo in albuminuric patients with T2DM and CKD. Canagliflozin lead to a 34% risk reduction in the progression of DKD, end-stage kidney disease (ESKD) or death from renal causes. In addition, it reduced significantly major adverse cardiovascular events. The DAPA-CKD trial included patients with non-DKD. In patients with eGFR 25-75 mL/minute/1.73 m² and albuminuria, dapagliflozin demonstrated a 44% of decrease in the composite renal outcome of doubling of serum creatinine, ESKD or death[8]. In order to obtain these results, it is fundamental to educate the patient about “sick day rules”, so he doesn’t have to experience the adverse effect. Additionally, GLP1RA also showed cardiovascular and renal benefits, probably linked to their direct action on blood pressure, glucose, weight and on improving endothelial dysfunction and inflammation. Several studies, like AWARD-10 and SUSTAIN-9, demonstrated the efficacy of combination therapy (SGLT2i+GLP-1RA). In association with these drugs, it is mandatory to initiate, with the patient consensus, an adequate life and diet, indeed adherence to a healthy lifestyle that involves regular physical activity, a healthy diet and abstinence from smoking, has been shown to improve survival from cardiovascular events and death. In particular, an individualized diet based on culture, disease severity, blood pressure, phosphorus and potassium levels may be ideal. Low protein diet promotes renoprotective effects similar to renin-angiotensin-aldosterone system blockage with ACEi or ARBs[9].

Diabetes is one of the most common causes of morbidity in the general population and, as a chronic disease, leads to the occurrence of micro- and macroangiopathic complications, the physiopathology of which is mainly related to the glycosylation of whey proteins and tissues with the formation of advanced glycation end products, production of superoxide, activation of protein kinase C, leading to endothelial dysfunction, hypertension and dyslipidemia often associated with DM, as well as proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia, which impair vascular self-regulation. Macroangiopathic complications result from the formation of atherosclerotic plaques in the large vessels, which lead to angina pectoris and myocardial infarction, transient ischemic attack and stroke as well as peripheral arterial disease. Microangiopathic complications include retinopathy, neuropathy and DKD. DKD occurs mainly in T2DM patients with high blood glucose levels, non-compliance with hypoglycemic therapy and a disease duration of more than 20 years, in contrast to patients with T1DM who develop DKD about 10 years after the onset of the disease[10]. It is the leading cause of renal failure in the general population and is associated with a high likelihood of progression to ESRD and dialysis. The clinical-laboratory sign is a gradual deterioration of renal function preceded by an initial stage of hyperfiltration, with or without microalbuminuria[11]. On ultrasound examination, the kidneys appear more voluminous in the early stages. Histologic examination reveals expansion of the mesangial matrix, thickening of the glomerular basement membrane, podocytopathy, glomerular and tubular damage, and even glomerulosclerosis and tubulointerstitial fibrosis[12]. As the disease progresses, tubulointerstitial and vascular lesions coexist in various forms, with the traditional nodular Kimmelstiel-Wilson lesions gradually becoming less prominent and giving way to less pronounced glomerulosclerotic lesions[13].

The pathogenesis of DKD is related to several factors: Hemodynamic, inflammatory and structural factors that are involved in the entire course of the disease, from onset to ESRD (Table 1).

Table 1 Diabetic kidney disease-staging, pathophysiology and treatment¹.

Aspect	Details
Definition	DKD is defined as a clinical diagnosis of CKD occurring in people with diabetes, marked by persistent albuminuria and/or reduced eGFR (< 60 mL/minute/1.73 m²), in the absence of other primary renal diseases
Pathogenesis	Chronic hyperglycemia → glomerular hypertension, mesangial expansion, basement membrane thickening, podocyte loss → fibrosis and tubular atrophy
eGFR-based G-Stages	G1: ≥ 90, G2: 60-89, G3a: 45-59, G3b: 30-44, G4: 15-29, G5: < 15 or dialysis
Albuminuria stages (UACR)	A1: < 30 mg/g (normal-mild), A2: 30-300 mg/g (moderate), A3: > 300 mg/g (severe/proteinuria)
Risk stratification	Combine GFR and albuminuria (G-stage + A-stage) → KDIGO Heatmap: Low risk: G1-A1, moderate: G2-A2 or G3a-A1, high: G3b-A2 or G2-A3, very high: G4 or A3 with G3+
Diagnostic criteria	Requires two abnormal values (eGFR and/or UACR) ≥ 3 months apart. Exclude non-diabetic kidney disease by history, serology, or biopsy if atypical
Histological features	Nodular glomerulosclerosis (Kimmelstiel-Wilson lesions), mesangial expansion, interstitial fibrosis, arteriolar hyalinosis
First-line medications	ACE inhibitors/ARBs-for all DKD with albuminuria (A2 or A3). SGLT2 inhibitors-for eGFR ≥ 20-25, albuminuria A2-A3, or cardiovascular risk. Statins-if ≥ 40 years or cardiovascular risk. Metformin if eGFR ≥ 30 and tolerated
SGLT2 inhibitor evidence	CREDENCE (2019): Canagliflozin ↓ ESRD, doubling of serum creatinine. DAPA-CKD (2020): Dapagliflozin ↓ composite kidney outcome even in non-diabetics. EMPA-KIDNEY (2023): Empagliflozin ↓ progression in broad CKD population
GLP-1 receptor agonists	Reduce albuminuria and cardiovascular events (e.g., semaglutide, liraglutide). Not proven to slow eGFR decline directly
Finerenone (non-steroidal MRA)	Reduces albuminuria and progression of DKD in patients with T2DM and albuminuria (A2-A3), with preserved GFR ≥ 25
Glycemic target	HbA1c: 7.0% in most (individualize). Avoid < 6.5% in advanced DKD (risk of hypoglycemia due to reduced insulin clearance)
BP target	< 130/80 mmHg if albuminuria ≥ 30 mg/gStart with RAAS blockade
Dietary management	Protein: 0.8 g/kg/day (non-dialysis). Sodium: < 2.3 g/day. Limit potassium and phosphorus if advanced CKD
Monitoring frequency	eGFR/UACR: Every 6 months if stable; every 3 months if high risk. Electrolytes: With RAAS, MRA, or SGLT2i, HbA1c: Every 3-6 months
Referral to nephrology	GFR < 30 (G4), rapid GFR decline (> 5 mL/minute/year)
Renal replacement therapy	GFR < 15 with uremic symptoms or refractory metabolic derangements: Consider dialysis or transplant

¹This table summarizes diabetic kidney disease by outlining its definition, staging based on estimated glomerular filtration rate and albuminuria, key pathological features, and evidence-based management strategies. It highlights the pathophysiology linking chronic hyperglycemia to kidney damage, classifies disease severity using Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, and presents treatment options including angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and mineralocorticoid receptor antagonists. The table also includes monitoring recommendations and referral criteria to optimize patient outcomes. References are provided from the latest KDIGO and American Diabetes Association guidelines, as well as pivotal clinical trials.

ACE: Angiotensin-converting enzyme; ADA: American diabetes association; ARBs Angiotensin II receptor blockers; BP: Blood pressure; CKD: Chronic kidney disease; DKD: Diabetic kidney disease; eGFR: Estimated glomerular filtration rate; GLP1: Glucagon-like peptide 1; HbA1c: Hemoglobin A1c; KDIGO: Kidney Disease: Improving Global Outcomes; MRA: Mineralocorticoid receptor antagonist; SGLT2: Sodium-glucose cotransporter 2; T2DM: Type 2 diabetes mellitus; UACR: Urine albumin-to-creatinine ratio.

HYPERGLYCEMIA

Numerous studies have shown that a 1% reduction in glycosylated hemoglobin, a marker of blood glucose levels over the last 120 days, reduces the risk of developing microalbuminuria by 33%[14]. Controlling blood glucose levels can therefore reduce the progression of DKD, except in patients with increased albuminuria. 20% of patients with T2DM develop DKD, even in the absence of albuminuria[11]. In addition, hyperglycemia is associated with several signaling pathways, such as transforming growth factor beta, angiotensin II and vascular endothelial growth factor, whose production is stimulated by the activation of protein kinase C, the accumulation of exosamines and polyols. There are three isoforms of TGF-beta: TGF-beta1 is secreted by all cells of the renal epithelium and interstitium, including inflammatory cells, and is crucial for cell differentiation and growth. TGF-beta2 is involved in tissue homeostasis, immune modulation, scar formation and embryonic development. TGF-beta3, on the other hand, is involved in embryogenesis, cell motility and apoptosis[15]. Isoform 1 in particular is involved in the process of hypertrophy in DKD[16].

HYPERTENSION

Hypertension is another important factor that contributes to the progression of DKD. In type 1 DM, hypertension occurs after the onset of macroalbuminuria as a result of kidney damage. In patients with T2DM, however, arterial hypertension is part of the patient's coexisting morbidities and is associated with other manifestations of metabolic syndrome. It is clear that poor pressure control accelerates the development of DKD. The target blood pressure that should be achieved in patients with DKD is < 130/80 mmHg, according to the American Heart Association, the American College of Cardiology and the American Diabetes Association[17].

INFLAMMATION

The cell damage caused by hyperglycemia promotes the release of proinflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 cytokine. Activation of these cytokines, which are linked to adhesion molecules, leads to the recruitment of inflammatory cells such as macrophages, monocytes, activated T lymphocytes and nucleotide-binding oligomerization domain and TOLL-like receptors (inflammasomes). The accumulation of macrophages in the glomerulus leads to further production of reactive oxygen species (ROS), cytokines and activation of proteases that contribute to renal damage and fibrosis, leading to the progression of DKD. Patients with DKD have higher TNF-α levels, which are even higher in patients with albuminuria. For this reason, many studies have focused on targeted therapeutics, e.g. pentoxifylline. This is a non-selective phosphodiesterase inhibitor derived from methylxanthine and has anti-inflammatory, antiproliferative and antifibrotic effects. It is also associated with antiproteinuric effects in DKD, which are associated with a reduction in urinary excretion of TNF-α[18,19]. Despite these indications, further large-scale prospective studies are required to prove the actual efficacy of this drug.

OXIDATIVE STRESS

The inflammatory process induces the production of ROS and thus a state of oxidative stress, which leads to damage to the kidney cells with a direct effect on the DNA and to dysfunction of the endothelium with reduced bioavailability of nitric oxide (NO). A key role is played by NADPH oxidase (NOX), which is closely involved in the oxidative stress associated with DKD. Some studies have demonstrated the efficacy of GKT137831 (setaxanib), an inhibitor of NOX1 and NOX4, in reducing glomerular hypertrophy, mesangial expansion, albuminuria and podocyte damage[20]. SGLT2 inhibitors have also been shown to be remarkably effective in reducing ROS production and slowing the progression of kidney damage[21].

DM has reached epidemic proportions: It has been estimated that more than 40% of people with diabetes will develop DKD, depending on several risk factors such as persistent high blood glucose levels, male sex, obesity, concomitant hypertension, inflammation, resistance to insulin, hypovitaminosis D, genetic polymorphisms, dyslipidemia and duration of the disease: DKD develops after ten to twenty years from diabetes onset. DKD is related to the characteristics of different populations: It is more frequent in African-Americans and Native Americans, despite this, progressive kidney disease is more frequent in Caucasians[21]. Normalization of blood glucose level decreases the risk of microalbuminuria and macroalbuminuria, that are the first manifestation of the disease. A diabetic patient for twenty to twenty-five years without having manifested microalbuminuria has low chance of developing DKD, more likely 1%. Almost 20% to 30% of the patients progress to microalbuminuria after 15 years of disease. Microalbuminuric patients have higher GFR due to the mechanism of hyperfiltration, while macroalbuminuric patients showed a more rapid GFR loss, leading to ESKD. It is important to identify the stage of DKD, in order to assure to the patient appropriate treatment. In T1DM the lifetime increasing incidence of macroalbuminuria is among 15%-25%, the incidence of microalbuminuria is 25%-40%. The progression of DKD in T1DM is unpredictable: EURODIAB type I diabetes study[22] showed that 14% of microalbuminuric patients developed macroalbuminuria above 7.3 years’ follow-up. In Joslin type 1 diabetes cohort[23], they highlight that “early renal function decline” is present in a third of microalbuminuric partecipants and also in normoalbuminuric patients. This suggests that albuminuria and GFR loss are strictly related, but they are also linked to different pathophysiological mechanisms[21]. On the other hand, the prevalence of DKD in T2DM is about 30%-50%, evolution from microalbuminuria to macroalbuminuria occurs at a rate of 2.3% per year. DKD is also strictly correlated to health consequences, typically cardiovascular disease, including micro and microangiopathies, that lead to a higher mortality risk and rate.

DKD AND MORTALITY

The global prevalence of diabetes continues to rise, paralleling the increasing incidence of DKD[3,24,25]. The microvascular changes have a significant impact on outcomes associated with diabetes, particularly with the risk of cardiovascular disease progression. Although the risk of all-cause mortality and cardiovascular disease is significantly increased in diabetic patients with both DKD and diabetic retinopathy, there appears to be a stronger correlation with an increased risk of death in DKD patients[26].

T2DM combined by renal disease can reduce both life expectancy compared to people without kidney involvement, leading to increased medical costs and a higher mortality rate[27]. Inadequate management of high blood pressure and cholesterol contributes to the onset and progression of diabetes-related problems, including DKD[28,29].

Muhammad et al[5] conducted a retrospective analysis on renal complications and diabetes-related mortality using death certificate data from the Center for Disease Control and Prevention's comprehensive online database for epidemiologic research analyzes covering the period from 1999 to 2020 and examining mortality associated with renal complications of diabetes in adults aged 35 years or older. The age-adjusted mortality rate (AAMR) differed between racial and ethnic groups, with the highest prevalence in the American Indian/Alaska Native population. Geographically, there were notable differences in AAMR between states and regions, with western states and non-metropolitan areas consistently showing increased AAMR throughout the research period. The persistent increase in AAMR over the years can be explained by a complex interplay of factors, including the increasing prevalence of the disease, longer disease duration, inadequate glycemic control, comorbidities, accessibility and quality of health care, and environmental and lifestyle influences. These findings highlight the significant disparities that exist between racial and ethnic groups and between genders, which may further disadvantage vulnerable populations. The restricted availability and access to quality healthcare services for diabetes and DKD, which include essential medicines, dialysis and kidney transplantation, may exacerbate the increased mortality rates associated with these conditions. This underscores the urgent need for improved health systems that focus on primary care to improve diabetes diagnosis, treatment and prevention of complications. A research of United States electronic medical data revealed that CKD was associated with the greatest incremental risk of all-cause mortality in people recently diagnosed with T2DM[30].

As a multisystemic disease leading to vascular damage through dysregulation of blood glucose levels, diabetes is a major contributor to increased mortality and worsening risk factors for fatal outcomes. Albuminuria and decrease in eGFR are independent risk factors for death. The prognosis for diabetics differs significantly depending on whether microvascular problems, including DKD, are present. Albuminuria is generally considered an early indicator of renal dysfunction and decreased renal function and is strongly associated with unfavourable outcomes in diabetic patients[31]. In addition, there is a strong association between albuminuria and mortality risk, even at slightly elevated albuminuria levels[32].

Several studies analysed kidney disease and diabetes as two major causes of mortality risk[33-35]. According to the findings of a study that was conducted between 1994 and 2008 and involved a large cohort of half a million adults, individuals who were diagnosed with diabetes and had early kidney involvement lost an average of sixteen years of life in comparison to the general population[36]. Evaluation of the Singapore National Healthcare Group CKD Registry revealed a high annual mortality rate of 64.1 per 1000 patients with DKD (95%CI: 60.2-68.3), with the mortality rate increasing with increasing severity of CKD[37].

Fox et al[38], in their meta-analysis with more than one million participants, found that a higher urinary albumin-to-creatinine ratio and a lower eGFR increased the risk of mortality from all causes and cardiovascular disease in people with or without diabetes. However, the absolute risks of death from all causes and cardiovascular disease were 1.2-1.9 times higher in patients with diabetes than in patients without diabetes, across the entire range of urine albumin-to-creatinine ratio and eGFR. In a large population-based study[39], the authors examined the incidence and risk variables associated with all-cause mortality and mortality from cardiovascular disease and end-stage renal disease in 8413 people with T2DM with and without DKD in the United Kingdom general population. In the DKD cohort, the incidence rates per 1000 person-years were 50.3 for all causes of death, 8.0 for cardiovascular disease and 6.9 for end-stage renal disease. In the DKD sample, lower kidney function at baseline was associated with an increased risk of renal insufficiency. They found that one in twenty people with type 2 diabetes and DKD die each year from complications related to these diseases.

Similarly, other population-based studies have shown that DKD is associated with a significantly increased risk of death in diabetics. Afkarian et al[40] analyzed cumulative 10-year mortality by diabetes and kidney disease status for 15,046 participants in the third National Health and Nutrition Examination Survey. Among individuals who had both diabetes and kidney disease, the standardized mortality rate was 31.1% (95%CI: 24.7%-37.5%), an absolute risk difference from the reference group of 23.4% (95%CI: 17.0%-29.9%). Conversely, diabetes without kidney disease was not associated with a high increase in mortality risk.

These findings may have significant consequences for risk assessment in clinical practice. There are several important issues that require further investigation, including whether the introduction of more comprehensive screening for renal failure and albuminuria leads to an increase in survival rates, the use of extensive biomarkers for DKD-onset risk and progression as well as the cost-effectiveness of such a strategy.

The use of novel agents such as sodium-glucose cotransporters and glucagon-like peptide 1 receptor agonists may be beneficial in controlling blood glucose levels and reversing physiological changes in DKD, thereby improving treatment outcomes and slowing disease progression.

CONCLUSION

Considering the worldwide health impact of DKD, it is imperative to focus prevention, early detection, referral, and vigorous management of DKD within primary care and from the first signs of renal involvement. Further research is needed to find successful ways to ensure optimal survival rates and improve the quality of life of diabetic patients by applying a personalized approach and patient-centered care[41] with timely and appropriate prescription of medications and reducing the potential risk factors for progression of both diabetes and kidney disease.