Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are the main risk factors for the development of DN. In general, screening for microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes and at diagnosis and annually thereafter in type 2 diabetes. Standard therapy is blood glucose and blood pressure control using the renin-angiotensin system blockade, targeting
Diabetic nephropathy (DN) is one of the most frequent and severe complications of diabetes mellitus (DM) and is associated with increased morbidity and mortality in diabetic patients [
DN develops after latency periods that may vary by several years in approximately one-third of patients with diabetes. It is still a matter of controversy whether individuals should be screened to find microalbuminuria or screened to predict DN, known as the personalized medicine approach, so as to allocate resources with more intensive therapy and early preventive measures only to the individuals most at risk [
The pathogenesis of DN is very complex and is still not fully understood, resulting in poor therapeutic outcomes. Standard therapy, with strict blood sugar and blood pressure control, has been shown to be unable to stop DN progression to ESRD [
The pathogenesis of DN development and progression is complex and multifactorial with the involvement of many pathways and mediators [
The role of oxidative stress in DN has been noted by the observation that inhibition of oxidative stress improves a feature associated with streptozotocin-induced DN [
The mechanisms of damage induced by oxidative stress can occur directly or indirectly. Oxidative stress can cause direct damage to podocytes, mesangial cells, and endothelial cells, resulting in proteinuria and tubulointerstitial fibrosis [
The renin-angiotensin-aldosterone system plays (RAAS) an important role in the progression of renal disease, and it has been shown that inhibition of RAAS can inhibit the progression of CKD which is characterized by decreased proteinuria and well-maintained renal function [
Based on existing evidence, it shows that Ang-II is a cytokine that has many effects on the kidneys [
In addition to circulating renin-angiotensin, many tissues such as the uterus, placenta, blood vessels, heart, brain, and, especially the adrenal cortex and kidneys, have local RAS [
It has been shown that immune and inflammatory responses play an important role in the pathogenesis of DN [
Persistent inflammation of the circulatory system and renal tissue is an important pathophysiological basis in the development of DN. Inflammation may be activated by metabolic, biochemical, and hemodynamic disorders known to be present in DN [
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Several studies have supported an interdependent relationship between inflammation and oxidative stress [
When oxidative stress appears as a primary disorder, inflammation develops as a secondary disorder and further increases oxidative stress. On the other hand, inflammation as a primary disorder can cause oxidative stress as a secondary disorder, which can further increase inflammation [
Relatively, the same thing happens in DN; it is difficult to determine the primary abnormality. What is clear is that DN has an increase in serum IL-6 and IL-18 levels [
Based on the description above, it has been proven that the inflammatory process plays an important role in the pathogenesis of DN. Inflammation in DN is probably activated by metabolic, biochemical, and hemodynamic disturbances that are known to be present in DN [
Conventionally, the natural history of DN consists of 5 stages, mainly based on the proposal by Mogensen et al. [
Based on the (ADA) recommendations, screening is carried out for everyone with type 2 diabetes by measuring renal function and albuminuria at diagnosis and annually thereafter; whereas in type 1 DM, it starts after 5 years of diagnosis. However, because the prevalence of microalbuminuria before 5 years in type 1 DM can reach 18% [
The definition of DN is based on current guidelines using four main criteria: a decline in renal function, diabetic retinopathy, proteinuria, and a reduction in GFR [
Basically, natural development of DN differs based on the type of diabetes and the presence of albuminuria (30-300 mg/day). In type 1 diabetes mellitus, DN rarely manifests within the first 10 years after diagnosis, but between 10 and 20 years, the incidence of DN is approximately 3% per year [
Classically, DN is characterized by the appearance of proteinuria followed by a progressive decline in renal function. However, some diabetic patients develop decreased renal function and vascular complications without proteinuria, known as nonproteinuric DN (NP-DN) [
In general, NP-DN is caused by abnormalities in the vascular or predominantly tubulointerstitial abnormalities [
In addition, there are other factors that also play a role: (1) Increased levels of uric acid, which can damage vascular elements and cause endothelial dysfunction through various mechanisms, including activation of the Toll-like receptor pathway [
With regard to prognosis, NP-DN has a better prognosis than DN with significant proteinuria. This is in accordance with the understanding so far, that the degree of proteinuria is a strong predictor of the risk of progression [
The diagnosis of NP-DN is based on an increase in the Renal Resistive Index (RRI), which measures renal vascular resistance. RRI measurements have been shown to be reliable for detecting and monitoring the development of DN and NP-DN [
Hyperglycemia, hypertension, obesity, smoking, race, men, dyslipidemia, age, and genetic factors are the main risk factors for the development and progression of DN [
Currently, renal biopsy for diagnostic purposes is indicated in cases of atypical presentations that suggest the presence of other renal disorders that may benefit from specific treatment [
In classic DN patients, standard therapy still focuses on glucose and blood pressure control, with the target of halting DN progression and regression of albuminuria. This albuminuria regression target is based on the assumption that decreased albuminuria in diabetic individual results in better renal and CVD outcomes [
In NP-DN patients, the main underlying abnormality is vascular, the principle of targeted therapy as well as cardiovascular risk factors that is seen in diabetic patients. In recent years, pharmacological alternatives for DN, such as heparin or heparin derivatives (Sulodexide) and antibody therapy, have been proposed for treating glomerular vascular syndrome [
Adequate glucose control is a standard foundation in preventing the development and progression of DN. The
The management of hyperglycemia in CKD, especially those accompanied by a decrease in GFR is a challenge, which requires a more specific understanding, especially in relation to drug choice [
The insulin sensitizers, biguanides and thiazolidinediones, and the inhibitors of
Based on the UKPDS study, a 10 mmHg reduction in systolic blood pressure was associated with a reduction in diabetic microvascular complications, including nephropathy. ADA recommends a blood pressure reduction target of <140/90 mmHg [
It has been shown that the standard management strategy for DN, which is strict glucose control and blood pressure with RAAS blockade as described above, is only able to slow down the rate of progression but not stop or reverse the disease. Therefore, new drugs targeting DN pathomechanisms, such as oxidative stress and inflammation, have become a major focus for the development of new therapies [
Besides the function of regulating sodium balance through mineralocorticoid receptor activation, aldosterone also has the effect of increasing inflammation and fibrosis [
Endothelin 1 (ET-1) is a strong vasoconstrictor and mitogenic factor that exhibits vasoactive, inflammatory, and profibrogenic properties and has implications for cardiovascular disease and CKD. ET-1 contributes to renal fibrosis through various mechanisms, promotes the accumulation of extracellular matrix components and endothelial cell proliferation, stimulates the epithelial-mesenchymal transition, and increases the production of cytokines and growth factors [
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a hormonal form of vitamin D, which is an endocrine hormone with various physiological functions [
A systematic review including clinical trials of the effects of active vitamin D (both paricalcitol and calcitriol) on the control of proteinuria in CKD patients concluded that these drugs provide a significant reduction in proteinuria in addition to blockade of the renin-angiotensin system [
Pentoxifylline (PTF) is a methylxanthine-derived phosphodiesterase inhibitor which is used primarily to treat peripheral vascular disease, as it has beneficial effects on microcirculatory blood flow [
High glucose causes a proinflammatory response in tubular cells and podocytes which is characterized by chemokine secretion that triggers renal inflammation [
The human body has antioxidants as a defense mechanism that counterbalances the effects of oxidants. Antioxidants are divided into enzymatic and nonenzymatic antioxidants. The main enzymatic antioxidants are superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px), haem oxygenase-1 (HO-1), and thioredoxin. The main nonenzymatic antioxidants are glutathione (GSH), vitamins (vitamins C and E), and
Resveratrol is a natural polyphenol compound that has been reported to have beneficial effects on cardiovascular disease, including kidney disease [
Activation of Nrf2 reduces renal inflammation by suppressing macrophage inflammatory response by blocking the transcription of proinflammatory cytokines including IL-1 and IL-6 [
The development and progression of DN are associated with numerous risk factors. In addition, DN patients are usually older, with longer duration of diabetes, and more often with comorbidities, so the therapeutic regimen of DN is usually multifactorial, which includes tight glycemic control, blood pressure control using RAAS inhibitors, lipid-lowering agents, weight loss, protein restriction, and smoking cessation. Although blood glucose and blood pressure levels are well controlled, and nonspecific measures are also implemented, the progression of DN cannot be stopped. Many diabetic patients develop ESRD, and disproportionate spending on health care becomes a tremendous socioeconomic burden on society. Therefore, there is an urgent need to improve the mechanistic understanding of DN and then develop new and effective therapeutic approaches to delay the development of DN. Also, to assess the success of the therapy, the reliable markers used in the progression of DN and ESRD should be identified. The use of this reliable marker is also important because many patients have DN without albuminuria (NP-DN).
In the future, it appears that vitamin D receptor activators (VDRA) and incretin-related drugs for glycemic control (DDP4 inhibitors and GLP-1 agonists) are promising therapies for stopping the progression of DN. Likewise, new drugs targeting DN pathomechanisms, such as oxidative stress, and inflammation have been a major focus for the development of new therapies.
The authors declare no conflict of interest.
The author would like to thank Winda and Dina who helped in the preparation of this article.