The incidence of diabetic nephropathy (DN) is rapidly increasing worldwide and in Asian countries, occurring in nearly 40% of Japanese diabetic patients. Over the past 20 years, DN-induced new-onset hemodialysis patients have increased significantly with the increasing number of diabetics. According to the 2013 annual report of the Japanese Society for Dialysis Therapy (JSDT), the total number of dialysis patients has exceeded 310,000, and diabetes has become the leading cause of end-stage renal disease (ESRD) (approximately 44%).
Genetic background in Asians
Although many factors such as hyperglycemia, hypertension, dyslipidemia, obesity, smoking and insulin resistance are involved in the development of DN, none of these factors are sufficient to predict which diabetic patients will develop or progress to DN. since not all diabetic patients with poorly controlled blood glucose and blood pressure develop kidney disease, and racial differences and family aggregation of DN have been observed, genetic factors may help explain the susceptibility to this disease.
Spontaneous animal models
Studies using spontaneous animal models are important to determine the pathogenesis and treatment of patients with DN. There are many spontaneous animal models such as NOD and Akita mice for studying type 1 diabetes, Ob/Ob, db/db for studying type 2 diabetes, TsumuraSuzuki obese diabetic (TSOD) mice and KK-Ay mice.
Clinical classification of diabetic nephropathy in Japan
The clinical diagnostic criteria for DN in Japan are: 1) history of diabetes mellitus for more than 5 years; 2) presence of diabetic retinopathy and/or neuropathy; 3) persistent proteinuria or albuminuria; 4) absence of severe hematuria and/or cytubular pattern; and 5) increased GFR and increased kidney volume (especially in early stages).
Of these, the presence of diabetic retinopathy and/or neuropathy is a key indicator for clinical diagnosis. Persistent proteinuria or albuminuria is also an important clinical marker. If a diabetic patient presents with severe hematuria and/or cellular tubularity, such as erythrocyte tubularity, urine cytology, ultrasound and CT scan are used to rule out malignancy, and a renal biopsy is performed for differential diagnosis. Increased GFR may be observed in the early stages of type 2 diabetes. Increased kidney volume can also be observed in diabetic patients by ultrasound or CT scan.
Based on these clinical features, the Japanese Diabetes Society (JDS) and the Japanese Society of Nephrology (JSN) revised the classification criteria for DN to fit the chronic kidney disease (CKD) classification criteria (CGA classification) established by the JSN in 2012.
Novel biomarkers
Albuminuria is the first asymptomatic clinical manifestation of microvascular damage in diabetes. Although albuminuria lacks specificity and sensitivity as a prognostic biomarker for DN progression, increasing evidence suggests that the presence of mild albuminuria indicates an increased risk of cardiovascular disease.
Recently, Moriya et al. demonstrated that the histopathological forms of DN are diverse and correlate with CKD staging. Considering that some Japanese diabetic patients with normal microalbuminuria and renal function show typical pathological changes of DN, there is an urgent need to discover highly specific and reliable biomarkers for diagnosis and prognosis other than albuminuria.
Kin et al. conducted a cross-sectional study in Korea to identify sociodemographic and health-related factors associated with diabetic retinopathy and DN. The relatively low screening rate for DN in Korea compared to Western countries may be due to differences in health systems, economic status, and population composition.
Chong et al. reported renal biopsy results in patients with diabetes mellitus with renal involvement. In the DN subgroup, Indian patients had a shorter duration of diabetes than Malasian and Chinese patients. For patients with non-diabetic kidney disease, useful clinical indicators included the presence of acute renal failure and microscopic hematuria. They concluded that renal biopsy should be considered in patients with type 2 diabetes mellitus combined with nephropathy.
1. Podocytes
Glomerulosclerosis in a variety of human glomerular diseases is associated with podocyte injury. The number of podocytes in each glomerulus may be an indicator of podocyte injury and may provide prognostic information in patients with DN. Progressive DN is associated with a decrease in the number of podocytes within each glomerulus. The remaining podocytes are forced to grow and extend the pedicles to maintain coverage of the same area. Since podocytes are unable to undergo mitosis in adults, the only way to respond to injury is through cellular hypertrophy, so the increased podocyte surface area reflects the degree of podocyte hypertrophy.
Macedo et al. reported that control of hyperglycemia prevented glomerular basement membrane (GBM) thickening in tetraoxacillin-induced early and late type 1 DN and also protected against a reduction in podocyte number, and Ishikawa et al. previously reported that in KK-Ay mice, podocyte injury may provide additional prognostic information. The prevailing mechanism of podocyte loss is thought to be due to necrosis, apoptosis and or autophagy resulting from detachment from the GBM.
In patients with DN, there is no direct evidence that apoptosis is the primary cause of foot cell loss. In Japanese diabetic patients, intact podocytes have been reported to be shed from the GBM, and Nakamura et al. suggested that podocytes in urine may be a useful marker for determining disease activity in DN patients.
2. Tumor necrosis factor receptor (TNFR)
Tumor necrosis factor (TNF) alpha binds to its two cell surface receptors (TNFR1 and TNFR2) to exert biological effects. Although the role of TNF and its receptors in renal disease, particularly DN, is unclear, recent studies have identified circulating levels of soluble TNFR as a strong predictor associated with reduced future GFR, ESRD and all-cause mortality in patients with type 1 and type 2 diabetes.
Notably this biomarker is very powerful when interpreting HbA1c, albuminuria, GFR and other inflammatory biomarkers such as TNFα, CRP and IL-6. Furthermore, it is interesting to note that the two TNFRs are equivalent predictors although they have completely different functions. Many studies have also been repeated after this study for validation and positive data results have been published. Unfortunately, the availability of this biomarker has not yet been completely and thoroughly studied in Japanese diabetic patients.
3.Mindin
Our team performed microarray analysis using glomeruli isolated from diabetic KK mice, expecting to find specific genes involved in the development of DN. In this study, we focused on mindin (also known as spondin2, SPON2) as a possible biomarker for several reasons.
First, the protein expression of mindin is significantly upregulated in glomeruli as DN progresses and was found to be predominantly localized in podocytes by immunohistochemical staining, and second, mindin is a secreted protein. In addition, previous reports confirmed that mindin plays an important role in immune response and inflammation. Indeed, the expression level of mindin in the urine of KK mice with advanced lesions was significantly higher than that in early lesions. In addition, urinary levels of mindin are higher in diabetic patients than in healthy individuals and progressively increase with DN progression.
Drug treatment
Zanchi et al. concluded that it is essential to monitor renal function frequently in patients with impaired renal function and to adjust the regimen of glucose-lowering drugs based on GFR and pharmacokinetic data. Due to the lack of large-scale clinical trials of oral hypoglycemic agents (OAD) in patients with renal failure, these recommendations will need to be updated frequently when the results of large randomized trials with longer follow-up are published.
1. Enterostatin-related drugs: DPP-4 inhibitors
Most OADs are contraindicated in advanced kidney disease. the use of DPP-4 inhibitors opens a new window for the treatment of diabetic kidney disease. Due to the low risk of hypoglycemia and weight gain and relatively high safety profile, DPP-4 inhibitors are now among the best-selling drugs in Japan.
In addition, a recent meta-analysis reported that the drug may show better glucose-lowering effectiveness in Asian populations than in other ethnic groups. Differences in body mass index (BMI) in different ethnic populations may mediate the efficacy of DPP-4 inhibitors in lowering HbA1c.
Iwasaki et al. demonstrated in 72 untreated Japanese patients with type 2 diabetes that lowering HbA1c by DPP-4 inhibitors showed a significant correlation with dietary fish intake and serum EPA and DHA levels, suggesting that the effectiveness of this drug may be related to dietary habits (Japanese food vs. Western food).
Numerous animal experiments using diabetic models have confirmed that DPP-4 inhibitors protect the endothelium of blood vessels and reduce albuminuria by reducing oxidative stress and inflammation. In humans, the effect of DPP-4 inhibitors in partially reducing albuminuria is independent of the improvement in glycemic control. Although the MARLINA study (Efficacy,Safety,andModificationofAlbuminuriainType2DiabetesSubjectswithRenalDiseasewithLinagliptin) is ongoing, information on the effectiveness of DPP-4 inhibitors in RenalDiseasewithLinagliptin), but there is not much information on the effectiveness of DPP-4 inhibitors in patients with renal disease.
2. RAAS inhibitors: ACEI, ARB and direct renin inhibitors
Angiotensin II (Ang II) has hemodynamic effects leading to increased intracapillary pressure in glomeruli, as well as non-hemodynamic effects, such as cell proliferation and extracellular matrix accumulation. These effects are exerted through the interaction of Ang II with its angiotensin II type 1 receptor (AT1). ACEI and ARB have been shown to improve the hemodynamics and structure of glomeruli in DN patients.
A double-blind randomized clinical trial by Katayama et al. in 2002 confirmed that both ACEIs (midazapril and captopril) prevented increased UAE in type 1 diabetic patients with microalbuminuria and massive albuminuria, and that BP target values may be less than 130/80 mmHg.
In 2011 Imai and Chan and colleagues studied the effect of olmesartan (an ARB) on the primary outcomes of doubling of blood creatinine, ESRD and death in 577 Japanese and Chinese patients with type 2 diabetes mellitus with massive proteinuria. The results found that olmesartan was well tolerated but did not improve outcomes when combined with ACEI
In patients with DN. The combination of ACEI (lenopril) and ARB (losartan) reduced proteinuria, but its safety and impact on renal disease progression are unclear. There was no benefit on mortality or cardiovascular events. The combination therapy increased the risk of hyperkalemia and acute kidney injury. Combination therapy with ACEI and ARB is therefore considered to be associated with an increased risk of adverse events in patients with type 2 DN in the United States.
In patients with type 2 diabetes and renal disease, the combination of aliskiren (direct renin inhibitor, DRI) and colesartan has a renoprotective effect independent of the antihypertensive effect. Treatment with 300 mg of aliskiren daily reduced mean AUE by 20% compared with placebo.
3. Other treatments
Na et al. reported the therapeutic effect of beraprost sodium (BPS) on arterial stiffness in patients with type 2 DN. BPS is a prostacyclin analogue with vasodilatory effects and also has an antiplatelet effect. This is the first trial to study the effects of BPS on cardiovascular biomarkers, albuminuria, renal function and lipid changes in patients with DN.
Wang et al. are conducting a randomized, double-blind, placebo-controlled study of the herbal extract Nephrolithiasis Rehabilitation Tablets to evaluate its effectiveness in the treatment of DN. The results will help provide clinicians with evidence-based recommendations.