Diabetic Nephropathy Treatment: Based On The Hotspots Of The Basic Point And Breaking Through The Focus Of The Target

Chronic diseases have become a public health problem that threatens the health of Chinese residents. Chronic kidney disease (CKD) has become one of the most important chronic diseases in China due to its high morbidity, high mortality, and high medical costs. Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes and has become the leading cause of CKD in China.

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What is even more serious is that the prevalence of diabetes in China is 10.9%, the prevalence of pre-diabetes is 35.7%, and the number of patients is 388 million. Therefore, it is urgent to strengthen the prevention and control of DKD. The "Opinions of the State Council on the Implementation of the Healthy China Action" also regards the prevention and treatment of diabetes and its complications as one of the four major chronic diseases that the country focuses on prevention and control.

However, due to the complex pathogenesis of DKD and the lack of specific intervention targets, the treatment effect is not ideal, and the incidence of DKD in the end stage is still rising [1]. This requires us to pay more attention to the treatment strategy of DKD and understand the progress and future direction of DKD treatment.

In the clinical treatment of DKD, it is necessary not only to base on the traditional classic basic drugs [renin-angiotensin system (RAS) blockers], but also to promote emerging hotspot strategies [sodium-glucose cotransporter 2 (SGLT2) inhibitors ], but also continue to explore new intervention targets; at the same time, open the bottleneck of DKD treatment from biological therapy, to delay the progress of DKD and improve the prognosis of patients.

1. The classic basis: RAS blockers

RAS blockers are both traditional basic and classic drugs in the treatment of DKD. The treatment of DKD can play the role of "killing three birds with one stone": controlling blood pressure, reducing urinary protein, and delaying the progress of kidney disease. Several large clinical studies have also confirmed the efficacy of RAS blockers in DKD.

The IDNT study (irbesartan DKD trial) included 1,715 patients with type 2 DKD and hypertension. The study showed that the risk of doubling the serum creatinine level in the irbesartan group was 33% lower than that in the placebo group and 37% lower than that in the amlodipine group. %, the risk of progression to end-stage renal disease (ESRD) was reduced by 23% compared with the two groups.

The RENAAL study (Angiotensin Ⅱ antagonist losartan reduces NIDDM endpoint study) also showed similar results. This study included 1,513 patients with type 2 diabetes and kidney disease in 29 countries. Compared with the placebo group, the risk of doubling the blood creatinine level in the losartan group was reduced by 25%, the risk of developing ESRD was reduced by 28%, and the proteinuria level was reduced by 35%.

Therefore, the 2020 American Diabetes Association (ADA) guidelines recommend angiotensin-converting enzyme inhibitors (angiotensin-converting enzyme inhibitors, ACEI) or angiotensin receptor blockers (angiotensin-receptor blockers, ARB) for the treatment of diabetes with urinary albumin Patients with elevated excretion (≥30 mg/g), especially strongly recommended for urinary albumin excretion rate ≥300 mg/g and/or estimated glomerular filtration rate (eGFR) <60 ml·min-1· (1.73 m2)-1 patient.

However, for simple diabetic patients, the use of RAS blockers to prevent the occurrence of proteinuria has not been supported by evidence-based medicine. A study involving 285 patients with type 1 diabetes with normal blood pressure and proteinuria found that losartan or enalapril did not reduce the incidence of albuminuria in patients with type 1 diabetes [2]. The results of the ROADMAP trial (Olmesartan and Diabetic Microalbuminuria Prevention Trial) showed that although olmesartan can delay the onset of microalbuminuria in patients with type 2 diabetes, the incidence of fatal cardiovascular events is relatively high, and its safety Worrying [3]. Therefore, for diabetic patients with normal blood pressure, normal urinary albumin-to-creatinine ratio (UACR) (<30 mg/g), and normal eGFR, the use of ACE inhibitors or ARBs for the primary prevention of CKD in diabetic patients is not recommended.

Since ACEI and ARB have definite renal protective effects, can ACEI and ARB combined in the form of dual-channel blockade exert better proteinuria-lowering and renal-protective effects? Several randomized controlled trials (RCTs) such as ONTARGET (a global trial of the efficacy of telmisartan alone and in combination with ramipril) and VA NEPHRON-D (Veterans Affairs Diabetic Nephropathy Study) showed that ARB combined with ACEI therapy does not increase the benefits of DKD patients, but significantly increases the risk of hyperkalemia and acute kidney injury. Therefore, the combined use of ACEI and ARB in the treatment of DKD is not recommended.

2. Emerging hot spots: SGLT2 inhibitors

SGLT2 inhibitors represented by canagliflozin, dapagliflozin, empagliflozin, etc. can inhibit the reabsorption of glucose and Na+. Reduce proteinuria and renoprotection. A study involving 12 900 patients with type 2 diabetes and kidney disease in 34 countries found that the UACR of the canagliflozin group was reduced by an average of 31% compared with the placebo group, and the relative risk of ESRD, doubling of serum creatinine level or death was reduced by 34%[ 4].

The DECLARE (RCT of Dapagliflozin Cardiovascular Outcomes) study confirmed that Dapagliflozin can reduce new-onset DKD, prevent, reverse, and delay the progression of kidney disease, and reduce renal hard end-point events by 47%, including a continuous decline in eGFR ≥ 40% [eGFR<60 ml·min-1·(1.73 m2)-1], progression to ESRD or nephropathy leading to death[5].

Another study showed that empagliflozin could delay the progression of renal function in patients with type 2 diabetes, reduce the risk of doubling serum creatinine by 44%, and reduce the risk of dialysis by 55% [6]. A meta-analysis published in The Lancet systematically reviewed three clinical trials of empagliflozin, canagliflozin, and dapagliflozin, with a total of 34,322 patients with type 2 diabetes. The results showed that SGLT2 inhibitors can make renal The combined risk of functional impairment, ESRD, or renal death is reduced by 45% [7]. Therefore, in the 2020 ADA guidelines, for patients with type 2 diabetes combined with CKD, eGFR≥30 ml min-1 (1.73 m2)-1, and UACR>30 mg/g (especially UACR>300 mg/g), it is To reduce the risk of CKD progression and/or cardiovascular events, SGLT2 inhibitors are recommended.

The author believes that SGLT2 inhibitors, as an emerging drug, have brought hope and dawn to the treatment of DKD. The renal protection effect is accurate and effective, and it is worthy of clinical promotion and application. However, the potential risks and adverse reactions of SGLT2 inhibitors cannot be ignored. On the one hand, this class of drugs constricts the afferent arteriole, reduces renal perfusion, and has the risk of reducing the glomerular filtration rate, which places corresponding demands on baseline renal function; on the other hand, SGLT2 inhibitors may increase urinary system and The risk of reproductive system infection, especially for DKD patients, unsatisfactory blood sugar control will make the infection worse; in addition, ketosis is also a problem that cannot be ignored. Therefore, in the clinical promotion of SGLT2 inhibitors, the benefits should be considered while the disadvantages should be avoided, and timely adjustments should be made.

3. The target of exploration: precision treatment

Whether it is traditional RAS blockers, or SGLT2 inhibitors, as well as glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, these drugs are effective in DKD The therapeutic effect of the drug may come from reducing the internal pressure of the glomerulus, improving high filtration, or from the renal protection effect of hypoglycemia and other than hypoglycemia, not from a specific precise target. Therefore, how to explore new intervention targets for DKD has attracted more and more attention.

A study explored the effect of selective endothelin α receptor antagonist atrasentan on proteinuria and renal prognosis in type 2 diabetes mellitus. The follow-up time was 2.2 (1.4, 2.9) years, and the endpoint event was defined as doubling of serum creatinine ( continuous ≥30 days), or ESRD [eGFR<15 ml min-1·(1.73 m2)-1, continuous ≥90 days, chronic dialysis ≥90 days, kidney transplantation or death from renal failure]. Among the 1,325 patients in the Sentan group, 79 (6.0%) had major composite renal endpoint events, and 105 (7.9%) of 1,323 patients in the placebo group had major composite renal endpoint events [8]. However, the investigators terminated the study early because the number of primary endpoint events was lower than expected.

On the other hand, the water and sodium retention caused by atrasentan increases the risk of heart failure and rehospitalization, which makes its clinical application unsatisfactory.

In addition, other studies have found that inhibitors of apoptosis signal-regulated kinase 1 (ASK-1) and vascular adhesion protein 1 (VAP-1) can reduce albuminuria in DKD. Our research group has conducted more than 30 years of research on DKD, especially the in-depth and systematic exploration of the intervention targets of DKD in the past 10 years, and confirmed that inhibiting glycogen synthase kinase 3β (GSK-3β) can alleviate DKD podocyte It was found that administration of vitamin D receptor agonists can protect podocytes and reduce proteinuria [9, 10].

On this basis, our research group is carrying out clinical observation research on GSK-3β inhibitors and vitamin D receptor agonists in the treatment of DKD, to discover the new application value of traditional drugs and realize the new use of old drugs; it is also working on the synthesis of inhibitors The small molecular compound of GSK-3β is expected to provide precise therapeutic targets and therapeutic drugs for the treatment of DKD.

4. Future Focus: Biological Therapy

In the high glucose state of diabetes, the paracrine function of endothelial progenitor cells (EPCs) is impaired, resulting in decreased expression of angiogenic factors in EPCs, decreased proliferation and migration ability, and pro-inflammatory and pro-fibrotic factor transforming growth factor Increased secretion of β1 (TGF-β1). In addition, diabetes reduces the formation of EPCs in the bone marrow, resulting in a reduction in circulating EPCs. Dysfunctional EPCs and decreased circulating levels of EPCs are associated with DKD progression.

Protecting the number and function of EPCs may become a new target for the treatment of DKD. In the acute glomerulonephritis (AGN) model, injection of bone marrow-derived EPCs can improve glomerular endothelial injury and mesangial activation, suggesting that EPCs can repair glomerular endothelial injury. In addition, studies have found that the administration of EPCs mobilizers to promote the mobilization of EPCs in the bone marrow has the potential to repair glomerular endothelial damage.

Statins, such as atorvastatin, promote the mobilization of EPCs in the bone marrow and increase circulating EPCs in the blood in the diabetic state independent of cholesterol-lowering effects; recombinant human erythropoietin (rhEPO) or its equivalent Drugs can participate in the process of repairing the cardiovascular system both in vivo and in vitro. Subcutaneous injection of darbepol alfa for 4 weeks can increase the number of EPCs subsets, improve endothelial function and vascular reactivity, and increase endothelial cell proliferation [11, 12]; Chemokine receptor antagonist AMD3100 (Plerixafor) can promote wound healing in diabetic rats by mobilizing EPCs [13].

Direct cell therapy has adverse reactions such as immune rejection and tumor risk, which limits the popularization and application of cell therapy to a certain extent. Stem cell-derived exosomes can not only exert the huge therapeutic potential of stem cells, but also make up for the risks brought about by cell therapy, and show strong repair and protection capabilities against kidney injury and other diseases.

Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Exo) can promote the proliferation of renal epithelial cells and effectively reduce the renal oxidative stress and apoptosis induced by cisplatin [14]. Stem cell-derived exosomal miR-let7c-MSC can effectively inhibit renal fibrosis and reduce renal injury in mouse models [15]. In addition, some researchers have found that bone marrow mesenchymal stem cell (BMSC)-derived exosomes can promote the proliferation of renal tubular epithelial cells by reducing apoptosis and activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, To play a protective role [16].

The research team found that BMSC exosomal miRNA improved DKD podocyte injury by regulating methylation (not yet published). Therefore, exosomes derived from stem cells are expected to become an emerging "cell-free" treatment method for the treatment of DKD and will have broad application prospects.

In short, the incidence of diabetes in China is increasing, the number of DKD patients is increasing, the proportion of end-stage DKD in dialysis patients is increasing, and the economic and social burden brought by DKD is becoming heavier. Prevention and control have become the main direction and main battlefield of CKD prevention and treatment.

On the one hand, we should respond to the national strategy and strengthen DKD science education and primary prevention; on the other hand, we should intensify basic research to reveal the mechanism of DKD, and focus on four points for DKD treatment: grasp the basic point, push the hot spot, and break the target point, Aim at the focus to improve the prognosis of DKD patients and reduce the occurrence of ESRD.

for more information:Ali.ma@wecistanche.com