Update Points And Treatment Progress Of American Diabetes Association Guidelines For Diabetic Nephropathy
Feb 23, 2023
Diabetic kidney disease (DKD) is a common chronic complication of diabetes and one of the important causes of end-stage renal disease (ESRD), which brings a heavy burden to patients and society. In recent years, due to the emergence of a large amount of evidence-based medical evidence, the guidelines for the diagnosis and treatment of DKD have undergone important updates. The author summarizes the update and research progress of the DKD diagnosis and treatment part of the 2020 American Diabetes Association (ADA) guidelines for readers.
1. Update of frequency of DKD screening and renal function assessment
In terms of screening recommendations, the guidelines for 2019 and 2020 are the same. It is recommended that all patients with type 2 diabetes and type 1 diabetes with a disease duration of ≥ 5 years should be tested for urinary albumin and estimated glomerular filtration rate (estimated glomerular filtration rate) at least once a year. filtration rate, eGFR) (evidence level B) [1, 2]. In the 2020 guidelines, recommendations for urine protein and renal function monitoring are newly added. To guide treatment, for urinary albumin/creatinine ratio (UACR) > 30 mg/g and/or eGFR < 60 ml·min- 1·(1.732)-1 diabetic patients should monitor urine protein and eGFR twice a year (evidence level C) [1].
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DKD screening has always been the main content recommended by the ADA guidelines. In addition to focusing on screening, the 2020 guidelines recommend that once a diabetic patient with DKD (or complicated by chronic kidney disease) is diagnosed to guide treatment, urine albumin, and eGFR.
The clinical diagnosis of DKD is mainly based on increased urinary albumin and/or decreased eGFR in diabetic patients [3]. Although UACR has the disadvantage of high variability among different tests, UACR is still the most convenient indicator for diagnosing DKD. After excluding exercise, infection, fever, congestive heart failure, menstruation, significant hyperglycemia, and significant hypertension within 24 hours, 2 or more of the 3 UACR increases (>30 mg/g) were measured within 3 to 6 months, DKD can be diagnosed. Increased UACR is a common manifestation of DKD, but in recent years, there have been more and more reports of decreased eGFR without increased UACR in diabetic patients [4] and decreased eGFR in diabetic patients without retinopathy and primary kidney disease [<60 ml· min-1·(1.732)-1] is also an index for diagnosing DKD. In the new ADA guidelines, once UACR>30 mg/g and/or eGFR<60 ml·min-1·(1.732)-1 are diagnosed as DKD in diabetic patients, it is recommended to increase the frequency of monitoring to guide treatment and monitor changes in the condition. Moreover, the recommended annual surveillance frequency is higher than that recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) [5] guidelines.
2 . Clinical application recommendations of SGLT2i and glucagon-like peptide 1 receptor agonist (GLP-1RA) updated
In the 2019 guidelines, for patients with type 2 diabetes mellitus and CKD, to reduce the risk of DKD progression and/or cardiovascular events, SGLT2i and/or glucagon-like peptide 1 receptor agonists (glucagon-like peptide 1 receptor agonists) should be considered. agonist, GLP-1RA) (level of evidence C) [2].
In the 2020 guidelines, for patients with type 2 diabetes combined with CKD monitoring, eGFR ≥ 30 ml min-1 (1.732)-1, UACR > 30 mg/g (especially UACR > 300 mg/g), to reduce the progression of CKD and/or the risk of cardiovascular events, it is recommended to use SGLT2i (evidence level A). For patients with type 2 diabetes and CKD who are at high risk of cardiovascular events, the use of GLP-1RA may reduce the risk of proteinuria progression and/or cardiovascular events (level of evidence C) [1].
By comparison, it can be found that the 2020 guidelines have undergone important updates compared with 2019. The 2019 guidelines recommend that patients with type 2 diabetes and CKD can be treated with SGLT2i and GLP-1RA, but the level of evidence (C) is low, and there is no difference in the recommendations of the two drugs. The 2020 guidelines pointed out that SGLT2i can delay the progression of CKD and/or reduce cardiovascular events, and the evidence is reliable, which is level A evidence. The recommendation of GLP-1RA has changed slightly, which is the same as the 2019 guideline recommendation, except that the application of GLP-1RA may delay the progression of DKD to may reduce the progression of urinary protein. The level of evidence is weak, and it is still level C evidence.
The therapeutic effect of SGLT2i on DKD has attracted much attention. In the previous large-scale cardiovascular outcome study of SGLT2i, it was found that in addition to reducing the primary endpoint of cardiovascular events, SGLT2i also achieved good results in the secondary endpoint of renal events. For example, the results of the EMPA-REG study (empagliflozin cardiovascular outcome study) [6] and CANVAS study (canagliflozin cardiovascular outcome assessment study) [7] showed that compared with placebo, SGLT2i reduced type 2 Risk of developing or worsening nephropathy in diabetic patients. Although the above studies have shown that patients with type 2 diabetes mellitus complicated with CKD benefit significantly from the renal endpoints of SGLT2i, the main purpose of these studies are to evaluate the cardiovascular safety of SGLT2i. The primary endpoint is cardiovascular events, and renal events are only secondary endpoints. Moreover, the population selected for these studies was mainly type 2 diabetes patients with cardiovascular disease or high-risk factors for cardiovascular disease, and the research population was not mainly selected for type 2 diabetes combined with CKD. Therefore, the test efficiency and reliability of renal endpoints are low, so the 2019 ADA guidelines pointed out that the use of SGLT2i in patients with DKD may delay the progression of renal disease, and the level of evidence is only grade C.
In 2019, the results of the large-scale clinical trial CREDENCE (Canagliflozin in Diabetic Patients with Diagnosed Renal Disease) were released, providing strong evidence for the application of SGLT2i in DKD. This study mainly enrolled patients with diabetes mellitus combined with CKD, and the primary endpoint was the renal clinical endpoint, which was in 4 401 cases of type 2 diabetes with mean UACR ≥ 300 mg/g and mean eGFR 56 ml·min-1·(1.732 )-1 study using canagliflozin and placebo in patients. The main composite endpoint is an end-stage renal disease, doubling of serum creatinine, or renal and cardiovascular death[8, 9]. The results showed that the risk of end-stage renal disease in the canagliflozin group was 32% lower than that in the placebo group, and the hazard ratio (hazard ratio, HR) was 0.68, 95% confidence interval (confidence interval, CI) was 0.54-0.86, P=0.002. In particular, it should be pointed out that canagliflozin benefited from the treatment of most patients with ACEI or ARB. Therefore, there is strong evidence that SGLT2i delays the progression of CKD in patients with type 2 diabetes, and the level of evidence was upgraded to A in the 2020 guidelines.
A secondary analysis of the CREDENCE study and the SGLT2i cardiovascular outcome study found that SGLT2i can reduce cardiovascular and renal events in patients with type 2 diabetes with an eGFR as low as 30 ml min-1 (1.732)-1, even independently of the hypoglycemic effect [10]. SGLT2i has the functions of inhibiting glucose reabsorption, reducing body weight, lowering blood pressure, and reducing renal interstitial pressure. SGLT2i can also reduce oxidative stress in the kidney, reduce angiotensinogen, and reduce the activity of the hemoprotein-containing protein 3 inflammatory complexes [11], these results support the renoprotective effect of SGLT2i independent of hypoglycemia.
In the secondary endpoint of the LEADER study (liraglutide cardiovascular outcome study), it was found that liraglutide can reduce the risk of new or worsening nephropathy in patients with type 2 diabetes by 22%, with an HR of 0.78 and a 95% CI of 0.66~0.93, P=0.007[12], and SUSTAIN-6 (semaglutide cardiovascular safety study) suggested that semaglutide reduced the risk of new or worsening DKD in patients with type 2 diabetes by 36%[13]. However, the primary endpoint of the above studies is cardiovascular events, and renal events are secondary endpoints, and the level of evidence is low. Therefore, in the 2020 ADA guidelines, the level of evidence related to GLP-1RA has not changed, and the benefit of GLP-1RA on DKD is also more scientifically described as "possibly reducing urinary protein", level of evidence C. At present, research on the definite therapeutic effect of GLP-1RA on DKD is underway, and it is expected that the FLOW trial of semaglutide will bring new information [14].
3. Use of ACEI or ARB
The 2019 guidelines recommend that for diabetic patients with normal blood pressure, normal UACR (<30 mg/g), and normal eGFR, the use of ACE inhibitors or ARBs for the primary prevention of chronic kidney disease is not recommended (evidence level B) [2].
The recommendations in the 2020 ADA guidelines are the same, but the level of evidence is upgraded to A[1].
ACEI or ARB is the preferred antihypertensive drugs for patients with diabetes mellitus and hypertension, eGFR<60 ml·min-1·(1.732)-1 and/or UACR≥300 mg/g, and the above applications have been proven to delay the progression of CKD[ 15]. As for whether blood pressure, UACR (<30 mg/g), and eGFR are normal in diabetic patients, whether to use ACEI or ARB for the primary prevention of CKD, the 2020 ADA guidelines propose that it is not recommended, and the level of evidence has been upgraded from B to A. The update is based on the following studies. In a study of type 1 diabetic patients without albuminuria or hypertension, ACE inhibitors or ARBs failed to prevent the development of diabetic glomerular disease assessed by renal biopsy [16]. This conclusion was further confirmed in another similar study in patients with type 2 diabetes [17]. The results of the above two long-term double-blind studies showed that in patients with type 1 and type 2 diabetes with normal blood pressure, normal UACR (<30 mg/g) and normal eGFR, ACEI or ARB had no renoprotective effect.
4. Added recommendations to focus on acute kidney injury
The 2020 guidelines add a new recommendation: in the absence of volume depletion, do not discontinue the use of renin-angiotensin system blockers due to mild increases in serum creatinine (<30%) (evidence level B) [1].
Acute kidney injury (AKI) is generally diagnosed by a short-term sustained increase in serum creatinine of 50% or more, which reflects a rapid decrease in eGFR [18]. Diabetic patients are at higher risk of AKI than non-diabetic patients [19]. Because AKI is associated with an increased risk of CKD progression and other adverse health outcomes, timely recognition and treatment of AKI are important. Risk factors for AKI include pre-existing CKD, use of drugs that cause kidney damage (such as nonsteroidal anti-inflammatory drugs), and use of drugs that alter renal blood flow and intrarenal hemodynamics. In particular, many antihypertensive drugs (eg, diuretics, ACE inhibitors, and ARBs) can reduce blood volume, renal blood flow, and/or glomerular filtration. Some scholars are concerned that SGLT2i may promote AKI by reducing blood volume, especially when combined with diuretics or other drugs that reduce glomerular filtration.
However, in the SGLT2i cardiovascular safety study, patients with normal or poor renal function [15] did not find that the application of SGLT2i increased the incidence of AKI compared with the placebo group. Analysis of the ACCORD-BP study showed that patients randomized to intensive antihypertensive therapy with a 30% increase in serum creatinine did not experience any increase in mortality or progression of renal disease [20, 21, 22]. Furthermore, none of the various biomarkers of AKI was significantly increased in patients with increased serum creatinine [22]. Therefore, when using renin-angiotensin system blockers, a small increase in serum creatinine (within 30% above baseline level) should not be confused with AKI [23]. Therefore, in the 2020 ADA guidelines, a special new recommendation is not to stop the use of ACE inhibitors and ARBs due to mild increases in serum creatinine (<30%) in the absence of volume depletion (evidence level B). This recommendation may also have certain reference significance for whether to continue using SGLT2i when encountering a slight increase in serum creatinine.
6. Nutrition
In the 2020 guidelines, for non-dialysis-dependent patients with diabetes mellitus and CKD, a low-protein diet is not recommended to delay the progress of DKD. The recommended dietary protein intake is about 0.8 g/kg body weight per day, and the level of evidence is raised from B to A[1]. This is because studies have confirmed that dietary protein intake below 0.8 g/kg per day does not affect glycemic control, cardiovascular risk, or progression of kidney disease [24]. For dialysis patients, malnutrition is the main problem [25], so in the 2020 guidelines, the reasons why dialysis patients should consider a higher level of dietary protein intake were supplemented.
7. Research progress of DKD therapeutic drugs
Currently, many studies are underway on the treatment of DKD, such as mineralocorticoid receptor antagonists, transforming growth factor-β inhibitors, glycation end product receptor antagonists, phosphodiesterase inhibitors, serotonin 2a receptor antagonists, traditional Chinese medicine and stem cells are also in the clinical research stage. The following is a brief introduction to the recently published DKD clinical research.
SONAR is a double-blind, randomized, placebo-controlled trial of the endothelin A receptor antagonist atrasentan. The results of the study were published in The Lancet in 2019 [26]. The inclusion criteria of the study were type 2 diabetic patients with persistent massive proteinuria despite the use of renin-angiotensin system inhibitors. Responder status was determined based on changes in proteinuria during open-label treatment. All subjects included in the SONAR study were divided into a response group (reduction of proteinuria >30% within 6 weeks of atrasentan application) and a non-response group, and the response group was randomly assigned to the atrasentan group (1 325 cases, 0.75 mg/d) or placebo group (1 323 cases), the median follow-up was 2.2 years (interquartile range, 1.4-2.9), and the main composite endpoint was doubling of serum creatinine, end-stage renal disease or renal death. The results of the study showed that the incidence rate of the two primary endpoints was 79 cases (6.0%) in the atrasentan group and 105 cases (7.9%) in the placebo group, HR was 0.65, 95% CI was 0.49-0.88, P=0.004 7. However, compared with placebo, atrasentan was more prone to fluid retention, but the rate of hospitalization for heart failure was not significantly increased in the atrasentan group, suggesting that endothelin receptor antagonists have a role in delaying the progression of renal disease in patients with DKD.
The PERL study is a study conducted on T1DM patients to evaluate whether allopurinol can reduce serum uric acid (SUA) to slow down the progression of DKD [27], which was released at the 2019 American Nephrology Annual Meeting test results. This double-blind, placebo-controlled, multicenter trial enrolled 530 patients with T1DM, whose eGFR was 40.0-99.9 ml min-1 (1.732)-1, serum uric acid ≥ 4.5 mg/dl, and trace To massive proteinuria (79.1%) or normal proteinuria with annual eGFR decline ≥ 3 ml·min-1·(1.732)-1, randomly divided into allopurinol group (n=267) or placebo group (n=263 ). The primary endpoint was a change in baseline-adjusted GFR level. After 3 years of treatment, the results showed that although allopurinol effectively lowered serum uric acid, there was no statistically significant difference in the decline in glomerular filtration rate between the two groups. PERL is the largest CKD trial on allopurinol treatment so far. In T1DM patients with mild to moderate GFR decline and serum uric acid higher than the median level, no significant benefit of serum uric acid reduction on renal disease progression was found.
The VITAL-DKD study is a study published in JAMA in 2019 [28]. The subjects of the study were 1 312 patients with type 2 diabetes with an average eGFR of 85 ml min-1 (1.732)-1. and omega-3 fatty acids can delay eGFR decline. After 5 years of research, the conclusion is that in patients with type 2 diabetes, routine supplementation of vitamin D or omega-3 fatty acids does not reduce the incidence of chronic kidney disease or delay the decline in eGFR.
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