How to prevent and delay the progression of chronic kidney disease in diabetic patients?

*Only for medical professionals to read for reference.
Comprehensively control the treatment and management of diabetic nephropathy.

Chronic kidney disease (CKD) is an important comorbidity of diabetes.

The Kidney Disease Prognosis Quality Initiative (KDOQI) of the American Kidney Foundation defines CKD as the presence of kidney damage or decline in renal function for ≥ 3 months.

CKD caused by diabetes is called diabetic nephropathy (DKD), which is one of the three main microvascular complications of diabetes.

DKD can progress to end-stage renal disease (ESRD) and requires renal replacement therapy.
DKD has gradually become the primary cause of CKD and ESRD.

Studies have shown that CKD significantly increases the risk of cardiovascular events, especially in diabetic patients, cardiovascular events usually occur earlier than ESRD.

Figure 1 Chronic kidney disease is closely related to other complications of diabetes.
As many as 30% of patients with type 1 diabetes (T1D) develop albuminuria 15 years after diagnosis, and nearly half develop DKD.

About 40% of patients with type 2 diabetes (T2D) have proteinuria 10 years after diagnosis.

This article provides the latest recommendations for the assessment and management of DKD to help patients prevent or slow the progression of DKD.

The classification of diabetic nephropathy CKD is defined as a persistent increase in urinary albumin excretion (albuminuria) and a decrease in the estimated glomerular filtration rate (GFR), or the presence of signs of progressive renal damage.

The patient's eGFR is the basis for CKD staging (1, 2, 3a, 3b, 4, or 5) (Table 1), and the degree of combined albuminuria (A1, A2, or A3) can indicate prognosis.

Table 1 How to determine the prognosis of CKD based on estimated GFR and albuminuria.
Green, low risk (if there are no other markers of kidney disease); yellow, moderately increased risk; orange, high risk; red, extremely high risk.
It is worth noting that, The degree of albuminuria may be independent of the progression of DKD.

At present, it is not clear what causes the progressive decrease in eGFR in DKD patients without albuminuria.

The recommended DKD screening program is to screen albuminuria every year in all T2D cases, T1D cases with a course of ≥5 years, and patients with diabetes and hypertension, to monitor whether there is an increase in creatinine level and a decrease in eGFR.

In order to diagnose DKD, the urine albumin/creatinine ratio (UACR) must be increased in ≥ 2 of the 3 urine specimens collected within 3 to 6 months.

In addition to kidney damage, exercise, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension within 24 hours before specimen collection can increase UACR.

The UACR classification is as follows: normal urine protein excretion: UACR <30 mg albumin/1g creatinine; increased urine protein excretion: UACR ≥30 mg/g; moderate increase in urine protein: UACR 30-300 mg/g, indicating potential kidney disease; urine Severe increase in protein:> 300 mg/g, usually followed by a gradual decrease in eGFR.

Without intervention, the average time for patients to progress to ESRD is 6 to 7 years (equivalent in T1D and T2D patients).

Clinical features of DKD DKD is usually a clinical diagnosis, seen in patients with long-term diabetes, albuminuria, retinopathy, or reduced eGFR without other major causes of kidney damage.

When T1D patients are diagnosed with DKD, there are often signs of retinopathy and neuropathy.

Therefore, the presence of retinopathy suggests that diabetes is a possible cause of CKD.

The presence of microvascular disease in T2D/DKD patients is not easy to predict.

In T2D patients without retinopathy, consideration of CKD causes other than DKD suggests that the cause of CKD is an underlying disease other than diabetes.

It is characterized by a rapid increase in albuminuria or a decrease in eGFR; urine sediment includes red blood cells or white blood cells; and nephrotic syndrome.

With the increasing prevalence of diabetes, patients with decreased eGFR are often diagnosed with DKD even if they are not accompanied by albuminuria, which emphasizes the importance of routine monitoring of eGFR in diabetic patients.

When calculating eGFR based on serum creatinine, the Chronic Kidney Disease Epidemiology Collaborative Group formula is preferred: When eGFR<60mL/min/1.
73m2, the prevalence of CKD-related complications increases, and it is necessary to carry out complication screening.

Management of DKD ■ Diet adjustment of high-quality low-protein diet: Excessive protein intake can aggravate proteinuria in patients with DKD, accelerate deterioration of renal function, and increase CVD mortality.

Therefore, for patients who have not undergone dialysis, the recommended daily dietary protein intake is 0.
8 g/kg body weight.

Dialysis patients may require higher protein intake to compensate for the loss of muscle mass caused by dialysis-related protein energy consumption.

Low-sodium diet: It has been proven that low sodium intake in CKD patients can lower blood pressure, thereby slowing the progression of kidney disease and reducing the risk of CVD.

The recommended dietary sodium intake for CKD patients is 1500-3000 mg/d.

Low potassium diet: Hyperkalemia is a serious complication of CKD.

For ESRD patients with serum potassium> 5.
5 mmol/L, a low-potassium diet is recommended.

■ Blood pressure control The prevention and treatment of hypertension is essential for slowing down the progression of CKD and reducing cardiovascular risk.

Blood pressure should be measured at each outpatient follow-up.

In addition to lifestyle changes, medications may be required to achieve the target blood pressure.

The American Diabetes Association recommends that the blood pressure target value for patients with hypertension and diabetes is ≤140/90mmHg, but at the same time pointed out that a lower blood pressure target value may be more suitable for DKD patients.

The American College of Cardiology recommends that the blood pressure target value for CKD hypertensive patients is ≤130/80mmHg※ Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) have renal protection and are recommended as First-line drugs for patients with diabetes, hypertension and eGFR<60mL/min/1.
73m2 and UACR>300 mg/g.

It can also be used when the UACR is 30~299mg/g.

Studies have shown that ACEI/ARB can slow down the progression of kidney disease in patients with DKD, and ACEI and ARB have similar preventive effects.

The combination of ACEI+ARB has no additional benefits and increases the risk of adverse events such as hyperkalemia and acute kidney injury.

In diabetic patients without hypertension, there is no evidence that ACEI/ARB treatment can prevent CKD.

In addition, women of childbearing age should use ACEI/ARB with caution, and take reliable contraceptive measures if taking them.

※ Diuretics thiazides and loop diuretics can enhance the antihypertensive effect of ACEI/ARB.

The KDOQI guidelines recommend that in patients who need two drugs to control blood pressure, diuretics should be considered in combination with ACEI/ARB.

If eGFR<30mL/min/1.
73m2, loop diuretics are preferred.

※ Non-dihydropyridine calcium channel blockers (CCB), the non-dihydropyridine CCB diltiazem and verapamil, are better than amlodipine and nifedipine in slowing down the progression of kidney disease due to their ability to reduce proteinuria Dihydropyridine CCB.

However, the anti-proteinuria effect of non-dihydropyridine CCB is not as strong as that of ACEI/ARB, and it does not enhance the effect of ACEI/ARB when used in combination.

For patients who cannot tolerate ACEI/ARB, non-dihydropyridine CCB can be used as an alternative medicine.

※ The mineralocorticoid receptor antagonist spironolactone and eplerenone combined with ACEI/ARB have been confirmed in short-term studies to reduce albuminuria.

■ Blood sugar control Strict control of blood sugar in diabetic patients can delay the occurrence of albuminuria and slow down the progression and decline of eGFR.

The target glycosylated hemoglobin (HbA1c) should be <7% to prevent or slow down the progression of DKD.

Figure 2 The relationship between blood glucose control and the incidence of CKD The risk of albumin excretion rate> 30 mg/d in T1D adult patients without CKD in the FinnDiane study (orange dots) and the distribution of blood glucose control in T1D patients with microalbuminuria (Histogram) Figure).

However, as blood glucose control becomes more intensive, patients with DKD are at increased risk of hypoglycemic events and increased mortality.

In light of these findings, some patients with DKD and severe comorbidities, ESRD, or limited life expectancy may need to set the HbA1c target at 8%.

■ Adjustment of hypoglycemic drugs In patients with stage 3~5 DKD, due to the significant decrease in creatinine clearance, some hypoglycemic drugs may need to be adjusted or discontinued.

※ Patients with sulfonylurea DKD should avoid using first-generation sulfonylurea drugs.

Glipizide and gliclazide are the first choice among second-generation sulfonylurea drugs because they do not increase the risk of hypoglycemia in patients with DKD, although patients taking these drugs still need to monitor blood glucose closely.

※ In 2016, the recommendation of metformin for the use of metformin for DKD patients was changed-the use should be based on the eGFR level.

Metformin can be safely used in patients with eGFR<60mL/min/1.
73m2 and undergoing close monitoring.

However, if eGFR<45mL/min/1.
73m2, metformin therapy should not be initiated.

※ In addition to the effects of hypoglycemic drugs that have a direct effect on the kidneys, several oral hypoglycemic drugs have a direct protective effect on the kidneys.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) can reduce albuminuria and slow down the decrease of eGFR, and has nothing to do with blood sugar control.

In addition, SGLT2i has also been shown to have cardiovascular benefits for DKD patients.

Glucagon-like peptide 1 receptor agonist (GLP-1RA) has been shown to delay and reduce the progression of DKD.

In addition, similar to SGLT2i, GLP-1RA shows cardiovascular benefits in DKD patients.

■ Dyslipidemia and DKD Due to the increased risk of CVD in patients with DKD, it is recommended that other intervenable risk factors, such as dyslipidemia, should be addressed in these patients.

Patients with diabetes and stage 1 to 4 DKD should be treated with high-intensity statins or combined with ezetimibe.

If the patient is taking statins and intends to initiate dialysis, he should weigh the benefits and risks and discuss with the patient whether to continue the medication.

Statins are not recommended for dialysis patients unless there are specific cardiovascular indications.

Compared with patients who did not receive dialysis treatment, the efficacy of statins in dialysis patients was significantly reduced.

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