How To Prevent And Delay The Progression Of Chronic Kidney Disease in Diabetic Patients?

Chronic kidney disease (CKD) is an important complication of diabetes. The Kidney Disease Outcome Quality Initiative (KDOQI) of the American Kidney Foundation defines CKD as the presence of renal impairment or decreased renal function for ≥3 months.

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CKD caused by diabetes is called diabetic kidney disease (DKD), which is one of the three major microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring 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, and cardiovascular events usually occur earlier than ESRD.

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.

Classification of diabetic nephropathy

CKD is defined as persistently elevated urinary albumin excretion (albuminuria) and decreased estimated glomerular filtration rate (GFR), or the presence of signs of progressive renal impairment. The patient's eGFR is the basis for CKD stage (1, 2, 3a, 3b, 4, or 5), and the degree of combined albuminuria (A1, A2, or A3) can indicate the prognosis.

Green, low risk (if no other kidney disease markers); yellow, moderately increased risk; orange, high risk; red, very high risk

Notably, the degree of albuminuria may be independent of the progression of DKD. The factors underlying the progressive decline in eGFR in normoalbuminuric DKD patients are unclear.

Recommended DKD Screening Protocol

In all T2D cases, T1D cases with a disease duration of ≥ 5 years, and patients with diabetes and hypertension, screen for albuminuria every year and monitor for elevated creatinine levels and decreased eGFR.

In order to confirm the diagnosis of DKD, it is necessary to meet the requirement of elevated urinary albumin/creatinine ratio (UACR) in ≥ 2 of the 3 urine samples collected within 3 to 6 months. In addition to renal impairment, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can increase UACR. UACR is graded as follows:

• Normal urinary protein excretion: UACR<30 mg albumin/1g creatinine;

• Increased urinary protein excretion: UACR ≥30 mg/g;

• Moderate increase in urine protein: UACR 30-300 mg/g, indicating potential kidney disease;

• Severe increase in urinary protein: > 300 mg/g, usually followed by a gradual decline in eGFR. In the absence of intervention, the mean time to progression to ESRD was 6–7 years (comparable in T1D and T2D patients).

Clinical features of DKD

DKD is usually a clinical diagnosis seen in patients with long-standing diabetes, albuminuria, retinopathy, or reduced eGFR and no other major cause of renal impairment. Signs of retinopathy and neuropathy are often present at the time of diagnosis of DKD in T1D patients. Thus, the presence of retinopathy suggests diabetes is a possible etiology of CKD.

The presence of microvascular disease in T2D/DKD patients is less predictable. In T2D patients without retinopathy, the cause of CKD other than DKD was considered, suggesting that the etiology of CKD is an underlying disease other than diabetes. Characterized by rapidly increasing albuminuria or decreased eGFR; urinary sediment including red or white blood cells; and nephrotic syndrome.

With the increasing prevalence of diabetes, patients with decreased eGFR are often diagnosed with DKD even without albuminuria, emphasizing 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 complication screening is necessary.

Management of DKDs

■ Diet adjustment

High-quality low-protein diet: Excessive protein intake can aggravate proteinuria, accelerate renal function deterioration, and increase CVD mortality in DKD patients. Therefore, for patients not receiving dialysis, the recommended daily dietary protein intake is 0.8 g/kg body weight. Dialysis patients may require higher protein intakes to compensate for loss of muscle mass due to dialysis-related protein energy expenditure.

Low-sodium diet: Low sodium intake in CKD patients has been shown to reduce blood pressure, thereby slowing the progression of kidney disease and reducing CVD risk. 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 >5.5mmol/L, a low-potassium diet is recommended.

■ blood pressure control

Prevention and treatment of hypertension are essential to slow down the progression of CKD and reduce cardiovascular risk. Blood pressure should be measured at each clinic visit. In addition to lifestyle changes, drug therapy may be needed to achieve target blood pressure.

The American Diabetes Association recommends a blood pressure target value of ≤140/90mmHg for hypertensive patients with diabetes but also points 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 of hypertensive patients with CKD be ≤130/80mmHg

※ Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB)

It has a renal protective effect and is recommended as the first-line drug for patients with diabetes, hypertension, and eGFR<60ml 1.73m2="" and="" uacr="">300 mg/g. It can also be used when UACR is 30~299mg/g.

Studies have shown that ACEI/ARB can slow down the progression of kidney disease in DKD patients, and the preventive efficacy of ACEI and ARB is similar. The combination of ACEI+ARB has no additional benefit and increases the risk of adverse events, such as hyperkalemia and acute kidney injury.

In nonhypertensive diabetic patients, there is no evidence that ACEI/ARB therapy prevents CKD.

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

※ Diuretics

Thiazides and loop diuretics can enhance the antihypertensive effect of ACEI/ARB. The KDOQI guidelines recommend that diuretics should be considered in combination with ACEI/ARB in patients requiring two drugs for blood pressure control. If eGFR<30mL/min/1.73m2, loop diuretics are preferred.

※ Non-dihydropyridine calcium channel blockers (CCB)

Non-dihydropyridine CCBs diltiazem and verapamil, due to their proteinuria-reducing effects, are superior to dihydropyridine CCBs such as amlodipine and nifedipine in slowing down the progression of kidney disease. However, the antiproteinuric effect of non-dihydropyridine CCBs is not as strong as that of ACEI/ARB, and the combined use does not enhance the effect of ACEI/ARB.

For patients who cannot tolerate ACEI/ARB, non-dihydropyridine CCBs can be used as alternative drugs.

※ Mineralocorticoid receptor antagonist

Spironolactone and eplerenone combined with ACEI/ARB have been shown to reduce albuminuria in short-term studies.

■ Blood sugar control

Tight glycemic control in diabetic patients delays the onset of albuminuria and slows the progression and decline in eGFR. The target glycated hemoglobin (HbA1c) should be<7% to prevent or slow down the progression of DKD.

Risk of albumin excretion > 30 mg/d in adults with T1D without CKD in the FinnDiane study (orange dots) and distribution of glycemic control in T1D patients with microalbuminuria (histogram).

However, with more intensive glycemic control, DKD patients have an increased risk of hypoglycemic events and increased mortality. Given these findings, some patients with DKD and severe comorbidities, ESRD, or limited life expectancy may require an HbA1c target of 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.

※ Sulfonylureas

Patients with DKD should avoid the use of first-generation sulfonylureas. Glipizide and gliclazide are preferred among the second-generation sulfonylureas because they do not increase the risk of hypoglycemia in patients with DKD, although close monitoring of blood glucose is still required in patients taking these drugs.

※ Metformin

In 2016, the recommendations for the use of metformin in DKD patients changed - use should be based on eGFR levels. Metformin can be safely used in patients with eGFR<60mL/min/1.73m2 and is closely monitored. However, if eGFR<45mL/min/1.73m2, metformin treatment should not be initiated.

※ Hypoglycemic drugs that have a direct effect on the kidneys

In addition to their effects on blood glucose levels, several oral hypoglycemic drugs have direct renal protective effects.

• Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce albuminuria and slow the decline in eGFR independent of glycemic control. In addition, SGLT2i has also been shown to have cardiovascular benefits in DKD patients.

• Glucagon-like peptide 1 receptor agonists (GLP-1RA) have been shown to delay and reduce the progression of DKD. Furthermore, similar to SGLT2i, GLP-1RA showed cardiovascular benefits in DKD patients.

■ Dyslipidemia and DKD

Due to the increased risk of CVD in patients with DKD, addressing other modifiable risk factors, such as dyslipidemia, is recommended in these patients. Patients with diabetes and stage 1-4 DKD should be treated with high-intensity statins or combined with ezetimibe.

If a patient is taking a statin and intends to initiate dialysis, the decision to continue the medication should be discussed with the patient based on the balance of benefits and risks. Statins are not recommended for dialysis patients unless there are specific cardiovascular indications. The efficacy of statins was significantly reduced in patients on dialysis compared with those not receiving dialysis.

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