New Progress in Diagnosis And Treatment Of Diabetic Nephropathy

Diabetic nephropathy, a clinical syndrome characterized by persistent proteinuria and progressive decline in renal function, is the leading cause of end-stage renal disease worldwide. Multifactorial interventions such as renin-angiotensin-aldosterone system inhibitors, control of blood pressure and blood sugar, appropriate exercise, and smoking cessation can significantly improve the prognosis of patients with diabetic nephropathy. At present, many new drugs for the prevention and treatment of diabetic nephropathy are being used in clinical practice, which can better protect kidney function and improve the prognosis of patients, but further research is still needed to evaluate the long-term therapeutic effect of these new drugs. The article focuses on the diagnostic approach to diabetic nephropathy and current therapeutic interventions.

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Diabetic nephropathy (DN) is a common and serious complication of diabetes mellitus (DM) and a common cause of the end-stage renal disease (ESRD), which can increase the mortality rate of DN patients. In developed countries, DN caused by type 2 diabetes mellitus (T2DM) is the main cause of ESRD. In developing countries, the incidence of DN is increasing year by year, and it has become one of the main causes of ESRD.

Although the current treatment methods for DN can alleviate the condition of patients to a certain extent, they still cannot completely prevent the progression of DN to ESRD. Therefore, timely diagnosis and standardized treatment are crucial.

1 diagnosis

1.1 Diagnosis of DN 

DN is one of the most important microvascular lesions in DM patients. Traditionally, DN is a clinical syndrome characterized by persistent proteinuria and progressive decline in renal function, with typical glomerular pathological changes. But gradually found that the clinical manifestations and course of DN are diverse. The term diabetic kidney disease (DKD) is now commonly used to describe diabetic patients with proteinuria or decreased renal function.

In 2007, the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines formulated by the Kidney Foundation (NKF) suggested that DKD be used instead of DN. In 2014, the American Diabetes Association (ADA) and NKF reached a consensus that DKD refers to chronic kidney disease caused by DM. DKD is usually a clinical diagnosis based on proteinuria and decreased estimated glomerular filtration rate (eGFR), and it can be said that the diagnosis of DKD usually refers to persistent proteinuria or decreased eGFR in the context of DM, deviating from specific renal Pathological connotation.

DN is rare within 10 years after T1DM is diagnosed, and 95% of T1DM patients with DN are also complicated with diabetic retinopathy. 10 years after diagnosis, proteinuria and diabetic retinopathy can be diagnosed as DN, but it develops after 25 to 30 years after diagnosis. The possibility of being a DN is low [1].

The history of T2DM is not helpful for the diagnosis of DN. Most patients cannot accurately define the start time of DN, and only 60%-65% of patients are diagnosed with diabetic retinopathy at the same time[1]. The main pathological changes of DN are glomerular lesions, including glomerular basement membrane thickening, mesangial widening, nodular sclerosis (K-W nodules), and advanced diabetic glomerulosclerosis.

In addition, interstitial fibrosis and tubular atrophy (IFTA), interstitial fibrosis, arteriolar hyalinosis, and arteriosclerosis are frequently present.

1.2 Diagnosis of normal proteinuric 

DN (nonproteinuric DN, NP-DN) In classic DN, proteinuria first appears, followed by a progressive decline in renal function. However, a subset of DN patients presents with decreased renal function and vascular complications without proteinuria, termed NPDN [2]. In 1994, Tsalamandris et al reported for the first time that DM patients did not have proteinuria, but progressive renal function decline.

Recent studies have shown that the incidence of proteinuria in DM and the decline in eGFR have an opposite trend, that is to say, the incidence of microalbuminuria has decreased, but the incidence of eGFR decline has increased [3]. This suggests that the onset and progression of renal decline may be independent of the development of proteinuria. In 2019, the joint statement of the Italian Society of Diabetes and the Italian Society of Nephrology pointed out that in addition to the classic proteinuric phenotype, DN also has two new proteinuric-independent phenotypes, namely "non-proteinuric renal damage" and "progressive renal damage". Decline", suggesting that the progression of DN to ESRD may occur through two different pathways, namely proteinuria and non-proteinuria[4].

2 treatment

2.1 Lifestyle intervention 

Lifestyle intervention is an important strategy to improve the prognosis of DN, including weight loss, the appropriate increase in physical activity, a low-salt and low-fat diet, and smoking cessation. Patients are encouraged to actively participate in self-management. The KDIGO guidelines recommend that the diet should be rich in vegetables, fruits, whole grains, fiber, legumes, plant-based protein, unsaturated fat, and nuts, with less intake of processed meat, refined carbohydrates, and sugary drinks; at least 150 minutes per week moderate-intensity physical activity, or reach a level that is compatible with its own cardiovascular and physical tolerance [5].

2.2 Control blood sugar 

Reasonable hypoglycemia can not only control blood sugar levels well but also delay the occurrence and development of proteinuria to a certain extent and protect renal function. DCCT, UKPDS, ADVANCE, and other studies have found that intensive hypoglycemia can reduce urinary protein, delay eGFR decline, and reduce the risk of microvascular complications including DN.

In contrast, the ACCORD study was terminated because it suggested a significantly higher risk of death in the intensive hypoglycemic group. The hypoglycemia should be lowered reasonably according to the individual condition of the patient to avoid the occurrence of hypoglycemia. The 2019 ADA recommends that the glycated hemoglobin (HbA1c) of non-pregnant adults should be <7%, and it can be used appropriately for patients with T2DM who have a short course of DM, only receive lifestyle intervention or metformin treatment, have a long life expectancy, or have no obvious cardiovascular disease A more stringent HbA1c target, such as 6.5%.

The 2020 KDIGO guidelines recommend that the individualized HbA1c target range for non-dialysis DM patients with CKD be 6.5%-8%[5]. For DN with elevated creatinine, when using oral hypoglycemic drugs, attention should be paid to adjusting the type and dose of drugs according to eGFR. The late stage of DM is often accompanied by damage to other organs. Care should be taken when choosing hypoglycemic drugs to avoid affecting other organ functions. Thiazolidinediones are contraindicated in patients with or at risk of heart failure. Currently more effective new hypoglycemic drugs include sodium-glucose transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 (glucagon-like peptide-1, GLP-1) receptor agonists, dipeptidyl peptide Enzyme-4 (dipeptidyl peptidase-4, DPP-4) inhibitors, etc.

2.2.1 SGLT2i 

SGLT2i is a new oral hypoglycemic drug that inhibits SGLT2 in the proximal renal tubule, blocks the reabsorption of sodium ions and glucose by the proximal tubule, increases urinary glucose excretion, and lowers blood sugar. Glucose reabsorption by proximal tubules is linearly related to blood glucose levels and glucose filtered by the kidney, so SGLT2i does not cause hypoglycemia, but patients with low eGFR may experience insufficient hypoglycemic effects. The renal protection mechanism of SGLT2i does not depend on blood sugar control, and is independent of cardiac benefits; SGLT2i constricts afferent arterioles through tubule feedback, reduces glomerular internal pressure, and relieves hyperfiltration; at the same time, it can also reduce vascular resistance, Weight loss and biomarkers of proximal tubular injury were reduced, thereby reducing proteinuria and delaying the progression of kidney disease.

EMPA-REG (empagliflozin) and DAPA-CKD (dapagliflozin) studies suggest that SGLT2i can delay the progression of kidney disease, improve renal outcomes, and have cardiac benefits in both DM and non-DM populations. The DECLARE-TIMI 58 study proved that dapagliflozin delayed the progression of kidney disease in patients with T2DM, regardless of whether it was complicated with coronary atherosclerotic heart disease [6]; and decreased the urinary albumin-to-creatinine ratio (UACR ) level and ESRD risk [7]. The CREDENCE study also showed that the canagliflozin group had a 30% lower risk of ESRD composite events, doubling of creatinine, and death from renal or cardiovascular causes compared with the placebo group [8].

2.2.2 GLP-1 receptor agonists 

GLP-1 receptor agonists (such as exenatide, liraglutide, and lixisenatide) exert their effects by stimulating the GLP-1 receptor. GLP-1 is an endocrine hormone secreted by L cells in the lower intestinal tract, which promotes the secretion of insulin by pancreatic islet cells, inhibits the secretion of glucagon, delays gastric emptying, and induces satiety. GLP-1 can inhibit the inflammatory effect of angiotensin Ⅱ, inhibit oxidative stress and proteinuria, and improve proteinuria, glomerular hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion in animal models [9]. The LEADER study found that liraglutide can reduce the risk of new-onset persistent massive proteinuria, doubling of creatinine, ESRD, and death from renal causes while benefiting from cardiovascular diseases [10-11].

The SUSTAIN-6 study also confirmed that semaglutide reduces the risk of new or worsening kidney disease in patients with T2DM [12]. The AWARD-7 study found that in patients with T2DM and moderate to severe CKD, dulaglutide once a week has a similar hypoglycemic effect to insulin glargine, but the decline in eGFR is less, indicating that dulaglutide is a safe and effective in patients with severe CKD [13]. The REWIND study confirmed that dulaglutide can reduce the risk of renal composite endpoint events (new massive proteinuria, sustained decline in eGFR ≥ 30%, and renal replacement therapy), suggesting that it has renal benefits while lowering blood sugar [14-15]. A recent meta-analysis also showed that GLP-1 receptor agonists can reduce the risk of the renal composite outcome by 17% (HR 0.83, 95% CI 0.78-0.89) [16].

2.2.3 DPP-4 inhibitors 

DPP-4 inhibitors (such as sitagliptin, linagliptin, saxagliptin, and alogliptin, etc.) increase the level of GLP-1 by inhibiting DPP-4, thereby Lower blood sugar. Linagliptin is mainly excreted through the enterohepatic circulation and is not affected by renal function. Other DPP-4 inhibitors are mainly excreted by the kidneys, and the dosage should be reduced in patients with moderate to severe renal insufficiency[4]. DPP-4 inhibitors also inhibited high glucose-induced transforming growth factor (TGF) β1 in proximal tubular cells, leading to a decrease in downstream Smad2 phosphorylation, thereby ameliorating renal fibrosis [17].

The SAVOR-TIMI 53 study found that saxagliptin can significantly reduce proteinuria in patients with T2DM, and its effect on reducing proteinuria is independent of hypoglycemic effect, and the changes in eGFR, time to start dialysis, kidney transplantation, and other renal outcomes are different than those in the placebo group No statistical significance [18-19]. The MARLINA study divided T2DM patients with high cardiovascular and renal risks into linagliptin or placebo treatment and found that linagliptin had no significant difference in cardiovascular and renal outcomes compared with the placebo group[20]. There is still insufficient evidence-based medical evidence on the renoprotective effect of these drugs.

2.3 Control of blood pressure 

Effective control of blood pressure can reduce the proteinuria level in patients with DN, delay the deterioration of renal function, and reduce the risk of cardiovascular complications[1]. In 2019, the ADA suggested that for patients with diabetes mellitus and hypertension with high cardiovascular risk, the blood pressure control target should be 130/80 mmHg (1 mmHg=0.133 kPa). The 2021 "Chinese Guidelines for Clinical Diagnosis and Treatment of Diabetic Kidney Diseases" recommends that blood pressure be <140/90 mmHg for patients over 65 years old, and <130/80 mmHg for patients under 65 years old, and blood pressure should be controlled at ≤130 when 24-hour urine albumin is ≥30 mg /80mmHg.

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) drugs are recommended for non-pregnant women to reduce blood pressure, reduce proteinuria in patients with DN, and delay renal function progression. IRMA-2 (Irbesa Tan), INNOVATION (telmisartan), IDNT (irbesartan), RENAAL (losartan) and other classic studies can be confirmed. At the same time, it can reduce the risk of cardiovascular events in patients with DN. ACEI and ARB drugs are the same in reducing proteinuria, delaying the progress of renal function and price. Renal function, potassium ions, and blood pressure should be monitored within 2 to 4 weeks of initiation or adjustment [5]. The combined use of ACEI and ARB is not associated with improved prognosis, but adverse events such as hypotension, syncope, and renal damage increase, so simultaneous use are not recommended.

Likewise, the concomitant use of direct renin inhibitors with ACE inhibitors and ARBs is not recommended due to the high risk of cardiovascular and renal events. The degree of proteinuria in the DN population is associated with the risk of renal failure, and ACEI and ARB drugs can reduce the degree of proteinuria, so KDIGO guidelines believe that ACEI and ARB treatment may be beneficial for DN patients without hypertension. However, existing data show that, for patients with neither proteinuria nor hypertension, ACEI and ARB treatment have no significant benefit [5].

Calcium channel blockers are a class of antihypertensive drugs that have no absolute renal contraindications. ACEI and ARB can be used in combination with patients with uncontrolled hypertension. Based on the results of experimental studies and small-scale clinical trials, diltiazem, a non-dihydropyridine calcium channel blocker, can reduce proteinuria and slow down the progression of DN[1].

Mineralocorticoid receptor antagonists (mineralocorticoid receptor antagonists, MRA) include spironolactone, eplerenone, and finerenone (third generation). Under physiological conditions, mineralocorticoids bind to receptors to regulate blood pressure and maintain the balance of water and electrolytes in the human body. However, under abnormally elevated plasma aldosterone levels or other pathological conditions, mineralocorticoid receptors are overactivated, prompting the expression of pro-inflammatory and pro-fibrotic gene transcription to increase in various cells, thereby causing inflammation and fibrosis.

Many studies have shown that the combination of MRA and ACEI or ARB can effectively control blood pressure, and reduce proteinuria and the incidence of cardiovascular events, but hyperkalemia should be avoided during application. Compared with spironolactone and eplerenone, the risk of hyperkalemia in the third-generation MRA finerenone is significantly lower, and the distribution in the heart and kidney is balanced, which can reduce the risk of kidney disease progression and cardiovascular events in patients with type 2 DM and CKD [21].

2.4 Vitamin D (vitamin D, VD) 

VD can inhibit the damage of podocytes, maintain the normal shape of podocytes, and have a negative regulatory effect on the renin-angiotensin (RAS) system. VD has strong anti-proteinuria and podocyte Protective effects. The biological effect of VD is achieved by binding to the VD receptor (vitamin D receptor, VDR). VDR is expressed in podocytes, and the VD/VDR signaling pathway has various renal protective effects such as anti-proteinuria, anti-fibrosis, anti-inflammation, regulation of renal immunity, and prevention of podocyte injury in DN patients. Paricalcitol is a vitamin D analogue. A systematic review of paricalcitol in the treatment of DN suggested that it can reduce urinary protein levels, but there is no convincing evidence that it can protect renal function [22].

2.5 Sulodexide 

Sulodexide is a highly purified dextran mixture that can reduce TGFβ1 and proteinuria levels in animal models of DM glomerulosclerosis [23]. However, the results of a large-scale randomized clinical trial (Sun-MACRO study) showed that sulodexide failed to show improvement in proteinuria and renal function [24]. A recent meta-analysis showed that sulodexide significantly reduced urinary protein excretion and had renoprotective effects in patients with DM, microalbuminuria, and macroalbuminuria [25].

2.6 Pentoxifylline (PTF) 

PTF delays the progression of renal fibrosis by inhibiting cell proliferation, reducing renal inflammation, and reducing the accumulation of extracellular matrix. Studies have shown that ACEI and ARB combined with PTF can alleviate the reduction of eGFR and reduce urinary albumin excretion [26].

2.7 Endothelin receptor antagonists 

Endothelin receptor antagonists can reduce proteinuria and blood pressure, but can also cause sodium ion retention. Avosentan, a non-selective endothelin receptor antagonist, can reduce urinary protein, but its high-dose use in the treatment of DM with CKD was discontinued due to the increased incidence of heart failure [27]. However, low-dose application of the selective endothelin receptor antagonist atrasentan can reduce urinary protein without causing significant fluid retention [28]. The SONAR study found that atrasentan can reduce the risk of renal events in patients with DM and CKD, indicating that selective endothelin receptor antagonists have a potential role in protecting the renal function of T2DM patients with high ESRD risk[29].

2.8 Bardoxolone methyl 

Bardoxolone methyl reduces oxidative stress products by activating Nrf2 and inhibiting the NF-κB pathway. Short-term studies have shown that it can increase eGFR in patients with T2DM but do not affect proteinuria[30]. However, the BEACON study found that bardoxolone methyl could not reduce the incidence of ESRD or the risk of cardiovascular death, but significantly increased cardiovascular events, so the study was terminated due to safety concerns [31]. Further analysis found that bardoxolone methyl can increase eGFR and UACR at the same time. Compared with the placebo group, bardoxolone methyl group UACR increased significantly; after 6 months, the increase of UACR was weakened; Regression analysis of variables identified baseline eGFR and eGFR over time as the main factors associated with changes in UACR, contrary to the traditional view that increased proteinuria usually reflects renal injury [32].

2.9 Pyridoxamine 

Pyridoxamine belongs to the vitamin B6 family. It can scavenge free radicals and carbonyl products, and block the synthesis of glycosylation products. A randomized double-blind placebo-controlled trial including 238 patients with DN confirmed that eGFR was significantly lower in patients taking vitamin B (P=0.02) [33]. Its protective effect on DN still needs to be confirmed by larger randomized controlled trials.

2.10 Hypoxia-inducible factor-proline hydroxylase inhibitor (hypoxia-inducible factor-proline hydroxylase inhibitor, HIF-PHI) 

DM tissue due to hypoxia-inducible factor-1 (hypoxia-inducible factor-1, HIF-1) Hypoxia due to insufficient activation and impaired adaptive response to hypoxia are important pathogenesis of DM and its complications. Therefore, increasing HIF-1 signaling may be a promising therapy for DM and its complications. Recent DM animal studies have shown that HIF-PHI can prevent and treat DN [34].

On the other hand, compared with renal anemia caused by other etiologies, DN anemia occurs earlier, has a higher incidence, is more severe, and is more difficult to correct. Insufficient EPO in DN anemia is more prominent in resistance, iron deficiency, and micro-inflammation, and is also related to the use of hypoglycemic drugs and autoimmune dysfunction. HIF-PHI drugs represented by roxadustat are convenient, safe, and effective to take orally, and can improve iron metabolism, and the curative effect is not affected by the micro-inflammatory state. Therefore, it is recommended that HIF-PHI drugs be the first choice in the treatment of DN anemia[35 ].

3 Conclusion

DN is a common and serious complication of DM, which brings great challenges to clinical care and is also the main cause of ESRD. DN is also closely related to cardiovascular events and increases the cardiovascular mortality and all-cause mortality of patients. Its clinical presentation and prognosis may vary, such as NPDN. The severity of proteinuria, however, remains an important marker of a higher risk of progression. Comprehensive management is advocated for DN, which combines the factors that reduce cardiovascular risk and slow down the progression of kidney disease, namely control of blood sugar and blood pressure, inhibition of the renin-angiotensin-aldosterone system, proper exercise, and smoking cessation. An effective combination of these interventions can reduce the risk of DN progression and other microvascular complications, cardiovascular events, and mortality. An individualized treatment plan should be formulated based on the actual situation of the patient.

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