Overview: Diabetic Nephropathy
Diabetic nephropathy is an important cause of end-stage renal failure in approximately 30% to 40% of patients with diabetes. Current treatment relies on early diagnosis, glycemic control, and intensive blood pressure therapy with priority renin-angiotensin system blockers.
Over the past 20 years, this treatment strategy has somewhat altered the outcome of diabetic kidney disease. Despite improvements in the pathophysiology of diabetic nephropathy, there is still no effective treatment.
A review of the pathogenesis and treatment of diabetic nephropathy by Dr. Gallagher et al. from St. Helier Hospital, UK, was published in the January 2016 issue of Diabetes, Obesity and Metabolism.
I.
Epidemiology of diabetic nephropathy
Diabetes is one of the leading causes of increased morbidity and mortality worldwide. According to IDF, the global prevalence of diabetes was 382 million in 2013 and will grow to 592 million within 25 years. The global mortality rate from diabetes is approximately 5 million per year, with more than 80% concentrated in low and middle income countries.
Up to 13% of adults with chronic kidney disease (CKD) have CKD, and more than 30% of them have advanced CKD. Diabetes significantly increases the risk of moderate to severe CKD.
Diabetic nephropathy is the most common cause of end-stage renal failure. The development of kidney disease contributes to the high mortality rate in diabetic patients.
Therefore, it is important to identify and treat patients with diabetic CKD.
II.
Hyperglycemia and diabetic nephropathy
1.Glucose and the pathogenesis of nephropathy
Hyperglycemia is a prerequisite for the development of diabetic nephropathy. Hyperglycemia mediates the development of renal disease through multiple signaling pathways, including the formation of advanced glycosylation end products (AGE), activation of protein kinase C (PKC) and stimulation of polyol metabolic pathways.
The effects of hyperglycemia on the kidney include oxidative stress, promotion of pro-inflammatory cytokine and pro-fibrogenic factor release, leading to alterations in intrarenal hemodynamics.
Together, these alterations lead to glomerular permeability changes, glomerular hyperfiltration rate, glomerular basement membrane thickening and glomerular thylakoid cell matrix synthesis, and ultimately glomerulosclerosis and interstitial fibrosis.
2.Hyperglycemia is the target of treatment
Hyperglycemia is an important factor in the prevention and treatment of diabetic nephropathy, and the level of blood glucose control is closely related to the occurrence of diabetic nephropathy. In diagnosed diabetic nephropathy, glycated glucose protein (HbA1c) is an effective indicator for predicting progression to microalbuminuria.
Studies have demonstrated that as HbA1c? values decrease, patients with microalbuminuria and macroalbuminuria also have a corresponding decrease compared to controls.
III.
Renin-angiotensin system and diabetic nephropathy
1. Local RAS activation
Glomerular hyperfiltration is a recognized marker of early diabetic nephropathy, and RAS is the only important factor contributing to pathophysiological changes. Angiotensin II (Ang II) produced by local tissues has an important role in hemodynamics. ang II stimulates sodium reabsorption at the proximal tubule, induces vasoconstriction in the small arteries of the exiting glomerulus, and increases glomerular capillary blood pressure and permeability.
Local non-hemodynamic effects include increased cytokine production, glomerular and tubular cell proliferation, extracellular matrix accumulation, and generation of reactive oxygen species. Together, these factors contribute to the progression of diabetic kidney disease.
2.RAS as a therapeutic target
Blocking RAS is currently the main method for treating proteinuric diabetic nephropathy. This approach is not only beneficial in controlling blood pressure, but also provides renal protection. Over the past 20 years, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) coupled with intensive glucose control therapy have been effective in altering renal prognosis and reducing the incidence of end-stage renal disease in patients with type 1 diabetes.
Although RAS inhibition is effective in preventing proteinuria in people with type 2 diabetes combined with hypertension, the results are less consistent in patients with type 2 diabetes with normal blood pressure. The effectiveness of RAS inhibition as a primary preventive measure in normotensive patients with type 1 diabetes is uncertain.
3. Combination of RAS inhibitors is controversial
In the treatment of diabetic nephropathy with RAS inhibitors, there is the phenomenon of “aldosterone escape”. Therefore, the combined use of drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) is considered.
Experimental studies have shown that ACE inhibitors and ARBs have synergistic effects in lowering blood pressure and inhibiting renin release. Results from clinical studies have also shown that ACE inhibitors combined with ARBs show some clinical therapeutic benefit, particularly in lowering proteinuria.
However, two key clinical studies showed negative results for ACE inhibition and dual ARB blockade. Despite a substantial reduction in proteinuria in the combination group, there was no significant benefit in terms of primary study endpoints such as reduced GFR, ESRD and death, and a significant increase in adverse outcomes such as hyperkalemia and acute kidney injury.
The direct renin inhibitor aliskiren, in combination with ACE or ARB, also showed safety concerns and no benefit in renal outcomes. Similar results were seen with aldosterone antagonists in combination with ACE inhibitors or ARBs.
Some experts on the Scientific Advisory Panel on Cardiovascular Issues suggested that dual RAS blockade therapy could be used in young patients with renal disease and severe proteinuria without comorbidities. Although the door to dual blockade is not completely closed, the EMA currently recommends that the combination should be strictly avoided in the diabetic population and in those with moderate to severe renal impairment.
IV.
Endothelin and diabetic nephropathy
1. Endothelin and the kidney
The endothelial cell-derived vasopressin endothelin-1 has a potent vasoconstrictive effect and helps maintain sodium balance and control blood pressure. Increased renal endothelin-1 gene expression can be observed in diabetic patients. Endothelin-1 is also involved in renal cell proliferation, podocyte injury and cellular matrix accumulation and fibrous degeneration.
2.The role of endothelin antagonists?
Experimental studies have shown that novel drugs that inhibit endothelin receptors show some therapeutic promise to effectively improve diabetic nephropathy and proteinuria. The selectivity of receptors is the key in these drugs, and poorly selective drugs have more adverse effects.
However, the results of clinical studies have shown that two endothelin receptor a antagonists, avosentan and atrasentan-assisted ACE inhibitors, are ineffective in treating residual proteinuria in patients with advanced proteinuric diabetic nephropathy. Studies have shown that avosentan increases cardiovascular side effects, mainly fluid overload and congestive heart failure. Avosentan can also cause peripheral edema.
V.
Sodium and diabetic nephropathy
1. Renal sodium/glucose reabsorption, a new therapeutic target?
Increased proximal tubular reabsorption and the inactivation of hyperglycemia-induced interglomerular feedback by synergistic sodium/glucose transport have an important role in the development of hyperfiltration in diabetic nephropathy. Selective inhibition of sodium-glucose transport protein 2 (SGLT2) reduces glomerular hyperfiltration. Dagliflozin has shown beneficial effects in improving eGFR and proteinuria. However, the primary study endpoint, HbA1c, was not significantly altered.
2. Blood pressure, sodium and diabetic nephropathy
Sodium has an important role in regulating blood pressure, and a moderate reduction in salt intake can lower blood pressure. International guidelines recommend that patients with chronic kidney disease reduce salt intake. Salt mediates kidney damage through its effect on blood pressure and urinary protein excretion, or directly on the kidney.
In diabetic patients, hyperinsulinemia promotes sodium reabsorption in the distal tubules, increases sodium-glucose transport protein and renin-angiotensin system activity, leading to elevated exchangeable sodium in the body.
Clinical meta-analyses have shown that modestly lowering salt intake in diabetic patients can lower blood pressure and reduce proteinuria without affecting insulin resistance.
Dietary restriction of sodium intake is also recognized as the primary adjunctive therapy, and restriction of sodium intake increases the hypoproteinuric effect of renin-angiotensin-aldosterone inhibitors. The optimal salt intake for diabetic patients is still controversial.
Summary
1, In the primary prevention of diabetic nephropathy, the role of glycemic control is unquestionable.
2, Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) not only lower blood pressure, but also have renoprotective effects.
3.Adverse reactions increase when combined with renin-angiotensin-aldosterone system (RAAS) blockers, and caution should be exercised.
4.Lifestyle interventions, especially limiting dietary sodium intake, are important adjuvant therapeutic measures.