Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease.

Background and aims: Outcome trials using sodium glucose cotransporter type 2 inhibitors have consistently shown their potential to preserve kidney function in diabetic and nondiabetic patients. Several mechanisms have been introduced which may explain the nephroprotective effect of sodium glucose cotransporter type 2 inhibitors beyond lowering blood glucose. This current narrative review has the objective to describe main underlying mechanisms causing a nephroprotective effect and to show similarities as well as differences between proposed mechanisms which can be observed in patients with diabetic and nondiabetic chronic kidney disease. Methods: We performed a narrative review of the literature on Pubmed and Embase. The research string comprised various combinations of items including "chronic kidney disease", "sodium glucose cotransporter 2 inhibitor" and "mechanisms". We searched for original research and review articles published until march, 2022. The databases were searched independently and the agreements by two authors were jointly obtained. Results: Sodium glucose cotransporter type 2 inhibitors show systemic, hemodynamic, and metabolic effects. Systemic effects include reduction of blood pressure without compensatory activation of the sympathetic nervous system. Hemodynamic effects include restoration of tubuloglomerular feedback which may improve pathologic hyperfiltration observed in most cases with chronic kidney disease. Current literature indicates that SGLT2i may not improve cortical oxygenation and may reduce medullar oxygenation. Conclusion: Sodium glucose cotransporter type 2 inhibitors cause nephroprotective effects by several mechanisms. However, several mediators which are involved in the underlying pathophysiology may be different between diabetic and nondiabetic patients.

Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitors in Combination with Angiotensin-Receptor Blockers in Nondiabetic Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: It is unclear whether angiotensin-converting enzyme inhibitors (ACEIs) in combination with angiotensin-receptor blockers (ARBs) are superior to ACEIs or ARBs alone in the treatment of nondiabetic chronic kidney disease (CKD). The present meta-analysis was designed to assess the efficacy and safety of ACEIs in combination with ARBs in nondiabetic CKD. METHODS: The PubMed, Embase, and Cochrane Library databases were searched to identify randomized controlled trials (RCTs) published prior to March 2020. A random-effects model was used to calculate the effect sizes of eligible studies. RESULTS: The present meta-analysis of 20 RCTs encompassing 1,398 patients with nondiabetic CKD demonstrated that ACEIs in combination with ARBs were superior to ACEIs or ARBs alone in reducing urine albumin excretion (SMD, -0.69; 95% CI, -1.13 to -0.25; P=0.002), urine protein excretion (SMD, -0.34; 95% CI, -0.46 to -0.23; P<0.001), and blood pressure (systolic blood pressure: WMD, -1.43; 95% CI, -2.42 to -0.44; P=0.005; diastolic blood pressure: WMD, -1.85; 95% CI, -2.67 to -1.04; P<0.001) without decreasing glomerular filtration rate (SMD, -0.07; 95% CI, -0.20 to 0.06; P=0.30) or increasing incidences of hyperkalaemia (RR, 1.70; 95% CI, 0.47 to 6.11; P=0.42) and hypotension (RR, 1.80; 95% CI, 0.67 to 4.86; P=0.25). CONCLUSION: Compared with ACEIs or ARBs alone, ACEIs in combination with ARBs are effective and safe in the treatment of nondiabetic CKD. ACEIs combined with ARBs may be a better choice to reduce proteinuria as long as they can be tolerated.

Olmesartan is More Effective Than Other Angiotensin Receptor Antagonists in Reducing Proteinuria in Patients With Chronic Kidney Disease Other Than Diabetic Nephropathy.

BACKGROUND: Angiotensin II receptor antagonists (ARBs) have a protective effect in patients with chronic kidney disease (CKD) by suppressing progression, possibly by controlling hypertension. One marker of progression in such patients is the degree of proteinuria. OBJECTIVE: We aimed to retrospectively examine the protective effect of ARBs (olmesartan, losartan, candesartan, and valsartan) on CKD patients without a history of diabetic nephropathy. METHODS: Data were retrieved from medical records of patients with a diagnosis of CKD (serum creatinine [Cre] <3.0 mg/dL [265.2 µmol/L] and urinary protein of 0.3-3.5 g/g Cre) who were treated with ARBs and those with diabetic nephropathy were excluded. Blood pressure, serum Cre, urinary protein, urinary Cre, and estimated glomerular filtration rate were measured before the research began and at 1, 3, 6, 12, and 24 months after the ARB treatment was started. RESULTS: Forty-four patients completed the research protocol. Of these, 10 took olmesartan, 13 took losartan, 9 took candesartan, 9 took valsartan, and 3 took telmisartan. Systolic blood pressure was decreased in all cases. The extent of this decrease 1 month after starting ARB treatment was greater for olmesartan than for candesartan (P < 0.05), and after 2 years, it was greater than for losartan (P < 0.05). Diastolic blood pressure decreased in all patients; this decrease was significantly greater with olmesartan 1 month after treatment started than with candesartan (P < 0.05). Olmesartan significantly decreased daily urinary protein compared with that with the other ARBs during follow-up. This decrease 1 month after starting ARB treatment was greater for olmesartan than losartan, valsartan, and candesartan (P < 0.01, P < 0.01, and P < 0.05, respectively), and after 2 years, this effect was still significant (P < 0.05, P < 0.01, and P < 0.01, respectively). CONCLUSIONS: Olmesartan is more effective in reducing urinary protein than other ARBs, suggesting that the renal protective effects of olmesartan may be better than those of other ARBs.