Diabetes mellitus (DM) is a pandemic health condition with increasing prevalence worldwide. The number of people with DM increased to 430 million people in 2014.1 Despite the great global efforts to follow the frequently updated, evidence-based management guidelines and the increasing knowledge of this condition, subjects with DM still have a life expectancy that is 10–15 years lower than non-diabetic individuals.2 End-stage kidney disease (ESKD) is most frequently caused by diabetic kidney disease (DKD) which affects 26 % of people with type 2 diabetes mellitus (T2DM).3

According to several research studies, the innate immune system contributes to the inflammation associated with DM.4,5 Through interactions with various pattern recognition receptors, the complement system participates in innate immune defense, which is another important cause of inflammation.6 Additionally, mounting data implicates the complement system in the etiology of diabetic nephropathy (DN), suggesting that complement activation may be used to detect patients at risk for this specific problem and employ them as treatment targets.7 C4d is one of the fragment of complement cascade and indicate that complement has been activated. Complement system is initiated by three mechanisms namely the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). As the lectin and classical complement pathways could both generate C4d, and as both pathways seem to contribute to the development of Diabetic kidney disease, we may use it as a marker of inflammation, and a drop in C4d levels can be used to indirectly indicate a decline in the inflammatory process and can be linked to change in estimated glomerular filtration rate (eGFR) and albuminuria.6,7

Complements activation has been linked to the pathophysiology of several diabetic kidney disorders. A proteomic analysis of laser-micro-dissected human kidney samples reveals that patients with DKD have elevated levels of complement proteins in their glomeruli.8 Pattern recognition molecules and complement regulatory proteins are considered to become glycated in hyperglycemia, which leads to an unchecked activation of the complement system and activates the lectin pathway.9,10

Large outcome trials of sodium-glucose transporters inhibitors (SGLT2I), already published during the past six years, have shown the drug`s renal protective effects in T2DM patients with or without chronic kidney disease (CKD).11 Renal hypertrophy and hyper-filtration are signs of the first stages of diabetic nephropathy. These signs are followed by increased albuminuria, decreased eGFR, and ultimately end-stage renal disease.12 When empagliflozin was added to standard of care in individuals with T2DM who had a high cardiovascular risk, there was a slower progression of kidney disease and a reduced rate of clinically meaningful renal events compared to placebo.13

Currently, the Food and Drug Administration (FDA) has approved three medication classes to treat DKD: SGLT2I, angiotensin II receptor antagonists and the inhibitors of angiotensin-converting enzyme. The aims of the present study were to determine the comorbid effects of empagliflozin on the positive outcomes of DKD and whether complements activation is pathogenic in the process of the disease.