Diabetes Mellitus （DM） is a metabolic disease characterized by hyperglycemia that results from improper insulin secretion and/or target tissues resistance to insulin. Long-lasting and recurrent hyperglycemia leads to the injury, dysfunction, and failure of internal organs, including the kidneys, thus causing DKD.

A developing epidemic of this metabolic disease is expected to four-fold increase the number of patients with DM, comparing the 1980s to the 2030s. The number of patients, estimated at 422 million in 2014, is expected to rise to 590 million by 2035 (according to the World Health Organization Report) [1,2]. Up to 40% of all individuals with DM will develop DKD, which will direct them to a path of progressive chronic kidney disease (CKD) and further increase their risk of end-stage renal disease (ESRD), cardiovascular diseases (CVD), and CVD-related death [3]. Progressive DKD is a leading reason for ESRD and the need for cost-consuming renal replacement therapies, both in Europe and the United States [4,5].

The straightforward definition of DKD is a chronic kidney disease with DM, resulting in hyperglycemia as the primary reason for kidney injury. Therefore, the classical clinical diagnosis is made bidirectionally. First, patients are screened for the presence of albuminuria, which is the lowest range proteinuria that can be found in the course of DKD. It is usually expressed as a fraction of the spot urine albumin-to-creatinine ratio. Values of ≥30 mg/g are pathologic, and this value needs to be confirmed in at least two out of three trials, made over 3 to 6 months.

Secondly, a regular assessment of serum creatinine concentration and the resulting estimation of the glomerular filtration rate (eGFR) value is made, with its pathologic values of <60 mL/min/1.73 m² or higher, when accompanied with albuminuria.

The above-mentioned allow for assigning an individual patient to a specific stage of CKD, according to given definitions, e.g., KDIGO (kidney disease improving global outcome) guidelines [6]. To increase the specificity of these criteria, clinicians take into account the presence of other diabetes-derived microangiopathies (e.g., diabetic retinopathy) and time that elapsed since the diagnosis of DM.

As can be clearly seen, DKD, when defined this way, is an indirect diagnosis, or a diagnosis of exclusion of other CKD etiologies. Firstly, there is always potentially a reason other than DKD for progressing renal failure with accompanying proteinuria (e.g., primary glomerulonephritis, atherosclerotic nephropathy, and paraproteinemia). Secondly, even though there is a well-known correlation between the length of DM and prevalence of proteinuria on the one hand, and the resulting correlation between proteinuria and the prevalence of renal failure on the other, we still miss a specific cut-off value for an individual patient [7]. There is neither a consensus on how long diabetes should be present in an individual to cause DKD, nor what the cut-off lines of proper glycemic control are, behind which the risk of DKD development rises. Thirdly, the clinical trajectories of DKD, that differ from classical one, will most probably avoid detection, especially at its early stages. To conclude, there are currently no reliable biomarkers for the early detection of impaired kidney function, which can enable therapeutic interventions to prevent or slow disease progression. Therefore, the theoretical golden standard in DKD should be the core needle biopsy, with its potential risks as an invasive procedure.

Kidney biopsy remains a basic diagnostic tool in the hands of clinical nephrologists. Still remaining a golden standard in DKD diagnosis, it is relatively rarely performed. Its main drawbacks are the relatively frequent complications (e.g., hematomas 11%, pain at the site 4.3%, and hematuria 3.5%) and possibility of more serious undesirable outcomes, such as bleeding requiring blood transfusions (1.6%), interventions to stop bleeding (0.3%), or death (0.06%) [8]. Therefore, being capable of providing clinicians with early and certain diagnosis, kidney biopsy in the course of DM is reserved only to clinically controversial cases (in the absence of retinopathy, sudden onset of proteinuria or nephrotic syndrome, presence of hematuria, and rapid decline of renal function).

Following the biopsy, light microscopy reveals characteristic glomerular changes in the course of diabetic nephropathy. They mostly consist of mesangial expansion that, in its most pronounced form, creates nodular lesions, such as the typical Kimmelstiel–Wilson nodule thickening of the glomerular basement membrane. Pathologic classifications of diabetic nephropathy concentrate on the stage of morphologic lesions, assessing the degree of mesangial expansion, in relation to capillary lesions (stages I—III), and presence of Kimmelstiel–Wilson nodules (stage III), ending at most advanced sclerosis of the glomerular vascular pole (stage IV by Tervaert et al.) [9,10]. The glomerulus is the primary site of diabetic injury in the kidney. Glomerular hypertrophy and podocyte depletion are glomerular hallmarks of progressive DKD, and the degree of podocyte loss correlates with the severity of the disease. Podocytes are highly specialized cells that wrap around glomerular capillaries. They comprise of a key component of the glomerular filtration barrier. Podocytes consist of three morphologically and functionally different segments: a cell body, major processes, and foot processes. The podocyte cell body gives rise to primary processes that branch into foot processes; in turn, the foot processes (FPs) of neighboring podocytes establish a highly branched, interdigitating pattern, known as a slit diaphragm. The slit diaphragm represents a signaling platform that regulates podocyte function and consists of many proteins, such as nephrin, podocin, Neph1, insulin receptor, and actin [11].

The podocyte slit diaphragms are the target of injury in many glomerular diseases, including arterial hypertension, inflammation, and DM.

Studies in patients with microalbuminuric type 1 diabetes demonstrated an increase in the width of podocyte foot processes, compared with that in the podocytes of healthy individuals. The width of foot processes was shown to directly correlate with the urinary albumin excretion rate. In addition, the number and density of podocytes have been reported to be markedly reduced in patients with either type 1 or 2 diabetes [12,13]. Therefore, exploring the mechanism of cell injury in DKD and finding new therapeutic targets and biomarkers may be helpful in distinguishing the patients at risk of kidney failure from those who are likely to recover function.