Diabetic kidney disease (DKD), formerly known as diabetic nephropathy (DN), is the most common microvascular complication in patients with diabetes (diabetes mellitus, DM) and one of the leading causes of death in patients with diabetes. Approximately 50% of end-stage kidney disease (ESKD) originates from DKD (1, 2). About 30 to 50% of DM patients in the world will develop to DKD (2, 3), and DKD patients have a higher risk of survival and mortality compared with simple DM patients (4). Since the concept of DKD was first proposed by the American Kidney Foundation in 2007, it has been widely recognized by the medical academic community, and related research has been deepened. Professional terms have also become more precise from overall planning, and more and more relevant markers have been discovered.

Viberti et al. found that the urinary total protein in patients with type 1 diabetes is within the reference interval, while the excretion of urinary albumin (UAlb) increases. Accordingly, they proposed the concept of microalbuminuria (previously known as albuminuria), that is, the albumin excretion rate (AER) is between 30 and 300 mg/d, which is used as a sensitive indicator of early renal damage in diabetes (5). Therefore, the process of DM complicated with chronic kidney disease (CKD) is a typical disease development with clinical manifestations of in turn increased UAlb excretion, microalbuminuria, macroalbuminuria (with reduced glomerular filtration), and ESKD. However, some DM patients show proteinuria in the normal range but were accompanied by renal insufficiency [estimated global filtration rate (EGFR) < 60 ml/(min/1.73 m²)] (6). This phenomenon, first noticed by Lane et al. in 1992 (7), is later called normoalbuminuric diabetic kidney disease (NADKD). Subsequently, more and more references have reported that such cases are common clinically (8–13).

DKD is a clinical diagnosis, and its etiology is initially thought to be proteinuria in DM patients. The definition is independent of traditional diagnostic markers of CKD, such as histological changes or decreased eGFR, and is initially limited to DM patients with macroalbuminuria. Since then, more sensitive methods for detecting urinary albumin have been developed with the innovation of medical testing technology. Compared with the early detection of macroalbuminuria, proteinuria detected by the new technology is called microalbuminuria, and diabetic patients with microalbuminuria are diagnosed with “early kidney disease. some scholars have also referred to NADKD as diabetic kidney disease without albuminuria (8), non-albuminuric renal disease (9), the non-albuminuric form of diabetes kidney disease (10), normoalbuminuric diabetic nephropathy (11), normoalbuminuric diabetes with renal insufficiency(NADRI) (12), or normoalbuminuric renal insufficiency (13) based on its clinical manifestations or characteristics in the process of clinical research due to the lack of uniform nomenclature.

Some scholars have equated urine proteins with urine albumins, which are called non-proteinuric non-proteinuric diabetic nephropathy (DKD) (14). According to clinical practice, it is inappropriate to call NADKD non-albuminuric or without albuminuria, and normal albuminuric is suitable because even healthy people will have some albumin molecules or fragments in their urine more or less. It is difficult to detect by conventional methods due to the small amount.

Traditionally, urine with UAlb excretion of 30-300 mg/d, or random urine concentration of 20-200 mg/L, or AER of 30-300 mg/d, or urinary albumin-creatinine ratio (UACR) of 30-300 mg/g is called microalbuminuria. The working group of urine albumin testing laboratory in the National Kidney Disease Education Program (NKDE) and the International Federation of Clinical Chemistry (IFCC) recommended the unification of microalbuminuria and macroalbuminuria under term urine albumin, and the abandonment of microalbumin to avoid confusion between microalbumin and small albumin molecule (15) ( Table 1 ). The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines for the management of chronic kidney disease also recommended that term microalbuminuria should no longer be used (16). Although terms microalbuminuria and urine microalbuminuria are still used in some fields, the purpose is to alert patients with diabetes and cardiovascular disease to the possibility of developing chronic kidney disease, not only DKD patients (16).

The National Kidney Foundation (NKF) and the Food and Drug Administration (FDA) redefined albuminuria in 2009 to strengthen the management of proteinuria in patients with chronic kidney disease (17). i) Those with UACR>300 mg/g are called very high albuminuria (previously called macroalbuminuria); ii) those with UACR between 30 and 300 mg/g are called high albuminuria (previously referred to as microalbuminuria); iii) those between 10 and 29 mg/g are called low albuminuria; iv) only those with UACR<10 mg/g are considered for NADKD ( Table 2 ).

According to this definition of the NKF/FDA working group, the old name NADKD (old) includes two parts of patients with hypoalbuminemia (UACR:10-29mg/g) and normoalbuminuria (UACR<10 mg/g), and its more accurate definition should be non-high albuminuria DKD (NHDKD) (18). Based on this new definition, patients who used to be called NADKD (old) are not actually “normal albumin” DKD in the true sense.

The work completes the following items to distinguish DKD patients with different levels of albuminuria, e.g., introducing a new concept according to the new definition of NKF/FDA, renaming the old name NADKD (old) to NHADKD, and defining patients with UACR between 10 and 29 mg/g as low albuminuric diabetic kidney disease (LADKD), patients with UACR < 10 mg/g as NADKD (it is a new concept unless otherwise stated in the work), DKD patients with high albuminuria as high albuminuria DKD (HADKD), and DKD patients with very high albuminuria as very-high albuminuria DKD (VADKD). According to the new definition, LADKD, HADKD, and VADKD are collectively referred to as increased albuminuria DKD (or DKD with increased albuminuria, IADKD) for description ( Table 2 ).

Many scholars still regard microalbuminuria (ACR between 30 and 300 mg/g) as a biochemical marker for the early diagnosis of DKD (19) and identify NADKD as the early stage of albuminuria DKD because of the different division of concepts. However, some patients with DKD have been found to have normoalbuminuria in clinical practice, accompanied by decreased renal function with reduced eGFR (2). Even if the eGFR decreases to the level of stage 3 CKD, they still show normoalbuminuria. Therefore, NADKD can no longer be simply regarded as the early stage of albuminuria DKD, and it is necessary to recognize and pay attention to NADKD.

The prevalence of NADKD in DKD varies with the method of proteinuria (mostly albumin detection) measurement, regions of the patients, inclusion criteria, and the line of judgment for proteinuria, and the results are in a wide variation ( Table 1 ). Patients with NADKD account for only 3.6% of patients with DKD (20), whereas it is as high as 77.9% in Ref (21). The proportion of NADKD in DKD is in the range of 20-70% (22–28). The results of a recent meta-analysis show that the overall prevalence of NADKD in patients with type 2 diabetes and renal insufficiency is 45.6%. That is 24.7% in patients with DKD (albuminuria or renal insufficiency) and 8.4% in all patients with type 2 diabetes, which means that albuminuria does not occur in almost half of patients with DKD and patients with reduced eGFR (29).

The reasons for the high prevalence of NADKD might be related to its pathogenesis (see later); however, the point of the matter is that these reports all use ACR > 30 mg/g or UAE > 30 mg/24 h as a line of judgment to discriminate between NADKD and albuminuric DKD. LADKD is judged as NADKD, and it is not clear whether the proportion of LADKD in it is high or low. Therefore, the roughly reliable prevalence of NADKD can only be clarified by reinvestigation based on the latest definition.

No institution can formulate clear diagnostic criteria for NADKD for the clinician because of our limited understanding of NADKD and different people having different perspectives.

DKD is usually clinically diagnosed based on the presence of proteinuria and/or decreased eGFR in the absence of signs or symptoms of other major causes of kidney damage (48). Nevertheless, patients with NADKD do not have the UACR. So if we only rely on the eGFR to make a diagnosis of NADKD patients, there will be greater difficulties. The eGFR is a calculation indicator based on serum (plasma) creatinine and/or cystatin C. The level of serum creatinine is easily affected by muscle quality, dietary protein intake, hyperlipidemia, hemolysis, and the method of detection (Jaffe’s method or enzymatic method). An eGFR has an obvious lack of reliability (12). Therefore, the diagnosis of NADKD is challenging.

According to relevant guidelines (16, 17, 48), the diagnosis of NADKD should meet at least the following conditions: i) diagnosis of diabetes according to the latest diagnostic criteria of the World Health Organization (WHO) or the American Diabetes Association (ADA); ii) under the following circumstances more than three months: urinary sediment abnormality, or renal tubular injury resulting in electrolytes and other abnormalities, or abnormal histological examinations, or imaging detected structural abnormalities, or a history of kidney transplantation, or eGFR < 60ml/(min/1.73 m²); iii) Have an examination once a month and at least twice in three months if AER<30 mg/24 h or ACR<30 mg/g is diagnosed as NADKD. It also can be diagnosed if AER < 10 mg/24h or ACR < 10 mg/g (or the range of reference values established by the local laboratory) (17, 37).

As far as kidney damage is concerned, the DKD essence is also a chronic kidney disease (CKD). NADKD is only the case part of DKD with normal albuminuria. KDIGO defines CKD as an abnormality of the renal structure and function lasting more than 3 months, which affects human health. According to it, renal structural abnormalities can be found by histological (renal biopsy) or imaging (CT, MR, or ultrasonic) examination. The method cannot determine whether the patient has proteinuria (or albuminuria), so ACR/AER is required to distinguish DKD and NADKD. Therefore, the diagnosis of DKD and NADKD by clinicians mainly depends on the detection of ACR/AER and eGFR in the traditional renal function index ( Figure 1 ).

Not all clinical laboratories in other countries reported eGFR except some clinical laboratories in Europe and America because of the tedious detection methods (AER), multiple influencing factors (creatinine) (16), and different degrees of popularity (cystatin C) (16) with no special requirements. The sensitivity of traditional biomarkers (such as ACR/AER and eGFR) for CKD diagnosis is poor, indicating that it is difficult to diagnose DKD/NADKD. Only relying on traditional biomarkers cannot meet the clinical application of NADKD. Therefore, some novel biomarkers emerge.

There are nearly 100 clinical markers for research, screening, or diagnosis of NADKD ( Supplementary Tables 1, 2 ). However, only the neutrophil gelatinase-associated lipocalin, cystatin C, vascular endothelial growth factor, and liver-type fatty acid-binding protein can achieve routine testing in clinical laboratories. These projects also have the most research and clinical applications in DKD/NADKD.

DKD is a common serious complication in DM patients, which is associated with renal failure, cardiovascular disease, and premature death. The pathological mechanism of DM complicated with CKD (i.e., DKD occurs) is extremely complex. The proportion of NADKD in DM or DKD patients has gradually increased. Although this may be related to the improvement of the therapeutic effect of DM and the potential renal pathological changes of NADKD, it brings greater difficulties to the diagnosis of DKD. NADKD was judged at the early stage of typical DKD in the past, which might be related to the disease stratification of NADKD. NADKD was falsely judged as NADKD.

DF/DFU is also a serious complication of DM. If the influence of renal injury on DF/DFU disease is ignored due to the missed diagnosis of NADKD, it will certainly aggravate the disease development and lead to serious outcomes for DM patients. Therefore, early diagnosis is essential to improve the prognosis of DM patients. Besides traditional (ACR/AER and eGFR) markers, some novel markers with higher sensitivity and better specificity, such as serum cystatin C, NGAL, L-FABP, and VEGF, should be used as routine evaluation indicators in the clinical management of DM. They can be used to predict the occurrence of DM complications and disease progression through regular examination, screen NADKD patients with concealed clinical manifestations as early as possible, give personalized intervention and/or treatment in time, manage DM, and control the occurrence and development of its complications.

NA and J-FF contributed to the conception and design of the article. NA, B-TW, and J-FF wrote the first draft of the manuscript. Y-WY and Z-HH performed the framework, tables and the figure. NA and J-FF revised important intellectual content critically for important intellectual content. All authors contributed to the article and approved the submitted version.

This work was supported by the Science and Technology Department of Sichuan Province (2015SZ0117, 2019YJ0701, and 21YYJC3525).

We would like to give our sincere appreciation to the reviewers for their helpful comments on this.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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