Normoalbuminuric diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is one of the primary causes of end-stage renal disease (ESRD). Early diagnosis is very important in preventing the development of DKD. Urinary albumin excretion rate (UAER) and glomerular filtration rate (GFR) are widely accepted as criteria for the diagnosis and clinical grading of DKD, and microalbuminuria has been recommended as the first clinical sign of DKD. The natural history of DKD has been divided into three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. However, this clinical paradigm has been questioned recently, as studies have shown that a portion of diabetes mellitus (DM) patients with normoalbuminuria have progressive renal insufficiency, referred to as normoalbuminuric diabetic kidney disease (NADKD) or nonalbuminuric diabetic nephropathy. Epidemiologic research has demonstrated that normoalbuminuric diabetic kidney disease is common, and the large number of NADKD patients suggests that the traditional paradigm needs to be shifted. Currently, the pathogenesis of NADKD remains unclear, but many clinical studies have identified some clinical and pathological features of NADKD. In addition, the long-term outcomes of NADKD patients remain controversial. In this article, we reviewed the latest studies addressing the pathogenesis, pathology, treatment and prevention of NADKD.

Keywords

diabetes / diabetic kidney disease / normoalbuminuria / renal impairment

Introduction

Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus (DM) [1] and the cause of almost half of all new cases end-stage renal disease (ESRD) in the US [2,3]. In 2007, the concept of diabetic kidney disease (DKD) was first proposed by the American Kidney Foundation [4]. The general progression of DKD starts with increasing urinary albumin excretion rate (UAER), leading to severe proteinuria, reduced estimated glomerular filtration rate (eGFR), and ESRD. Therefore, UAER or the urinary albumin to creatinine ratio (UACR) is the most important criterion for early diagnosis for DKD [5]. However, some DM patients with renal insufficiency (eGFR<60 ml/(min·1.73 m²)) have normal-range proteinuria. In 1994, Tsalamandria and colleagues [6] first described DM patients who exhibited no clinically significant proteinuria but had renal insufficiency (eGFR<60 ml/(min·1.73 m²)) and progressed to DKD, a condition described as normoalbuminuric diabetic kidney disease (NADKD), nonalbuminuric diabetic nephropathy or diabetic kidney disease without albuminuria [7–10].

The latest DKD diagnostic criteria proposed by the American Diabetes Association (ADA) in 2015 include UAER>30 mg/24h or eGFR<60 ml/(min·1.73 m²) [11], reflecting the fact that a portion of DM patients have normal-range albuminuria with renal insufficiency, which meets the criteria for DKD. Based on the concepts described by Zelmanovitzde [12] in 1997 and other sources [7,13–16], we propose the following diagnostic criteria for NADKD: (1) conformance to the latest World Health Organization (WHO) or American Diabetes Association (ADA) diagnostic criteria of diabetes; (2) eGFR<60 ml/(min·1.73 m²); (3) urine protein excretion rate<20 µg/min at least twice within six months, random urine protein<17 mg/L, UAER<30 mg/24 h (under normal use of antihypertensive drugs), or UACR<30 mg/g; (4) exclusion of other secondary kidney diseases.

Epidemiology of NADKD

The prevalence of patients with type 2 diabetes mellitus ranges from 25% to 50% in different studies and counties [12,17–20], and the prevalence of NADKD is not low (Table 1) [7,9,13,17,20–24]. Over 15 years of follow-up (1977–1991), the UK Prospective Diabetes Study (UKPDS) found that 28% of type 2 DM patients had NADKD, whereas just 38% of DM patients developed proteinuria [17]. The third study by the National Health and Nutrition Examination Survey (NHANES III) in 2003 showed that the prevalence of NADKD was 14.29% (n = 171/1197) in type 2 DM patients [21]. The Renal Insufficiency and Cardiovascular Events (RIACE) research group found that, among type 2 DM patients with chronic kidney disease (CKD) stages 3–5, 21.66% (393/1814) had no proteinuria, and 29.71% (539/1814) had proteinuria [22]. In addition, another group reported that, among 5072 DM patients, 31% had CKD stages 3–5, and 63% had normoalbuminuria [23]. A study by Giuseppe [20] also revealed that, among 2959 DM patients with renal dysfunction, 1673 (56.6%) were normoalbuminuric, with 912 (30.8%) and 374 (12.6%) patients presenting with microalbuminuria and proteinuria, respectively. Boronat et al. [24] reported that 21.8% of DKD patients have normoalbuminuria, 20.5% have microalbuminuria, and 57.7% have severe proteinuria. The Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes (DEMAND) study reported that 17.2% (1044/6072) of patients with CKD stages 3–5 had NADKD [13], and in a study by Mottl et al. [9], NADKD accounted for 77.3% of the cases. Furthermore, the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/ EDIC) showed that in type 1 DM patients who developed to eGFR<60 ml/(min·1.73 m²), 22.47% (20/89) had UAER<30 m/24 h [25]. Evidently, NADKD is one of the main manifestations of DKD, but the prevalence varies across studies, potentially due to the different methods for measuring proteinuria or previous treatments to alleviate proteinuria. Treatment with renin-angiotensin-aldosterone system (RAAS) blockers may reduce or eliminate the incidence of urinary protein [26].

Moreover, the prevalence of NADKD varies by race. Thomas et al. [19] found that the burden of NADKD is much higher in Caucasian populations than among indigenous Australian and Asian populations; of 506 NADKD patients, 91% were Caucasian, while 2% were Indigenous Australian, and 7% were Asian. Morbidity also varies by country and region.

Compared to DKD patients with UAER>30 mg/24h, the proportion of women was significantly higher than that of men among NADKD patients. A multicenter study conducted by Molitch and colleagues [25] with follow-up over 19 years showed that 89 patients with type 1 DM developed an eGFR<60 ml/(min·1.73 m²); of those, 20 (22.47%) had AER<30 mg/d, and 81% (17/21)were women, but in the microalbuminuria (30–300 mg/d) group (14/89) and the macroalbuminuria (>300 mg/d) group (54/89), 64.3% (9/14) and 51.85% (28/54) were women. The gender differences might relate to the lower glomerular filtration rate in women compared to men [27]. A meta-analysis study found that men with CKD of various etiologies show a more rapid decline in renal function than women, but in the NADKD group, the loss of eGFR in women was even faster than in men [6,28]. This may be related to female hormone levels, as reported by Porrini et al. [29]. However, the effect of hormones on renal disease in women is controversial. Several studies investigating the role of female hormones through animal models have yielded opposite results; in type 1 DM, 17b-estradiol could regulate signaling of transforming growth factor b to protect women from accelerated decline in renal function [30]. However, a few studies have indicated that estrogen may have contradictory effects [31] on GFR among women with diabetes.

Pathophysiology of NADKD

The microangiopathy typically observed in DKD patients with albuminuria is not common in NADKD patients. In their study, An et al. [32] found that the percentage of patients with retinopathy was 16% (7/44) in the NADKD group, whereas it was 56% (28/50) and 81% (46/57) in the microalbuminuria group and the macroalbuminuria group, respectively [32]. Similarly, Kramer and colleagues [21] found an incidence of retinopathy of 28% in NADKD patients, compared to 45% in the microalbuminuria group. Moreover, some studies have shown that macroangiopathy is more prevalent in NADKD patients. A clinical study by Boronat et al. [24] with 78 DKD patients found that in the NADKD group, 47.1% (8/17) had coronary heart disease, and 52.9% (9/17) had apparent retinopathy; however, in the albuminuria group, the prevalence of coronary heart disease was only 29.5% (18/61), and the prevalence of retinopathy reached 59.0% (36/61). It is believed that NADKD may be not directly related to microangiopathy [7,33].

Further studies have shown that eGFR decreases in type 2 diabetes patients and is associated with increases in carotid intimal-medial thickness, carotid stiffness, and the intrarenal arterial resistance index [34]. It has been reported that compared to DM patients with eGFR>60 ml/(min·1.73 m²), those with eGFR<60 ml/(min·1.73 m²) had a higher renal artery resistance index independent of albuminuria [34,35], indicating that renal vascular lesions may be involved in the pathogenesis of NADKD. Boeri et al. [36] conducted a study of 30 DM patients in which they measured the resistive index of the interlobar arteries and found that intrarenal arteriosclerosis was mainly responsible for kidney function impairment in type 2 DM patients, without affecting the albumin excretion rate. This suggested that GFR decline in type 2 DM patients is partly due to increasing arteriosclerosis.

In addition, cardiovascular disease and metabolic syndrome are associated with NADKD, as there is a positive correlation between the prevalence of NADKD and those conditions [14,37]. Lamet al. [38] demonstrated that the association between cholesterol-lowering therapy and renal function progression in type 2 DM is independent of the albumin excretion rate. These studies provided clinical evidence for the role of macroangiopathy in the development of NADKD patients, which may contribute to the development of renal dysfunction in NADKD [35].

RAAS blockers are a traditional class of drugs for reducing proteinuria in DKD patients. Clinical research has shown that most NADKD patients had used a RAAS blocker [7]. Recent evidence suggests that once NADKD patients stop using the RAAS blockers, they progress to microalbuminuria [39]. An and colleagues [32] observed 151 DKD patients with renal insufficiency before treatment with RAAS inhibitors and reported the proportion of normoalbuminuria, microalbuminuria, and proteinuria at 29.1%, 33.1%, and 37.8%, respectively; however, after treatment with a RAAS inhibitor, the proportions were 35.3%, 41.2%, and 23.5%. The Nephrologic Diabetes Complications Trial (BENEDICT) included 1204 type 2 DM patients divided into two groups; 5.8% (35/601) of patients developed microalbuminuria in the angiotensin converting enzyme (ACE) inhibitor treatment group, compared to 10.9% (66/603) in the control group [40]. These results indicated that ACE inhibitors can reduce microalbuminuria and prevent the progression of DM. Recently, Porrini et al. [29] proposed that progression to NADKD might be partly due to treatment with RAAS blockers in patients with DM, which can reduce proteinuria but not improve the GFR. Thus, we should pay more attention to the relationship between RAAS inhibitors and NADKD.

The tubulointerstitium is composed of tubular epithelium, vascular structures, and interstitium and accounts for 90% of renal tissue [42]. The classical interstitial pathological changes in diabetic nephropathy [43] include tubular basement membrane thickening, interstitial fibrosis, tubular atrophy, and arteriosclerosis. Lane et al. [44] found that interstitial expansion is independently associated with decreased renal function in type 1 DM. Another study demonstrated that interstitial fibrosis contributes to further renal function decline compared to glomerular injury, and this decline was independent of albuminuria [45]. This suggested that declining of eGFR is partly related to interstitial injury in type 2 DM. Further studies in NADKD patients had similar results. Ekinci et al. [39] found that 3 in 8 (37.5%) NADKD patients had interstitial and vascular lesions by renal biopsy, and only 1 in 23 (4.3%) proteinuria patients had interstitial and vascular lesions. This suggested that tubulointerstitial damage may be involved in the development of NADKD. Given the importance of renal interstitial damage in NADKD patients, it is necessary to not only detect renal function decline in a timely fashion but also to detect tubular injury.

Previous studies have confirmed that TNFa and other inflammatory cytokines are involved in the DKD immune and inflammatory response [46]. Perkins et al. [47] showed that early decline in renal function was always associated with significantly increased IL-6, IL-8, monocyte chemo-attractant, and other inflammatory markers in urine. In addition, many studies have found that TNFa is involved in the pathogenesis of diabetic nephropathy with albuminuria and that the Fas pathway mediating apoptosis may play a role in the progression of diabetic nephropathy [48–50]. Niewczas et al. [51] observed 363 normoalbuminuria and 304 microalbuminuria patients with type 1 DM and showed that the concentration of serum TNFa (sTNFR1, sTNFR2) or Fas-pathways cytokines (sFasL and sFas) was associated with decreased eGFR independent of albuminuria. In the Cholesterol and Recurrent Events (CARE) study, serum TNF receptor 2 (sTNFR2) was found to be associated with the progression of kidney function loss [52]. Several studies have indicated that serum concentrations of TNF receptors (sTNFR1, sTNFR2) could be influenced by their upstream regulators, such as TNFa or IL1 and ADAM17 [53]. Many studies have shown that TNFa reduces glomerular blood flow directly and increases glomerular vasoconstriction, thus decreasing glomerular filtration rate [48]. This indicates that immune inflammation plays an important role in the decrease of renal function in NADKD.

It is widely believed that renal function decline due to acute kidney injury (AKI) is transient and that renal impairment can be completely restored. However, recent clinical studies have shown that AKI can eventually result in chronic kidney disease as well, even though renal function has recovered [54]. Several mechanisms have been proposed for the progression of AKI to CKD, such as nephron loss, inflammation, endothelial injury with vascular rarefaction and hypoxia, epigenetic changes, and cell cycle arrest in epithelial cells [55–58]. DM is one of the important risk factors for the development of AKI [59–61]. Thakar et al. [62] conducted a longitudinal study observing 3679 DM patients and found that AKI was a risk factor for CKD (HR 3.56; 95% CI 2.76‒4.61) compared with DM patients without AKI, and the risk was independent of albuminuria. Onuigbo and colleagues [63] also reported that once AKI appeared in DM patients, renal function decline was more likely, and this was independent of urine protein levels. Therefore, we propose that AKI may be another important risk factor for renal function decrease in NADKD patients.

Furthermore, the prevalence of NADKD varies across ethnic groups, suggesting that genetic susceptibility may be involved in the development of the disease. Polymorphism in the protein kinase C-b gene in DM patients is associated with eGFR decline [64]. Although there are a great number of studies on DKD susceptibility genes, the real causative genes or susceptibility genes involved in the pathogenesis and progression of NADKD have not yet been identified.

Pathology of NADKD

The observed pathological changes differ between NADKD and DKD with microalbuminuria or macroalbuminuria. Shimizu et al. [65] showed that NADKD patients have more severe renal pathological changes compared to patients with normal eGFR, including mesangial matrix proliferation, hyaline degeneration of renal arteries, and increased glomerular fibrosis [27,65]. Ekinci et al. [39] found that 3 in 8 NADKD patients showed typical glomerular changes, whereas the prevalence in patients with microalbuminuria and macroalbuminuria was 5/6 and 17/17. Yagil et al. [66] experimented on rat models (Cohen diabetic-resistant rats) and found that the pathological changes of Cohen diabetic-sensitive rats (an experimental model of type 2 diabetes mellitus that develops normoalbuminuric DKD) included mesangial matrix proliferation, thickened glomerular basement membrane, and increased type IV collagen in the glomeruli and interstitium. The renal pathological changes typical of NADKD are tubular and interstitial damage, but the mechanism of NADKD remains unclear.

Clinical features of NADKD

Several studies mentioned above indicated that retinopathy is more frequent in albuminuric patients than in normoalbuminuric patients [21,22,32]. However, opinions on this matter differ. The prevalence of retinopathy in NADKD patients varies across studies. A study from RIACE with 2959 DKD patients with renal impairment found that 2028 (68.5%) patients had no retinopathy, 1280 (43.2%) NADKD patients had neither proteinuria nor retinopathy, and 538 patients (18.2%) showed both proteinuria and retinopathy [20]. The varying prevalence of retinopathy might be due to different observation methods, or it could be that the development of NADKD does not depend on microangiopathic lesions.

Type 2 DM with albuminuria is an independent risk factor for cardiovascular disease (CVD), but the burden of CVD in NADKD is even higher [20]. For patients within the normoalbuminuria range (UAER<30 mg/24h), the burden of CVD varies. In a cross-sectional analysis, normoalbuminuric patients were divided into normal albuminuria (NA) (UAER<10 mg/24h) and low albuminuria (LA) (UAER 10–29 mg/24h) groups, and the burden of acute cardiovascular events, ulcers, coronary events, and peripheral vascular events was significantly higher in the LA group [67,68]. Therefore, NADKD patients should undergo quantitative detection of albuminuria, and those with UAER 10–29 mg/24h should receive vigilant follow-up for CVD events. As we can see from Fig. 1, the burden of diabetes complications in normoalbuminuric patients is lower than in DM patients with albuminuria. Boronat et al. [24] observed 78 DKD patients and found that in the normoalbuminuric group (21.8%), the BMI and waist circumference were significantly higher than in the microalbuminuria (20.5%) and macroalbuminuria (57.7%) groups. In addition, the average low-density lipoprotein (LDL) level was 1.02 mmol/L (90.4 mg/dl) in the NADKD group, compared to 0.85 mmol/L (75.1 mg/dl) in the control group. Another study found that NADKD is associated with higher hemoglobin levels. The risk factors associated with NADKD might include obesity, hyperlipidemia, and high hemoglobin. The clinical characteristics are summarized in Table 2.

Perkins et al. [69] found that eGFR declined faster in DKD patients with proteinuria compared to NADKD patients. Rigalleau and colleagues [16] showed that NADKD patients had a lower risk for progression to ESRD than DM patients with proteinuria after 38 months of follow-up. This finding was consistent with what Boronat et al. [24] reported, possibly because normoalbuminuria alleviates eGFR decline [14].

A multi-center study found that among type 2 DM patients with renal dysfunction, all-cause mortality in the normoalbuminuric DKD group was not significantly lower compared to the proteinuric DKD group [70] and was higher when compared to the normal eGFR DKD group, suggesting that eGFR is a risk factor for death independent of proteinuria [65]. Therefore, monitoring renal function in NADKD patients is very important for predicting prognosis [21].

Diagnostic biomarkers of NADKD

Neutrophil gelatinase-associated lipocalin (NGAL), a small protein that belongs to the lipocal superfamily, usually increases before the excretion of urine microalbumin in type 1 DM patients [71]. Some research also found that urine levels of NGAL increased progressively from ACR 10 mg/g creatinine to 30 mg/g creatinine in diabetic patients [72]. NGAL is now considered a reliable indicator of NADKD with high sensitivity and specificity [8]. Lim et al. [73] also found that zinc-a (2)-glycoprotein may be a urinary biomarker for NADKD. Moreover, several studies have indicated that liver-type fatty acid binding protein (L-FABP) and heart-type fatty acid binding protein (H-FABP) were important indicators of renal tubular injury, which can help in the diagnosis of NADKD [74,75].

Prevention of NADKD

K/DOQI guidelines recommend that the diagnosis of DKD should be based on not only monitoring UAER and fundus changes but also assessment of eGFR [76]. The MDRD [77] or Cockcroft-Gault formula can be applied for the calculation of eGFR [78]. In addition, numerous studies have shown that the development of NADKD is closely related to gender, age, smoking, macrovascular disease, metabolic syndrome, and environmental factors [21,32]. Thus, female sex, old age, and metabolic syndrome are risk factors for NADKD. Regular monitoring of eGFR in high-risk patients could assist in timely diagnosis [79].

Currently, we do not have effective therapies for NADKD. It is generally believed that reducing urinary protein by controlling glucose, blood pressure, blood lipids, and other factors in DKD patients can protect renal function and especially delay the progression to chronic renal failure [80], but whether this is equally effective in NADKD patients remains to be shown [81,82]. Satirapoj et al. [83,84] showed that glycosaminoglycans (GAGs) could inhibit TGF-b1 transcription, which is induced by high levels of glucose, and protect against renal fibrosis in early-stage DM or DKD patients, but the efficacy in NADKD patients remains to be confirmed. Whether RAAS inhibitors can be used for NADKD treatment is also currently unclear. Dwyer et al. [85] proposed that RAAS inhibitors may play a protective role in NADKD progression by decreasing proteinuria, but more research is needed to confirm this.

Conclusions

In short, DM patients with renal insufficiency (eGFR<60 ml/(min·1.73 m²)) but urinary protein levels in the normal range and in whom other secondary kidney diseases (e.g., hypertensive nephropathy and obstructive nephropathy) are excluded should be considered as having DKD according to the latest ADA diagnostic criteria. Current clinical and basic research on such patients is lacking, and we need more multicenter, large-sample clinical research and investigations to further our understanding of NADKD.

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