Non-albuminuric renal impairment has become the prevailing DKD phenotype in individuals with type 2 diabetes and reduced eGFR, though it is still unclear whether it differs from the albuminuric phenotypes regarding the pathogenesis, prognosis and possibly treatment.
The increasing prevalence of the non-albuminuric DKD phenotype over the last decades may reflect the increasing age of the population, but the increase in prevalence of reduced eGFR was observed in both younger and older individuals from the NHANES III 1988–1994 cohort . More likely, it may be related to the increasingly widespread use of blockers of the renin–angiotensin system (RAS) , favouring prevention of albuminuria and/or regression of micro/macroalbuminuria to normoalbuminuria [32, 33]. However, the NHANES III 1988–1994 findings only partly support this hypothesis, as reduction of albuminuria was associated with an absolute, not relative, increase in prevalence of reduced eGFR . In addition, the progressive lowering of average blood pressure during the past two decades among adults with diabetes may have resulted in reduction of renal perfusion pressure and, hence, of eGFR in some of these individuals . The increasing prevalence of the non-albuminuric phenotype may also reflect the continuing decrease in mortality  and progression to end-stage renal disease  observed in recent years in diabetic people because of improved treatment, but reduction in mortality was confined to individuals with albuminuria (see below). The weak association with diabetic retinopathy and the lack of association with HbA1c [6, 11, 36] suggest that non-albuminuric DKD may represent a distinct phenotype, with macroangiopathy instead of microangiopathy as the prevailing underlying pathology [4, 5]. This would be the case especially in individuals with type 2 diabetes, who present with several CVD risk factors in addition to hyperglycaemia, including hypertension, dyslipidaemia, central obesity and ageing itself, all of which may contribute to renal injury, though to a varying extent in each individual [4, 5]. Unfortunately, the clinical phenotype cannot be related to a specific anatomical phenotype, with presence or absence of albuminuria corresponding to typical glomerular or atypical vascular and/or tubulo-interstitial lesions, respectively. In fact, among individuals with reduced eGFR, those with micro/macroalbuminuria were found to have typical glomerular lesions, whereas half of those with normoalbuminuria showed atypical lesions, but the other half still presented with diabetic glomerulosclerosis, though associated with varying degrees of arteriosclerosis . Moreover, a wide spectrum of renal pathology, including atypical lesions, was also observed in individuals with type 2 diabetes with preserved renal function and microalbuminuria , whereas typical (glomerular) microangiopathic lesions were detected in individuals with type 1 diabetes and normoalbuminuric renal impairment . For these reasons, true diabetic nephropathy (glomerulosclerosis) cannot be distinguished on a clinical basis from ischaemic or hypertensive renal disease occurring in individuals with type 2 diabetes, thus prompting the use of DKD to encompass all types of renal dysfunction occurring in diabetic individuals, except for those of true non-diabetic nature [2, 4, 5].
To date, few data are available on the rate of death in both diabetic and non-diabetic individuals presenting with non-albuminuric DKD. Two meta-analyses from the general population [17, 18] and high-CVD-risk cohorts (including diabetic individuals)  showed that all-cause and CVD mortality increase for eGFR values below 45 or 60 ml min−1 1.73 m−2 in the presence of ACR <10 mg/g or dipstick-negative proteinuria. Information on mortality rates associated with the non-albuminuric phenotype has been derived from studies in individuals with type 2 diabetes, though the results are not univocal. A post hoc analysis of the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study (10,640 participants) showed that risk of CVD death associated with non-albuminuric DKD was similar to that of microalbuminuria with an eGFR ≥90 ml min−1 1.73 m−2, but lower than that of microalbuminuria with an eGFR 60–89 ml min−1 1.73 m−2 and of macroalbuminuria with an eGFR >60 ml min−1 1.73 m−2 . Conversely, a post hoc analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (9795 participants) showed that the non-albuminuric phenotype was associated with a higher risk of CVD, non-CVD and all-cause death compared with that of microalbuminuria with an eGFR >60 ml min−1 1.73 m−2 and even of macroalbuminuria ≥90 ml min−1 1.73 m−2 . However, the results of these two post hoc analyses might have been affected by the selection criteria for trial entry, resulting in a limited number of individuals with eGFR <60 ml min−1 1.73 m−2, which did not allow grading of mortality risk within the range of reduced eGFR. The community-based Casale Monferrato Study (1565 persons) detected a significant trend towards an increase in mortality risk with decreasing eGFR only in macroalbuminuric individuals . In contrast, in the Cardiovascular Health Study (691 older diabetic adults), the adjusted risk of death was similar for albuminuria alone and reduced cystatin C-based eGFR alone . Linking the NHANES III data with the National Death Index (1430 persons) revealed that the standardised 10 year mortality in the non-albuminuric phenotype was intermediate between the albuminuric DKD phenotypes without and with reduced eGFR . Of note, serial cross-sectional analyses of the NHANES III data showed that mortality rates in adults with diabetes trended downward for individuals with increased albuminuria, but increased for those with decreased eGFR and normoalbuminuria from 1988 to 2006 . These time-dependent changes in mortality associated with albuminuria alone vs reduced eGFR alone may also explain, at least partly, the different mortality data reported by previous studies [9, 10, 20, 21, 40].
Our study specifically addressed mortality in individuals with type 2 diabetes and non-albuminuric DKD and graded the risk of death according to the extent of albuminuria and eGFR loss within the normal and reduced range, respectively. The results indicated that non-albuminuric renal impairment is associated with a significant risk of death, despite the risk associated with reduced eGFR values sometimes being underestimated in the absence of albuminuria. The adjusted HR of reduced eGFR alone was similar to that of albuminuria alone. Moreover, in normoalbuminuric participants with eGFR 45–59 ml min−1 1.73 m−2, risk was similar to that of individuals with microalbuminuria alone and, in those with eGFR <45 ml min−1 1.73 m−2, it was similar to that of participants with macroalbuminuria alone.
These results are consistent with the very recent report from NHANES III showing that, in the 2003–2006 population, age-standardised mortality risk with non-albuminuric DKD was indeed higher than for microalbuminuria alone and macroalbuminuria with eGFR ≥90 ml min−1 1.73 m−2, but lower than for macroalbuminuria with eGFR 60–89 60 ml min−1 1.73 m−2 . Data from both the RIACE and the NHANES III cohorts point to a major prognostic value of CKD irrespective of albuminuria and indicate that changes in treatment, particularly the increasing use of RAS blockers resulting in lower blood pressure levels, have not impacted favourably on mortality in the non-albuminuric phenotype. The lack of effective therapeutic interventions in individuals presenting with this phenotype may also be because, so far, clinical trials have focused almost exclusively on individuals with micro- or macroalbuminuria. The finding that, in individuals aged <55 years, non-albuminuric DKD was associated with the highest risk of death has no obvious explanation and must be interpreted with caution owing to the very small number of individuals in this group.
At RECPAM analysis, variables associated with mortality risk in each DKD phenotype include history of CVD and traditional CVD risk factors, consistent with the major contribution of CVD to excess death in diabetic individuals . Previous CVD events and HDL-cholesterol are the main determinants of mortality in all DKD phenotypes, in accordance with the strict relation of renal impairment with CVD morbidity and mortality  and the predictive value of HDL-cholesterol for CVD outcomes in individuals with type 2 diabetes , especially in those on target for LDL-cholesterol . The inverse association of mortality with LDL-cholesterol and diastolic BP (and with total cholesterol and systolic BP in Cox regression analysis) likely represents an indication effect, i.e. individuals with more complications who are therefore at higher risk of death were treated more intensively and, as a consequence, presented with lower cholesterol and BP levels. In addition, this analysis demonstrates that the other variables associated with all-cause mortality differ among DKD phenotypes, thus supporting the concept that the non-albuminuric form is distinct from the albuminuric ones. In particular, AER levels within the normoalbuminuric range, together with higher eWC, were shown to affect mortality in individuals with non-albuminuric DKD without prevalent CVD. Conversely, death in the non-albuminuric phenotype was not associated with classic ‘microvascular signatures’ such as glycaemic exposure (HbA1c, diabetes duration) and diabetic retinopathy, at variance with the albuminuric phenotypes and consistent with the hypothesis of a prevailing macrovascular nature of underlying lesions .
The strengths of this study include the specific focus on the non-albuminuric DKD phenotype, the large size of the cohort, the completeness of baseline and follow-up data, the analysis of a contemporary and real-life dataset and the application of RECPAM analysis, which allowed the identification of clinical features of subgroups with distinct mortality risks within each DKD phenotype. Furthermore, our cohort may be considered as representative of type 2 diabetic individuals not receiving dialysis attending tertiary referral diabetes clinics in Italy. The main limitation is that these individuals do not represent the totality of people with type 2 diabetes, as a proportion are not followed in such centres. Other limitations are the relatively low number of participants with eGFR <30 ml min−1 1.73 m−2, the lack of information on causes of death and the possible, though inevitable, misclassification of some individuals into DKD phenotypes, due to the influence of drug treatment on both albuminuria and serum creatinine and imprecision of GFR estimation from creatinine, which may cause either under- or overestimation of eGFR. However, Rigalleau et al showed that correlation of eGFR with isotopic GFR was not weaker in non-albuminuric than in albuminuric individuals with reduced eGFR , indicating that the likelihood of eGFR underestimation is not restricted to the non-albuminuric phenotype. In addition, factors such as age and use of RAS blockers, which may affect eGFR (and albuminuria) and impact on mortality independently of renal function, were similar in non-albuminuric and albuminuric individuals with reduced eGFR from the RIACE cohort (use of RAS blockers was also similar in non-albuminuric and albuminuric individuals with preserved eGFR). Other potential limitations of the methods have been extensively addressed elsewhere [11, 22,23,24, 29, 30, 36].
In conclusion, the non-albuminuric DKD phenotype is a strong predictor of all-cause mortality in individuals with type 2 diabetes, particularly so in individuals with eGFR <45 ml min−1 1.73 m−2, who have a risk of all-cause mortality that is higher than individuals with microalbuminuria alone and similar to those with macroalbuminuria alone, especially if AER is in the low albuminuria range. Determinants of mortality risk in non-albuminuric renal impairment differ, at least in part, from those of the albuminuric forms, thus indicating that this is a distinct phenotype. These data indicate a major prognostic impact of CKD irrespective of albuminuria and suggest that individuals with non-albuminuric DKD deserve a higher level of attention and care than is generally provided. In particular, the rising mortality rate associated with this increasingly prevalent non-albuminuric DKD phenotype  indicates the need for effective intervention strategies and public health policies focusing on reduced eGFR.