The present study provides evidence that supports the clinical value of assessing criteria for SPS in people with type 2 diabetes regardless of their baseline renal function. Specifically, we found that an eGFRcyst/eGFRcreat ratio of <0.60, the current criterion defining the presence of SPS [6], was significantly and independently associated with 10 year mortality in representative, community-based participants with type 2 diabetes after adjustment for a wide range of potentially confounding variables. The impact was large, conferring a 56% increased risk of death compared with those with an eGFRcyst/eGFRcreat ratio ≥0.60. However, the effect was even greater in the participants who had normoalbuminuria and a normal eGFR at baseline, with a 155% increased risk of death when the eGFRcyst/eGFRcreat ratio was <0.60. SPS was not uncommon in the FDS2 cohort, affecting around 10% of study participants overall at baseline including 7.6% of those without conventional biochemical markers of DKD. These findings suggest that assessing eGFR using both creatinine- and cystatin C-based equations to determine the ratio of the two is likely to add value to the clinical assessment of all individuals with type 2 diabetes and assist with identification of people who may benefit from intensification of measures that prevent the development of CVD and DKD, and perhaps other complications associated with mortality.

Our results for type 2 diabetes are consistent with those published recently from three other large diabetes cohorts [9], although with an increased risk of death (56%) that was lower than in those of the other studies (89–158%). This lower relative mortality likely reflects, at least in part, the larger range of variables available for inclusion in adjusted models in the present analyses. Another difference was the baseline prevalence of SPS, which was 10% in the representative, community-based FDS2 participants with type 2 diabetes and thus greater than that in the other three cohorts (2.0–4.0%) [9] which may have involved relatively healthy people with diabetes [19]. In addition, the three other diabetes-specific studies would have included variable numbers of people with type 1 and other diabetes types [9] that could account for around one in every seven cases [13] and which may have a different impact on the relationship between eGFRcyst/eGFRcreat ratio and death compared with type 2 diabetes. In the present analyses of available data from the limited number of participants with type 1 diabetes, the increased mortality associated with an eGFRcyst/eGFRcreat ratio <0.60 was explained by age, but larger scale studies would be needed to explore this association in more detail. Nevertheless, it is possible that factors such as suboptimal glycaemic control and microvascular disease that underlie the relatively high mortality rate in type 1 vs type 2 diabetes [20, 21] could diminish a contribution by SPS.

An eGFRcyst/eGFRcreat ratio <0.60 was independently associated with subsequent mortality in people with type 2 diabetes and normal indices of renal function (uACR and eGFR) in the present study. This relationship has also been found in older people from the general population [8] and general hospital outpatient clinic attendees [22] but has not been assessed previously in the context of type 2 diabetes. The greater increased risk of death associated with an eGFRcyst/eGFRcreat ratio <0.60 in this subgroup (155%) compared with the type 2 diabetes cohort as a whole (56%) might be explained by the greater contribution of CVD and its risk factors to mortality in the whole cohort (as in the comparison of variables in Table 2 vs Table 4).

The term SPS is based on the pore model of glomerular disease, which proposes that a decrease in the diameter of a fraction of the pores of the glomerular membrane impairs the filtration of larger molecules including cystatin C to a greater extent than smaller molecules such as water or creatinine [2]. A recent study in people with DKD found that thickening of the glomerular basement membrane was inversely correlated with the eGFRcyst/eGFRcreat ratio, consistent with the SPS hypothesis [23]. In addition, a study carried out in Japanese adults with diabetes found that a greater eGFRcyst than eGFRcreat category was associated with mortality, although the authors did not interpret their results in terms of eGFR ratios or SPS [24]. It seems likely that associations with mortality are explained in part by proteomic changes associated with SPS [3], including an increased propensity for atherogenesis that is reflected by selective reduction in filtration of 5–30 kDa molecules such as cystatin C and others, some of which may have causative pathological associations [4].

Our results have potential clinical implications. Current Kidney Disease Improving Global Outcomes guidelines endorse the use of eGFRcyst for confirmatory testing in specific circumstances when the eGFRcreat is likely to be less accurate, such as with low muscle mass [25, 26]. However, in both the general population and people with diabetes, the value of assessing eGFR using cystatin C continues to be debated given that eGFRcyst correlates only fairly with measured GFR and is not substantially superior to eGFRcreat in this regard [10, 27]. In addition, other international guidelines do not support the use of cystatin C measurement in chronic kidney disease management [28]. Another major consideration is the greater cost of cystatin C compared with creatinine measurement as the reagent cost for a cystatin C test is approximately AUD $6 (USD $4) compared with AUD $1 (USD $0.70) for a creatinine measurement by modern enzymatic methods.

While eGFRcyst appears superior to eGFRcreat in determining risk of all-cause and cardiovascular mortality [1], our data suggest that measuring both simultaneously may have additional clinical value in type 2 diabetes. Such dual measurement may be particularly valuable early in the course of diabetes before the appearance of established predictors of DKD, as was seen in one in 13 of the FDS2 participants who had no microalbuminuria or reduction in eGFR at baseline. Although an analysis of the relationship between the eGFRcyst/eGFRcreat ratio and specific causes of death was beyond the scope of the present study and would be constrained by a lack of statistical power, reported associations between SPS and adverse cardiorenal outcomes [3,4,5] suggest that these individuals would benefit from more aggressive CVD risk reduction and/or measures aimed at reducing the risk of future DKD. There is the need for further studies to explore this hypothesis.

The present study has limitations. First, observational studies can be affected by bias related to study recruitment and retention. Another methodological limitation relates to the Cox modelling where, to avoid collinearity, the mortality hazards were assessed without including eGFRcreat, a known powerful risk factor, in the parsimonious model before entering the eGFRcyst/eGFRcreat ratio. The use of stepwise variable selection also has limitations, with the potential for biased coefficients and p values, and inflated model fit statistics. The study strengths include the representative nature of the FDS2 cohort, the comprehensive nature of the baseline assessment and the long-running validated WADLS, which systematically collects accurate data on all hospitalisations and deaths in the state of WA.

In conclusion, notwithstanding issues relating to assay cost, the present data support simultaneous measurement of serum creatinine and cystatin C and calculation of a simple ratio (eGFRcyst/eGFRcreat) in all people with type 2 diabetes as a useful clinical test for the development of cardiorenal complications associated with mortality. This includes individuals with previously normal renal function by conventional indices (eGFR and uACR).