Plasma zinc-α2-glycoprotein predicts normoalbuminuric CKD progression in diabetics

Plasma levels of zinc-α2-glycoprotein (ZAG) may help predict the progression of nonalbuminuric chronic kidney disease (CKD) in patients with type 2 diabetes, according to a Singapore study.

“In the present study, we demonstrated for the first time that elevated baseline plasma ZAG levels predicted risk of CKD progression and rapid estimated glomerular filtration rate (eGFR) decline in type 2 diabetes among individuals with normoalbuminuria at entry,” researchers said.

“This observation may be clinically important because the presence (and deterioration) of albuminuria is currently the best biomarker available in the clinics to predict CKD progression,” they added.

Of the 341 patients (mean age, 57±10 years; 52 percent male), 16 percent (n=54) showed progression of CKD over a mean follow-up duration of 4.0±1.0 years. Progression occurred under normoalbuminuric conditions. [Diabet Med 2020;doi:10.1111/dme.14313]

Aside from having had diabetes for a longer time and lower eGFR levels, progressors also showed significantly elevated median levels of ZAG at baseline relative to their nonprogressing counterparts (49.7 vs 42.6 µg/mL, 17-percent change; p=0.011). Moreover, there were significantly more progressors in the topmost tertile of ZAG, relative to the other two categories (p=0.019).

Cox proportional hazards regression analysis showed that being in the highest tertile of plasma ZAG concentrations more than doubled the risk of CKD progression in the study sample (hazard ratio [HR], 2.11, 95 percent confidence interval [CI], 1.06–4.21; p=0.033). The second middle tertile was associated with only a marginal increase in risk (HR, 1.68, 95 percent CI, 0.76–3.71; p=0.196).

Taking ZAG levels as a natural log-transformed continuous variable yielded the same outcome (HR, 1.64, 95 percent CI, 1.02–2.62; p=0.04).

Even on its own, baseline plasma ZAG, taken as a continuous variable, had a high C-index value of 0.65, (95 percent CI, 0.56–0.73; p<0.001). When further combined with the use of antagonists of the renin angiotensin system (RAS), the C-index value jumped to 0.71 (95 percent CI, 0.64–0.78; p<0.001). When categorical ZAG was used instead, the C-index was 0.70, (95 percent CI, 0.63–0.77).

Including ZAG, either as a continuous (p=0.003) or categorical (p=0.006) variable, significantly improves the risk predictive capacity of RAS antagonists alone for CKD progression.

“[A}mong normoalbuminuric individuals with type 2 diabetes, no suitable biomarker predictive of renal progression is available at present,” the researchers said. If ZAG is eventually verified to be a strong indicator of CKD in this population, it may provide a good alternative to albuminuria and improve clinical practice.

“Nevertheless, due to the heterogeneity of CKD and hence its disease progression trajectories, it is unlikely that ZAG would singly display a strong discriminative power,” they added. “Combining ZAG with other molecular biomarker candidates and clinical markers may potentially improve risk prediction of nonalbuminuric CKD.”

Future studies are required to establish these markers and to determine whether or not plasma ZAG can also indicate treatment response.