King's College London

Context and Objective

Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in type 2 diabetes mellitus (T2DM) patients with relatively preserved renal function is unknown.

Design, setting, participants and measurements

Single-centre observational follow-up study of 101 patients with T2DM and eGFR >45 ml/min, [91% on renin angiotensin system (RAS) blockade] followed for a median (range) of 9 (2-13) years.

Main Outcome

Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, fibroblast growth factor-23 (FGF-23) levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements.

Results

Patients with residual microalbuminuria (MA) despite RAS blockade (n=53) had significantly lower levels of sKlotho median, interquartile range (IQR), 184.7 (130.5-271.8) pg/ml compared to patients without MA (n=39) pg/ml 235.2 (172.0-289.4) p=0.03.

Of the cohort, 21% reached the primary outcome. A 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (Hazard ratio 0.27, 95% CI 0.15-0.52, p<0.001) independent of traditional risk factors in a competing risk analysis. Patients with sKlotho level below the median of 204.4 pg/ml had nearly a 4 fold higher cumulative incidence of the primary outcome compared to those above the median (24% vs 6.2%, p=0.01).

Conclusions

In T2DM patients with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk-markers. sKlotho is a novel bio-marker of renal dysfunction and potential treatment target for renoprotection in T2DM.