Increased urinary renin in type 1 diabetes patients with nephropathy

Background: Prorenin has been reported to be increased in plasma from patients with Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) with complications. By contrast, plasma renin activity is often reduced in such patients. There is little information on either renin or prorenin in urine of patients with diabetes and renal complications. Recent studies have shown that the soluble prorenin receptor can non-enzymatically activate prorenin, and therefore activate Renin-Angiotensin-System (RAS). Proteolytic and non-proteolytic activation of prorenin could be important in kidney RAS overactivity in diabetic kidney disease (DKD). We evaluated urinary active renin as well as prorenin in biosamples from subjects with T1D who have developed overt DKD and controls who have not, despite similar or longer diabetes duration (>25 years). Methods: Biosamples and clinical data from people with T1D were obtained from the Kidney Research Institute DKD Repository of the University of Washington. DKD was defined as either eGFR <60 mL/min per 1.73 m² (n=29) or urine ACR ≥300 mg/g (n=22). A total of 31 subjects met these criteria for DKD. People with longstanding diabetes but no evidence of DKD had ≥28 years of T1D, estimated eGFR >60 mL/min per 1.73 m² and ACR <30 mg/g (n=40). Samples for active renin were first concentrated before applying to ELISA. Urinary prorenin was measured using ELISA detecting prorenin only. Results: As expected from selection criteria, median ACR was much higher in the group with DKD than the control group with longstanding type 1 diabetes without DKD. Accordingly, median ACR exceeded 300 mg/g in people with DKD, but was normal (<30 mg/g) in the control group; p<0.001. Median urine active renin/Cr was increased in subjects with DKD 3.2 pg/mg (2.3, 10.5) as compared to those without it 1.8 pg/mg (0.9, 3.8); p=0.002. Prorenin was detectable in 81% (25/31) of samples from the cases but only in 50% of the urines (20/40) from the controls with diabetes who did not have diabetic kidney disease. For the statistical analysis, the values below the lower limit of quantification (LLOQ) were set to 0.5 x LLOQ; Median urine Prorenin/Cr (IQR) was significantly higher in DKD biosamples 99 (29, 311) pg/mg than in biosamples from those without DKD 38 (20, 77) pg/mg p=0.012. There was a significant positive correlation between urinary prorenin and active renin protein (0.691, p<0.001). Conclusions: Both active renin and prorenin are increased in the urine from patients with DKD as compared to those who have escaped this complication after longstanding diabetes. Urinary prorenin could be a source of increased urinary active renin and contribute to activation of RAS in persons with type 1 diabetes who have DKD. Prospective studies are needed to examine the potential predictive value of urinary prorenin and active renin as biomarkers for the development of DKD.