Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus

Abstract

Objective: To examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR).

Design: Plasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure.

Results: Baseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1-8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1-7) and hyp3-bradykinin (1-7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1-8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033).

Conclusions: Higher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

Fig 1. Associations of baseline plasma BK(1–7) and hyp3-BK(1–7) with baseline Sv(PGBM/glom) in the 130 women and 116 men from RASS.

Residuals were computed by regressing each of the variables on baseline age, duration of diabetes, HbA1c, mean arterial pressure, and treatment assignment. Residuals are plotted on logarithmic scales.

Fig 2. Associations of baseline plasma BK and the sum of all unmodified bradykinin peptides with the ratio (5-year/baseline) of Sv(PGBM/glom) in the 243 RASS participants.

Residuals were computed by regressing each of the variables on sex, baseline age, duration of diabetes, HbA1c, mean arterial pressure, treatment assignment, and baseline Sv(PGBM/glom). Residuals are plotted on logarithmic scales. Values above the dashed line reflect an increase in Sv(PGBM/glom) and those below the line a decrease over 5 years.

Fig 3. Associations of baseline BK and hyp3-BK(1–8) with change in cortical interstitial fractional volume [Vv(Int/cortex)] in the 66 participants assigned to placebo, the 63 participants assigned to enalapril, and the 60 participants assigned to losartan in RASS.

Residuals were computed by regressing each of the variables on baseline age, duration of diabetes, HbA1c, mean arterial pressure, treatment assignment and baseline Vv(Int/cortex). Residuals are plotted on logarithmic scales. Values above the dashed lines reflect an increase in Vv(Int/cortex) and those below the lines a decrease over 5 years.