Tubular and Glomerular Injury in Diabetes and the Impact of ACE Inhibition

Abstract

OBJECTIVEWe studied tubular and glomerular damage in type 1 diabetic patients by measuring urinary–liver fatty acid binding protein (U-LFABP) and albuminuria. Subsequently, we evaluated the effect of ACE inhibition on U-LFABP in patients with diabetic nephropathy.RESEARCH DESIGN AND METHODSWe studied Caucasians with type 1 diabetes: 58 with normoalbuminuria (urinary albumin <30 mg/24 h), 45 with persistent microalbuminuria (30–300 mg/24 h), and 45 with persistent macroalbuminuria (≥300 mg/24 h). A control group consisted of 57 healthy individuals. The groups were matched by sex and duration of diabetes. In addition, U-LFABP was measured in 48 type 1 diabetic patients with diabetic nephropathy in a randomized crossover trial consisting of 2 months of treatment with 20, 40, and 60 mg lisinopril once daily in random order.RESULTSIn the cross-sectional study, levels of U-LFABP were significantly higher in normoalbuminuric patients versus those in the control group (median 2.6 [interquartile range 1.3–4.1] vs. 19 [0.8–3.0] μg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8–8.3] μg/g creatinine and nephropathy group 71.2 [8.1–123.4], P < 0.05 for all comparisons). U-LFABP correlates with the urinary albumin-to-creatinine ratio (R2 = 0.54, P < 0.001). In the intervention study, all doses of lisinopril significantly reduced urinary albumin excretion rate and U-LFABP from baseline. The reductions in U-LFABP were 43, 46, and 40% with increasing doses of lisinopril (NS).CONCLUSIONSAn early and progressive increase in tubulointerstitial damage as reflected by increased U-LFABP levels occurs in type 1 diabetic patients and is associated with albuminuria. Furthermore, ACE inhibition reduces the tubular and glomerular damage and dysfunction.

Urinary Neutrophil Gelatinase-Associated Lipocalin and Progression of Diabetic Nephropathy in Type 1 Diabetic Patients in a Four-Year Follow-Up Study

“…In our previous cross-sectional study, we found no evidence of an extrarenal production of NGAL which supports the hypothesis of NGAL as a specific marker of renal damage [8]. In chronic kidney disease (CKD) of mixed etiology, it has been shown that the level of u-NGAL reflects the degree of inflammation and activity in the disease and that it predicts progression in CKD [9,10].…”

“…NGAL is produced in epithelial cells and neutrophils in most tissues and is a marker of renal tubular damage [5]. Previously, we have shown that urinary levels of the tubular markers NGAL [6] and urinary liver-type fatty acid-binding protein [7,8] are increased in T1D patients, even before they develop signs of glomerular damage, i.e. micro- or macroalbuminuria.…”

Renal function in diabetic nephropathy

“…Suzuki et al [80] performed a crosssectional study in 356 adult type 2 diabetic patients and found a significant association between the stage of diabetic nephropathy and ULFABP, although no significant difference between the normoalbuminuric and microalbuminuric groups was seen. Stine et al [81] have shown that ULFABP, is elevated in type 1 diabetic patients compared with nondiabetic healthy control subjects and that the level further increases with micro and macroalbuminuria, reflecting increased tubular damage. There were no significant correlations between ULFABP and sex, age, or A1C.…”

Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy

“…3,11,12 It has been reported that tubular proteinuria occurs even in the early stage of DN with normal urine protein excretion rate, suggesting tubulointerstitial damage might happen earlier than the glomerular damage. 13 Renal tubular epithelial-myofibroblast transdifferentiation plays a very important role in the development of tubular lesion and tubulointerstitial fibrosis. 14,15 In the diabetic kidney, the extensive infiltration of monocytes/macrophages can cause the accumulation of extracellular matrix, thickening of the glomerular basement membrane, and the subsequent development of interstitial fibrosis and glomerular sclerosis.…”