Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function

Abstract

Objective: The structural basis of normoalbuminuric renal insufficiency in patients with type 2 diabetes remains to be elucidated. We compared renal biopsy findings in patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) and measured GFR of <60 mL/min/1.73 m2, associated with either normo-, micro-, or macroalbuminuria.

Research design and methods: In patients with normo- (n = 8) or microalbuminuria (n = 6), renal biopsies were performed according to a research protocol. In patients with macroalbuminuria (n = 17), biopsies were performed according to clinical indication. Findings were categorized according to the Fioretto classification: category 1 (C1), normal/near normal; category 2 (C2), typical diabetic nephropathy (DN) with predominantly glomerular changes; and category 3 (C3), atypical with disproportionately severe interstitial/tubular/vascular damage and with no/mild diabetic glomerular changes.

Results: In our study population (mean eGFR 35 mL/min/1.73 m2), typical glomerular changes (C2) of DN were observed in 22 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 subjects with normoalbuminuria (P = 0.002). By contrast, predominantly interstitial or vascular changes (C3) were seen in only 1 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 normoalbuminuric subjects (P = 0.08). Mesangial area increased progressively from normal controls to patients with type 2 diabetes and normo-, micro-, and macroalbuminuria. Varying degrees of arteriosclerosis, although not necessarily the predominant pattern, were seen in seven of eight subjects with normoalbuminuria.

Conclusions: Typical renal structural changes of DN were observed in patients with type 2 diabetes and elevated albuminuria. By contrast, in normoalbuminuric renal insufficiency, these changes were seen less frequently, likely reflecting greater contributions from aging, hypertension, and arteriosclerosis.

Figure 1

Study protocol. Fourteen patients had research renal biopsies, and 17 patients with macroalbuminuria had renal biopsies for clinical reasons. As part of the study protocol, after ceasing RAS inhibitor therapy for 4–6 weeks prebiopsy, 2 out of 10 patients with normoalbuminuria developed microalbuminuria (“pseudonormoalbuminuria”), making the total number of patients with normoalbuminuria eight and with microalbuminuria six. Normo, normoalbuminuria; micro, microalbuminuria; macro; macroalbuminuria.

Figure 2

Histological appearances representative of normoalbuminuric cases. A: Patient 1, from Table 3, demonstrating normal glomerulus and arteries, Fioretto C1. B: Patient 3, from Table 3, demonstrating advanced diabetic GS and arteriosclerosis (inset), Fioretto C2. C: Patient 8, from Table 3, demonstrating minimal glomerular mesangial expansion and severe arteriosclerosis (inset), Fioretto C3 (all images periodic acid–Schiff stain, original magnification ×200).

Figure 3

Mean mesangial area (micron²) across normal controls (normal C), patients with type 2 diabetes and normoalbuminuria (normo), patients with type 2 diabetes and microalbuminuria (micro), and patients with type 2 diabetes and macroalbuminuria (macro). P = 0.02, one-way ANOVA for mean mesangial area across the four groups.