Atubular Glomeruli and Glomerulotubular Junction Abnormalities in Diabetic Nephropathy

Abstract

Abstract. Atubular glomeruli (AG) have been described in several renal disorders. However, little attention has been paid to AG in diabetic nephropathy (DN). Preliminary studies suggested that tip lesions were frequently present in type 1 diabetic (D) patients with proteinuria. The aim of this study was to determine the frequency of AG and their possible relationship with tip lesions in DN. Renal biopsies from eight proteinuric type 1 D patients with normal to moderately reduced GFR (76 Ϯ 26 ml/min per 1.73 m 2 ) and eight normal subjects were studied by light (LM) and electron microscopy (EM). Glomerular volume, volume of the glomerular corpuscle, which is tuft, and the fractional volumes of proximal, distal, and atrophic tubules per cortex were estimated using appropriate stereologic methods. Glomerulotubular junctions were examined on serial sections and classified into glomeruli attached to: normal tubules (NT); short atrophic tubules (SAT); long atrophic tubules (LAT); atrophic tubules with no observable glomerular opening (ATNO); and atubular glomeruli (AG). EM studies showed typical diabetic changes in biopsies, including increased GBM width (P Ͻ 0.00001) and mesangial fractional volume (P Ͻ 0.0001) and decreased filtration surface density (P Ͻ 0.01) compared with normal subjects. Seventeen percent of glomeruli in the D patients were atubular, and 51% were attached to atrophic tubules. Tip lesions were present in all SAT, 64% of LAT, 82% of ATNO, and only 9% of NT and were never observed in normal subjects. The relative volume of AG was smaller than glomeruli in other categories (P Ͻ 0.05). Fractional volume of proximal (P Ͻ 0.01) and distal (P Ͻ0.01) tubules per cortex were decreased, while fractional volume of cortical interstitium (P Ͻ0.00001) and atrophic tubules (P Ͻ0.01) were increased in D patients. Fractional volume of atrophic tubules, %AG, and percent of glomeruli with tip lesion explained 94% of the GFR variability in diabetic patients (P Ͻ0.05). Thus, AG and glomerulotubular junction abnormalities may be important in the development and progression of DN.Atubular glomeruli (AG) have been described in several renal disorders (1,2). AG, by definition, have open circulation but no observable tubular attachment and are thus presumably nonfunctioning (3). This phenomenon, first described by Oliver (4) as a finding in chronic Bright disease in humans, had been confirmed in experimental chronic pyelonephritis (5,6). Marcussen et al. (7-13) studied atubular glomeruli in cisplatin-and lithium-induced nephropathies in rats and chronic pyelonephritis and renal artery stenosis in humans. More recently, this phenomenon was documented in Adriamycin-induced nephrosis and the remnant kidney model in rats (14,15). An important contribution of AG to renal function impairment has been hypothesized (2,15). However, despite that 44% of all new cases of end-stage renal disease in the United States are due to diabetes, little attention has been paid to the possible role of this entity in diabetic nephropathy (1,2). ...

Glomerulotubular Junction Abnormalities Are Associated with Proteinuria in Type 1 Diabetes

“…These abnormalities were closely associated with tip lesions (glomerular tuft to Bowman's capsule adhesions [TBCA] at GTJ area), a finding reported in a variety of renal diseases with clinical proteinuria (5)(6)(7). This study also found that, along with the classical diabetic glomerulopathy lesions, these GTJA, together with tubulointerstitial parameters, predicted most of the variability in GFR among these proteinuric patients (4). However, because NA and MA patients were not included, the relationship of GTJA and AG to AER could not be assessed in this study.…”

“…Glomeruli that are attached to normal tubules in proteinuric patients are larger than those that are attached to normal tubules of patients in the other type 1 diabetes groups, perhaps representing compensatory hypertrophy. However, as described elsewhere, AG in proteinuric patients are reduced in volume, whereas glomeruli with ATNO are of intermediate size (4).…”

“…The groups were matched for age, gender, and diabetes age at onset and duration in groups with type 1 diabetes ( Table 1). Some of the data from three of the proteinuric patients with type 1 diabetes and one of the control subjects were published previously (4). All studies were performed with permission of the Committee on the Use of Human Subjects in Research at the University of Minnesota and after informed consent was obtained.…”

“…Index of arteriolar hyalinosis was determined on serial sections semiquantitatively as detailed elsewhere (14). Images of renal cortex acquired by systematic uniform random sampling were used to estimate the fractional volumes of interstitium in which no connection between the Bowman's space and the tubular lumen is discernible ( Figure 1C); and AG, in which no tubular attachment to the glomerulus is found ( Figure 1D) (4). SAT were scored ϩ 1, LAT as ϩ2, ATNO as ϩ3, and AG as ϩ4, and the index of junctional atrophy (IJA) was calculated as the average of scores among glomeruli (4).…”

Podocyte‐derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36

“…While the glomerulus is widely recognized as the primary site of injury in DN, tubular injury is also prominent. Tubular hypertrophy and interstitial inflammation are seen early in the course of DN [4–6] and with disease progression tubular atrophy and interstitial fibrosis develop in concert with declining renal function [5,7]. Cross-talk between podocytes and the tubular epithelium is believed to play an important role in the development of tubulointerstitial fibrosis and renal functional decline; however, the mechanisms by which this occurs are not fully understood [8–10].…”