Glomerulotubular Junction Abnormalities Are Associated with Proteinuria in Type 1 Diabetes

Abstract

Glomerulotubular junction abnormalities, frequent in proteinuric patients with type 1 diabetes, may contribute to the progressive GFR loss in overt diabetic nephropathy. Glomerulotubular junction abnormalities were examined in patients who have type 1 diabetes with a wide range of albumin excretion rates (AER). Renal biopsies from five normoalbuminuric patients, five microalbuminuric patients, six proteinuric patients, and five control subjects were studied by light and electron microscopy. Light microscopy specimens were serially sectioned to find and classify glomerulotubular junctions. Glomerular structural parameters were estimated using stereologic methods. Glomerulotubular junction abnormalities were found in 2% of glomeruli from control and normoalbuminuric patients and in 4% of glomeruli from microalbuminuric patients. In contrast, 71% of glomeruli from proteinuric patients had glomerulotubular junction abnormalities, including five (8%) atubular glomeruli. Electron microscopy findings were typical of diabetic nephropathy. Piece-wise linear regression models with glomerular, glomerulotubular junction, and interstitial parameters as independent variables provided greater GFR (92%; P < 0.005) and AER (95%; P < 0.01) prediction than multiple regression models (81% for GFR and 72% for AER). Thus, glomerular adhesions and glomerulotubular junction abnormalities help to explain the progressive GFR loss that is associated with onset of proteinuria in type 1 diabetes. Moreover, nonlinear models provide better fit for structural-functional relationships in patients with type 1 diabetes.

Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis

“…Atubular glomeruli are commonly observed in various types of CKD, [41][42][43][44] and also reported in animal models of tubular injury. 45,46 Our data indicate that selective proximal tubule injury is sufficient to cause atubular glomeruli.…”

The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007

“…Additional abnormalities include global glomerular sclerosis [23] and interstitial expansion [21]. More recently, we reported that the onset of proteinuria is associated with the development of new glomerular lesions, specifically, widespread abnormalities of the junction of the proximal tubule with the glomerulus, which ultimately lead to separation of the glomerulus from its tubule (atubular glomeruli) and, thus, loss of glomerular function [24,25].…”

“…However, in advanced stages of the disease, interstitial, tubular and glomerulo-tubular junction injuries drive the progression towards ESRD [24,25].…”

Are glomerular volume differences between type 1 and type 2 diabetic patients pathologically significant?

“…may contribute to the decline in GFR [25]. There are no published data on type 2 diabetes, but it is possible that there are fewer atubular glomeruli resulting in better preservation of GFR; or conversely, that there is a higher frequency of atubular glomeruli resulting in glomerular enlargement of the remaining functional glomeruli and subsequent preservation of GFR.…”