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NDT Advance Access published online on June 16, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn351
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Prevalence of atubular glomeruli in type 2 diabetic patients with nephropathy

Kathryn E. White1, Sally M. Marshall1 and Rudolf W. Bilous2

1 School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne 2 James Cook University Hospital, Middlesbrough, UK

Correspondence and offprint requests to: Kathryn E. White, EM Research Services, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Tel/Fax: +44-191-2226966; E-mail: k.e.white{at}ncl.ac.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Atubular glomeruli have been identified in a number of chronic renal diseases and have been linked to declining renal function. In type 1 diabetes they are present predominantly in proteinuric patients. We investigated the prevalence of atubular glomeruli in type 2 diabetes and their relationship to renal function.

Methods. Renal biopsies from 12 type 2 diabetic patients with nephropathy were processed for light and electron microscopy and analysed using standard stereological techniques. Abnormalities at the glomerular tubular junction were quantified using an index of junctional atrophy (IJA).

Results. There was no relationship between the degree of proteinuria and the presence of atubular glomeruli or atrophic tubules. Creatinine clearance correlated with the IJA (r = –0.70, P = 0.011), percent sclerosed glomeruli (r = –0.59, P = 0.027) and interstitial volume fraction (r = –0.54, P = 0.037). The IJA also correlated with foot process width and volume fraction interstitium (r = 0.58, P = 0.049 for both). Percent sclerosed glomeruli correlated with mesangial (r = 0.65, P = 0.012) and interstitial (r = 0.69, P = 0.007) volume fractions.

Conclusions. In contrast to type 1 diabetes, atubular glomeruli and atrophic tubules occur in type 2 diabetic patients with low levels of proteinuria; their development may influence the progressive change in GFR. Both glomerular and interstitial damage may lead to the development of atubular glomeruli in type 2 diabetic nephropathy.

Keywords: diabetic glomerulopathy; glomerular filtration rate; morphology; proteinuria



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The relationship between renal structure and function in diabetic patients has been described in a number of previous studies [1–4]. It is well established that the characteristic lesions of diabetic nephropathy—mesangial expansion and thickening of the glomerular basement membrane (GBM)—correlate with the level of proteinuria. Decline in GFR can be partly explained by the loss of filtration surface that accompanies mesangial expansion [5,6], but only approximately 33% of GFR variability can be explained by changes in this structural parameter [7]. This is due to the fact that GFR must depend upon the total available glomerular filtration surface, a parameter that is difficult to determine accurately in diabetic patients, as it requires an estimate of the total number of functioning glomeruli. Another factor that influences glomerular filtration is hydraulic permeability, which decreases with increased GBM thickness and decreased filtration slit frequency [8].

Atubular glomeruli, which are likely to be non-functioning, have been described in a number of different renal diseases, including type 1 diabetes [9–12]. In type 1 diabetes, atubular glomeruli and other glomerulotubular junction abnormalities (GTJA) were essentially restricted to patients with overt proteinuria and were negatively correlated with GFR [11,13]. We are unaware of any published data on atubular glomeruli in type 2 diabetes.

The aim of our study was to determine the prevalence of atubular glomeruli and other GTJAs in a group of type 2 diabetic patients with nephropathy and explore their relationship with GFR.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
The type 2 diabetic patients were part of a previous study assessing the effects of perindopril on renal structure and were recruited between 1990 and 1991 [14]. Patients were eligible if they had type 2 diabetes according to the criteria of the National Diabetes Data Group [15] and if they were between 25 and 65 years old. Patients <40 years old were required to have a known duration of diabetes of at least 2 years and did not require insulin for the first 2 years.

All studies were performed in accordance with the guidelines proposed in the Declaration of Helsinki. Approval was obtained from local independent review bodies and informed signed consent was obtained from each patient.

There was a 3-month pre-inclusion period to control glycaemia and blood pressure. Blood pressure had to be controlled to a target of <160/85 mmHg without the use of ACE inhibitors or calcium channel blockers; the {alpha}-blocker prazosin was used preferentially with or without diuretics.

At the end of the pre-inclusion period, a percutaneous renal biopsy was performed and examined by one of us (R.W.B.) and a pathologist to confirm diabetic glomerulosclerosis. To be included, biopsies had to show characteristic lesions of diabetic glomerulopathy—GBM thickening, diffuse mesangial expansion and/or classic Kimmelstiel–Wilson nodules. All type 2 patients with ischaemic nephropathy without any histological characteristics of diabetic glomerulopathy were excluded.

The identification of atubular glomeruli requires serial sectioning of at least six glomeruli. Only 12 patients who had sufficient biopsy material for determination of atubular glomeruli were included in this present study. There were no clinical differences between these patients and the whole cohort of 22 patients. The total biopsy series examined by light microscopy and a cohort of patients examined by electron microscopy have been described elsewhere [14,16]. All of the patients were receiving anti-hypertensive treatment and seven were receiving insulin therapy. Data presented here are from biopsies performed at the start of the study, prior to randomization and before any patient commenced perindopril.

Biopsy material was available from 10 non-diabetic kidney donors at time of transplantation (mean age 38 years, 5 males).

Clinical measurements
The clinical methods have been reported previously [14]. Briefly, blood pressure was measured as the average of three readings taken 1 min apart using a calibrated mercury sphygmomanometer. All urine passed during a 24-h period was collected for creatinine clearance (ClCr) and urine protein excretion. Creatinine concentration was assessed by a colorimetric method using picric acid. Urine protein concentration was determined by a colorimetric method using pyrogallol red.

Laboratory methods
For light microscopy, renal biopsies were fixed in Dubosq-Brazil fixative and embedded in paraffin. For electron microscopy, small pieces of tissue were fixed in 2% glutaraldehyde, post-fixed in osmium tetroxide, dehydrated in acetone and embedded in epoxy resin.

Light microscopy
One-micron serial sections were taken through the block and stained with toluidine blue for light microscopy. The glomerulotubular junction (GTJ) was identified in each glomerulus and scored as normal (0), atrophic tubule (1) or atubular (2) [17]. The index of junctional atrophy (IJA) was calculated as the average score of at least 6 glomeruli [11]. An atrophic tubule was defined as having flattened epithelium with no brush border and thickened tubular basement membrane. This could occur over just a few cells or a long segment of the proximal tubule (Figure 1B). The presence of tuft adhesions at the GTJ was noted (Figure 1C). An atubular glomerulus was defined as having no tubular connection (Figure 1D).


Figure 1
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  		Fig. 1 Images of (A) glomerulus with normal tubule (arrow); (B) glomerulus with atrophic tubule, note the flattened epithelial cells (arrow); (C) atrophic tubule (AT) and tuft adhesion at the glomerular tubular junction (arrow); and (D) atubular glomerulus, Bowman's capsule is thickened at the site opposite the vascular pole where the tubule should be (arrow).

 
Light microscopy was also used to estimate mean glomerular volume (MGV), volume fraction of interstitium and percent sclerosed glomeruli. For determination of MGV, a grid of points was superimposed on the toluidine blue sections, 20 µm apart, and points landing on the glomerulus (defined by the minimal string polygon enclosing the glomerular tuft [18]) were counted at a magnification of x360. Using the Cavalieri principle [19], MGV is calculated as


Formula

where t is the section thickness.

Volume fraction of interstitium was estimated by point counting on paraffin sections stained with Masson's trichrome [14]. The percentage of sclerosed glomeruli was estimated from both paraffin and resin embedded tissue in order to increase the sample size. A glomerulus was considered sclerosed when no open capillary loops were observed. The number of sclerosed glomeruli was expressed as a percentage of the total number of glomeruli, and at least 15 glomeruli per biopsy had to be counted for the measurement to be considered valid (range 16–100; mean 49).

Electron microscopy
Morphometric measurements were made on a single glomerular profile from 5 glomeruli per biopsy. Electron micrographs of the entire profile were printed at a final magnification of x2000. Mesangial volume fraction was estimated by point counting using a test grid of coarse to fine points in a ratio 1:8. Filtration surface density was estimated by counting intersections between test lines and capillary loops [20], and multiplying this parameter by glomerular volume gives filtration surface per glomerulus.

Higher magnification micrographs (final print x10 000) were taken by systematic random sampling of the glomerular tuft area. These were used to estimate the GBM width by the orthogonal intercept method [21,22] and the podocyte foot process width (FPW) from the ratio of surface density to slit length density [4,23].

Statistical analyses
Values for proteinuria were not normally distributed and were logarithmically transformed. Analysis was carried out using SPSS 11.0. Comparisons between groups were performed using Student's t-test or ANOVA for multiple comparisons. Relationships between parameters were analysed using Pearson's correlation coefficient. Stepwise linear regression was performed using creatinine clearance as the outcome variable. An adjusted R2 was used due to the large numbers of predictors in the model. A two-tailed P value < 0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
The clinical and structural characteristics of the 12 patients are shown in Table 1. The patients have also been divided into those with proteinuria above and below 500 mg/24 h, as diabetic patients with proteinuria above 500 mg/24 h are classified on a clinical basis as having overt nephropathy. There were no differences between patients based on their level of proteinuria.


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  		Table 1 Clinical and structural characteristics of 12 type 2 diabetic patients with nephropathy. The patients have been divided into those with proteinuria above and below 500 mg/24 h

 
Nine of the 12 biopsies contained some glomeruli with atrophic tubules and five patients had atubular glomeruli. All six of the patients with proteinuria below 500 mg/24 h had some glomeruli with atrophic tubules, and three had atubular glomeruli (Table 2). Of all the glomeruli examined in the diabetic patients, 26% had GTJAs and 7% were atubular. In contrast, of the glomeruli examined in the normal biopsies, 9% had GTJAs and none were atubular. Sixty-eight percent of glomeruli with atrophic tubules had tuft adhesions in the area of the GTJ (Table 2) (Figure 1C). In this region there was thickening and reduplication of Bowman's capsule with an amorphous material between the layers. In six of the nine patients with GTJAs, there were some glomeruli with capillaries containing foam cells at the adhesion site. Atubular glomeruli had thickened Bowman's capsule in the region where the GTJ would be expected to be (opposite the vascular pole) (Figure 1D). All atubular glomeruli had tuft adhesions, but only 57% appeared to be in the region of the GTJ although the precise location of the GTJ is difficult to determine.


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  		Table 2 Data on normal glomerulotubular junctions, atrophic tubules and atubular glomeruli in 12 type 2 diabetic patients

 
The structural characteristics of atubular glomeruli were compared to functioning glomeruli within the same biopsies. The results are shown in Table 3. Atubular glomeruli were significantly smaller than functioning glomeruli in the same biopsy (Figure 2). There were no differences in mesangial volume fraction, GBM width or FPW between atubular and functioning glomeruli in the same biopsy. Filtration surface per glomerulus was non-significantly reduced in atubular glomeruli in the same biopsy, partly as a result of their smaller size.


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  		Table 3 Structural characteristics of glomeruli in biopsies with or without atubular glomeruli

 

Figure 2
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  		Fig. 2 Graph showing mean glomerular volume in type 2 diabetic patients. The glomeruli have been divided into atubular and functioning glomeruli from the same biopsies and functioning glomeruli from biopsies that contain no atubular glomeruli. Atubular glomeruli are significantly smaller than functioning glomeruli (P = 0.016). Symbols {Delta} and {circ} represent statistical outliers.

 
Comparing atubular glomeruli with functioning glomeruli from biopsies that contained no atubular glomeruli gave similar results, i.e. reduced glomerular volume and corresponding reduction in filtration surface but no differences in other structural parameters (Table 3).

There was no significant relationship between proteinuria and IJA (Figure 3). The patient with the lowest proteinuria (73 mg/24 h) had 11% of glomeruli with atrophic tubules. Creatinine clearance correlated with IJA (r = –0.70, P = 0.011), percent sclerosed glomeruli (r = –0.59, P = 0.027) and interstitial volume fraction (r = –0.54, P = 0.037). The IJA also correlated with FPW and volume fraction interstitium (r = 0.58, P = 0.049 for both). Percent sclerosed glomeruli correlated with mesangial (r = 0.65, P = 0.012) and interstitial (r = 0.69, P = 0.007) volume fractions.


Figure 3
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  		Fig. 3 Graph showing that there is no relationship between the index of junctional atrophy and proteinuria in 12 type 2 diabetic patients with nephropathy. Symbol {blacktriangleup} represents patients with proteinuria ≥500 mg/ 24 h; Figure 3 represents those with proteinuria <500 mg/24 h.

 
Stepwise linear regression analysis showed that IJA, percent sclerosed glomeruli, mesangial volume fraction and FPW were independent predictors of ClCr with a combined Ra2 = 0.90, P = 0.001 (Table 4).


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  		Table 4 Linear regression analysis with creatinine clearance as the dependent variable

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
It has previously been suggested that atubular glomeruli and GTJAs in type 1 diabetic patients are a result of podocyte damage and are therefore predominantly found in patients with clinical proteinuria [11]. In this study we have shown that there is no relationship between atubular glomeruli and the level of proteinuria in type 2 diabetic patients. This does not rule out proteinuria as a contributory factor in the development of GTJAs. The degree of proteinuria required for the development of these lesions may simply be lower than that seen in our patients, who mostly had levels >300 mg/ 24 h. In support of this, atubular glomeruli were observed in one patient with total proteinuria of only 120 mg/24 h.

The lack of a relationship between proteinuria and GTJA might suggest that some patients could have proteinuria with few or no glomerular lesions. However, all biopsies had characteristic features of diabetic glomerulopathy and there was a direct correlation between mesangial volume fraction and proteinuria (data not shown)—a well-recognized relationship in diabetic nephropathy.

The formation of atubular glomeruli could occur in two ways depending on the primary disease process. Atubular glomeruli have been reported in several, mainly tubulointerstitial diseases in which tubular atrophy and interstitial fibrosis result in the glomerulus losing its connection with the proximal tubule [17]. The remaining atubular glomeruli were reported to have open capillaries and minor ultrastructural changes, though were generally smaller than those glomeruli attached to normal tubules.

A primary glomerular disease could also lead to atubular glomeruli via tuft adhesions, perhaps secondary to podocyte loss, and glomerulosclerosis. In this case the atubular glomerulus would be expected to have more extensive ultrastructural damage.

In our study, we confirmed that atubular glomeruli were significantly smaller than glomeruli attached to normal tubules in the same biopsy. The atubular glomeruli were all structurally abnormal, with typical diabetic lesions. However, the lesions were no worse in the atubular glomeruli than in glomeruli with atrophic or normal tubules. This might suggest that the predominant cause of atubular glomeruli in these patients was tubular-interstitial damage.

However, we also found that IJA correlated both with the volume fraction of interstitium and podocyte FPW. Widening of foot processes can occur in response to podocyte loss, which we have reported previously in this group of type 2 patients [24]. Extensive podocyte loss will eventually lead to denuded areas of GBM and it is at these points that tuft adhesions might occur. If atrophic tubules and tuft adhesions at the GTJ are a precursor of atubular glomeruli, this suggests that both glomerular and interstitial factors are involved in their development.

It is difficult to compare the results in our type 2 patients directly with those previously reported in type 1 diabetes [11] in which atubular glomeruli and GTJAs were essentially restricted to proteinuric patients. It should be noted that in the type 1 study proteinuria was measured on multiple 24-h urine collections compared to one 24-h collection in our patients. The IJA is based on only a few glomeruli and could therefore be a quite variable index. In addition, equal weighting is given to normal, atrophic tubules and atubular glomeruli, when it is possible that these do not develop and progress in a linear fashion. Factors such as age and duration may have an influence on the prevalence of GTJAs. In type 2 diabetes there are often more advanced tubulointerstitial lesions [25], which could result in the development of atubular glomeruli at an earlier stage of nephropathy. The patients in this study were being treated for hypertension and therefore hypertension-related changes cannot be ruled out as a factor in the development of atubular glomeruli. Arteriolar hyalinosis was evident in some glomeruli although this was not quantified. The study by Najafian et al. [11] suggested that overt proteinuria might induce new mechanisms of nephron injury—our data would suggest that the lesions can occur before overt proteinuria develops.

Biopsy material from diabetic patients is difficult to obtain, and the number of glomeruli suitable for analysis is often low. The type 1 study by Najafian et al. included 16 patients and looked at similar numbers of glomeruli per patient. Examining more glomeruli or more patients could reveal relationships that we have missed. However, the fact remains that even in this small group of patients there are atubular glomeruli and GTJ abnormalities in patients without overt proteinuria.

Atubular glomeruli and atrophic tubules appear to influence creatinine clearance. Multiple linear regression analysis showed that the IJA was an independent predictor of ClCr. Combined with other structural parameters known to have a detrimental effect on renal function the model explained 90% of the ClCr variability. This suggests a degree of interplay between different structural parameters that together can influence ClCr, and by implication GFR. It should be pointed out that using four predictors with only a small number of cases could result in an overestimation of the predictability value. Using an adjusted r2 is meant to compensate for many predictors each ‘explaining’ small portions of the variation by chance; however, some over-fitting of the data cannot be completely ruled out. The results from the linear regression analysis are similar to those reported in type 1 patients, where a model that included IJA as an independent predictor explained 92% of GFR variability [11].

GFR is determined by the total filtration surface area per kidney. Therefore, a reduction in functioning glomeruli, by glomerulosclerosis or the formation of atubular glomeruli, will result in a decline. Percent sclerosed glomeruli correlated with both mesangial and interstitial volume fraction, which suggests two routes for glomerular occlusion—one from within the glomerulus and one from without [26]. It is likely that atubular glomeruli might also develop via these two pathways.

In conclusion, atubular glomeruli and GTJAs occur in type 2 diabetic patients with nephropathy, at both low and high levels of proteinuria, and have a negative relationship with GFR. Although interstitial fibrosis is recognized as the final common pathway of multiple scarring insults to the kidney, both glomerular and interstitial lesions appear likely to contribute to the decline in GFR by leading to the development of non-functioning glomeruli.



   Acknowledgments
 
We would like to thank the staff of the EM Research Services, Newcastle University for their technical assistance and members of the Diabiopsies Group.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5. 2.08
Accepted in revised form: 29. 5.08


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