Original Articles

The Relevance of Periglomerular Fibrosis in the Evaluation of Routine Needle Core Renal Biopsies Joseph Jenkins, MD; Sergey V. Brodsky, MD, PhD; Anjali A. Satoskar, MD; Gyongyi Nadasdy, MD; Tibor Nadasdy, MD

Context.—Renal interstitial fibrosis Nextent, sclerotic glomeruli correlate

and, to a lesser with poor renal function. However, not all nonfunctional glomeruli are sclerotic. Many or most glomeruli with periglomerular fibrosis, while retaining blood flow, probably do not filter; therefore, they may not contribute to renal function. Objective.—To examine the relationship of periglomerular fibrosis and the sum of globally sclerotic glomeruli and glomeruli with periglomerular fibrosis (GSG+PF) with interstitial fibrosis and renal function. Design.—Native kidney biopsies from 177 patients with chronic renal injury were assessed for interstitial fibrosis, glomerular sclerosis, and GSG+PF. Renal biopsies with active or acute lesions were not included. The percentage of globally sclerotic glomeruli and GSG+PF was correlated with the degree of interstitial fibrosis and serum creatinine levels.

Results.—The percentage of GSG+PF correlates better with the degree of interstitial fibrosis and renal function than does the percentage of globally sclerotic glomeruli alone. This appears particularly true in chronic renal diseases of patients without diabetes. The number of globally sclerotic glomeruli correlates better with interstitial fibrosis and renal function than does the sum of globally and segmentally sclerotic glomeruli. Conclusions.—The percentage of GSG+PF in a renal biopsy specimen provides a better estimate of chronic renal injury than does the percentage of sclerotic glomeruli alone, probably because many or most glomeruli with periglomerular fibrosis are nonfunctional. Therefore, we recommend that the number of glomeruli with periglomerular fibrosis also be provided in the renal biopsy report. (Arch Pathol Lab Med. 2011;135:117–122)

long time ago, interstitial volume and interstitial A fibrosis were recognized as correlating better with renal function than were glomerular changes. Although

have open capillaries, and only minor ultrastructural changes are seen.9 Usually, atubular glomeruli also reveal periglomerular fibrosis. In our and others’ experience, periglomerular fibrosis cannot be equated with atubular glomeruli because, many times, connection of the Bowman space to the proximal tubule is preserved.10 However, the glomerulotubular junction is almost always stenotic in glomeruli with periglomerular fibrosis, and the adjoining proximal tubule is usually atrophic.10,11 Even if these glomeruli retain some degree of filtration, they probably do not contribute to renal function, and it is likely that most glomeruli with periglomerular fibrosis, just like sclerotic glomeruli, are nonfunctional. Therefore, we recently started to provide the number of glomeruli with periglomerular fibrosis in every renal biopsy specimen. The goal of our study was to determine the relevance of periglomerular fibrosis in chronic renal injury. In particular, we were interested in whether the sum of globally sclerotic glomeruli and glomeruli with periglomerular fibrosis (GSG+PF) shows a better correlation with interstitial fibrosis and renal function than does sclerotic glomeruli only. We also wanted to determine whether the percentage of interstitial fibrosis or the percentage of GSG+PF provided a better estimate of renal function in a renal biopsy specimen.

1,2,3

providing the number or percentage of globally and segmentally sclerotic glomeruli in a renal biopsy specimen is routine practice,4 in many instances, the percentage of sclerotic glomeruli does not reflect renal function well. This is true not only in primary tubulointerstitial diseases but also sometimes in glomerular diseases.5 However, not all glomeruli with open capillaries are functional glomeruli. Atubular glomeruli (glomeruli without connection to the proximal tubule) were first described by Oliver6 in 1937. Later, atubular glomeruli were shown to constitute a significant portion of the glomerular population in many chronic diseases, both in humans and in experimental animals.7,8 Obviously, atubular glomeruli are nonfunctional because they do not filter. Atubular glomeruli tend to be smaller (in volume) than glomeruli with intact tubular connections and may have somewhat ischemic, wrinkledappearing capillary loops. However, atubular glomeruli Accepted for publication March 29, 2010. From the Department of Pathology, The Ohio State University, Columbus. The authors have no relevant financial interest in the products or companies described in this article. Presented as a poster at the 98th Annual Meeting of the United States and Canadian Academy of Pathology, Boston, Massachusetts, March 9, 2009. Reprints: Tibor Nadasdy, MD, Department of Pathology, The Ohio State University, M015 Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210 (e-mail: [email protected]). Arch Pathol Lab Med—Vol 135, January 2011

MATERIALS AND METHODS We began counting the number of glomeruli with periglomerular fibrosis in renal biopsy specimens 2 years ago. For this study, we reviewed our renal biopsy files and selected 177 native kidney biopsies that were taken from adult patients with chronic renal diseases. All biopsies had variable degrees of interstitial Periglomerular Fibrosis—Jenkins et al

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fibrosis, from mild to severe. Biopsies with acute injury or active proliferative changes (such as proliferative glomerulonephritis, interstitial nephritis, acute tubular necrosis, thrombotic microangiopathies, or vasculitis) were not included. Only biopsies containing more than 10 glomeruli were studied. The most common diagnosis was diabetic nephropathy (n 5 59; 33%) followed by primary and secondary forms of focal segmental glomerular sclerosis (n 5 37; 21%), hypertensive and atherosclerotic renal disease (n 5 30; 17%), membranous nephropathy (n 5 19; 11%), primary chronic tubulointerstitial nephritis (n 5 7; 4%), amyloidosis/monoclonal immunoglobulin deposition disease (n 5 7; 4%), thin basement membrane nephropathy/Alport syndrome (n 5 6; 3%), minimal change disease superimposed on nephrosclerosis (n 5 4; 2%), fibrillary glomerulonephritis (n 5 3; 2%), inactive membranoproliferative glomerulonephritis or idiopathic nodular glomerular sclerosis (n 5 3; 2%), inactive lupus nephritis (n 5 1; 1%), and fibronectin glomerulopathy (n 5 1; 1%). There are 2 main patterns of glomerular solidification (Figure 1): In most primary and secondary glomerular diseases, glomeruli undergo matrix overproduction or impaired matrix degradation and turn globally sclerotic with material that is positive for periodic acid–Schiff (PAS) and methenamine silver occupying most of the Bowman space. In such glomeruli, hyalin change is frequently admixed with the sclerosis.12,13 We call these glomeruli ‘‘true’’ sclerotic glomeruli (Figure 1, A). The other main type of glomerular solidification is when the glomerular capillary tuft retracts to the vascular pole, and the Bowman capsule is filled with interstitial-type collagen. Such glomeruli usually have wrinkled, frequently lamellated, Bowman capsule basement membrane (Figure 1, B). We call these glomeruli ‘‘obsolescent’’ glomeruli, and they are usually the result of normal aging and chronic vascular disease (nephrosclerosis).13,14,15 These glomeruli may sometimes be difficult to differentiate from fibrous crescents, but cases of crescentic glomerulonephritis were not included in our study. Sometimes, there may be overlaps between the 2 major patterns of glomerular solidifications, but in this article, for simplicity, we designate both true sclerotic glomeruli and obsolescent glomeruli as globally sclerotic glomeruli. We define segmentally sclerotic glomeruli in tissue sections as glomeruli with open glomerular capillaries in at least 25% of the glomerular surface area; the remaining area of the glomerulus is obliterated by PAS- and methenamine silver–positive sclerotic material and/or hyalin. We consider sclerotic glomeruli with only rare open, wrinkled capillaries as globally sclerotic. Periglomerular fibrosis has not been rigorously defined in the literature. We define periglomerular fibrosis as glomeruli with open capillaries, but lamellated, frequently wrinkled, Bowman capsular basement membrane and circumferential layers of interstitial-type collagen around, within, or between the usually thickened, frequently lamellated, Bowman capsule basement membrane (Figure 2). The lesion could be more appropriately called Bowman capsular thickening because in renal pathology, an increase in basement membrane material is called sclerosis, whereas an increase in interstitial type collagen is designated as fibrosis. In periglomerular fibrosis, it is common to see increased interstitial type collagen admixed with Bowman capsular basement membrane material. The interstitial-type collagen may be present outside the Bowman capsular basement membrane, between layers of the lamellated basement membrane, or even inside the Bowman capsular basement membrane (Figure 2, A through C). Periglomerular fibrosis may be circumferential but is not always so. The lesion is usually more prominent at the tubular pole of the glomerulus than at the vascular pole. We considered a glomerulus to have periglomerular fibrosis if it was present at least 50% of the glomerular circumference and involved the tubular pole. In such instances, the adjoining proximal tubule was invariably atrophic. These atrophic, proximal tubules may preserve a narrow connection to the Bowman capsule but are frequently 118

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Figure 1. Main forms of glomerular solidification. A, In globally sclerotic glomeruli, the glomerular capillary tuft undergoes periodic acid–Schiff (PAS)-positive sclerosis, occupying the entire Bowman capsule. B, In an obsolescent glomerulus, the PAS-positive glomerular capillaries retract to the vascular pole, and the Bowman capsule is filled with faintly PAS-positive interstitial type collagen. The Bowman capsular basement membrane is usually thickened and lamellated, but it usually does not show prominent disruption (original magnifications 3200).

completely cut off at the glomerulotubular junction (atubular glomeruli) (Figure 2, B and C). The examined parameters were scored at the time of the biopsy evaluation. The number of globally sclerotic glomeruli, segmentally sclerotic glomeruli, and glomeruli with periglomerular fibrosis were provided in all renal biopsy reports. The degree of interstitial fibrosis was also estimated in every biopsy specimen, based on Masson trichrome, hematoxylin-eosin, and PAS stains, and was given in percentages (to the nearest 5%) involving the renal cortex. A database was developed that was based on review of the renal biopsy reports of the 177 biopsies selected for this study (see above). The percentages of globally and segmentally sclerotic glomeruli and of glomeruli with periglomerular fibrosis, as well as the degree (percentage) of interstitial fibrosis, were correlated with the serum creatinine level at the time of the biopsy. Our hypothesis was that most glomeruli with periglomerular fibrosis do not filter; therefore, from a functional point of view, such glomeruli may be equivalent to sclerotic glomeruli. To test whether the sum of GSG+PF correlates better with renal function, we calculated the percentage of GSG+PF in every biopsy. We also correlated the degree of interstitial fibrosis with the percentage of Periglomerular Fibrosis—Jenkins et al

globally sclerotic glomeruli, GSG+PF, and the sum of globally and segmentally sclerotic glomeruli. The biopsies were then subdivided into 2 groups: (1) biopsies with diabetic nephropathy (n 5 59; 33%), and (2) biopsies without diabetic nephropathy (n 5 118; 67%).

Statistical Analysis Correlations between different variables were analyzed by the Pearson product moment correlational analysis. The coefficient of determination (R2) was calculated for each pair. Data were analyzed using Prizm statistical software (GraphPad Software, San Diego, California).

Figure 2. Light microscopic appearance of periglomerular fibrosis. A, A glomerulus is surrounded by a lamellated, thickened, Bowman capsular basement membrane and layers of collagen. Note the open glomerular capillary loops. B, A glomerulus with periglomerular fibrosis and stenosis or disconnection at the glomerulotubular junction (arrow). In this glomerulus, the glomerular capillaries appear wrinkled but are open. The tubule belonging to the glomerulus is atrophic with thickened basement membrane. C, Two glomeruli with periglomerular fibrosis. The glomerulus on the left does not appear to have a connection with the adjoining atrophic proximal tubule (arrow). The glomerulus on the right has periglomerular fibrosis that becomes more and more prominent, the farther away it is from the vascular pole. In this slide, periodic acid–Schiff (PAS) and Masson trichrome stains were combined. Note the PAS-positive (dark purple), thick, lamellated, Arch Pathol Lab Med—Vol 135, January 2011

RESULTS The GSG+PF correlated better (a higher R2 value) with interstitial fibrosis than did sclerotic glomeruli alone (Figure 3, A and B). The sum of globally and segmentally sclerotic glomeruli showed a slightly weaker correlation with the degree of interstitial fibrosis than did the sclerotic glomeruli alone (Figure 3, A and C). The number of glomeruli with periglomerular fibrosis alone also correlated with the degree of interstitial fibrosis (Figure 3, D). Similarly, the percentage of GSG+PF showed a better correlation with renal function than did the percentage of sclerotic glomeruli alone (Figure 4, A and B). In addition, the sum of segmentally and globally sclerotic glomeruli did not correlate as well with renal function as did globally sclerotic glomeruli alone (Figure 4, C). Interstitial fibrosis showed the best correlation with the serum creatinine level at the time of the biopsy (Figure 4, D). The number of glomeruli with periglomerular fibrosis alone did not have a statistically significant correlation with the serum creatinine levels at the time of the biopsy, although there was a positive tendency (R2 5 0.0144, P 5 .11). However, if we looked at biopsies with nondiabetic renal diseases only, there was a weak correlation (Table 1). The percentage of glomeruli with periglomerular fibrosis did not correlate with the percentage of globally sclerotic glomeruli (R2 5 0.0064, P 5 .29) in the biopsy specimens. In patients with diabetic nephropathy, the number of GSG+PF did not correlate better with the serum creatinine level than did the number of sclerotic glomeruli alone (Table 1). Only in patients without diabetes mellitus did the number of GSG+PF correlate better with serum creatinine levels than the number of sclerotic glomeruli only. However, even in patients with diabetic nephropathy, GSG+PF correlated better with the degree of interstitial fibrosis than did the globally sclerotic glomeruli alone (Table 1). In diabetic nephropathy, the degree of interstitial fibrosis correlated much better with renal function than any examined pattern of chronic glomerular injury (Table 1). Periglomerular fibrosis, global glomerular sclerosis, and, in particular, interstitial fibrosis were more prominent in biopsies with diabetic nephropathy (Table 2). In contrast, segmental glomerular sclerosis was more common in biopsies from nondiabetic patients.

r Bowman capsular basement membrane and the blue, interstitial-type collagen between the layers of the basement membrane (PAS, original magnifications 3200 [A and B]; original magnification 3200 [C]). Periglomerular Fibrosis—Jenkins et al

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Figure 3. A, Correlations among interstitial fibrosis and the percentages of globally sclerotic glomeruli (GSG). B, The sum of GSG and glomeruli with periglomerular fibrosis (GSG+PF). C, The sum of GSG and segmentally sclerotic glomeruli (GSG+SSG). D, Glomeruli with periglomerular fibrosis (PF). The strongest correlation was noted among interstitial fibrosis and GSG+PF.

COMMENT Our results indicate that the percentage of GSG+PF shows a stronger correlation with the degree of interstitial fibrosis and with the serum creatinine levels than does the percentage of globally sclerotic glomeruli alone. These results provide further argument that glomeruli with periglomerular fibrosis (or at least a large proportion of them) are nonfunctional. If they were functional, the correlation between GSG+PF and interstitial fibrosis or renal function would be weaker than the correlation between globally sclerotic glomeruli alone and interstitial fibrosis or renal function. This is also demonstrated by the finding that if we add segmentally sclerotic glomeruli to globally sclerotic glomeruli, it weakens the correlations slightly. Therefore, in contrast to glomeruli with periglomerular fibrosis, most segmentally sclerotic glomeruli are functional and contribute to renal filtration. The number of segmentally sclerotic glomeruli is routinely provided in renal biopsy reports. However, it appears that adding the number of glomeruli with periglomerular fibrosis to glomeruli with global sclerosis provides a better estimate of the degree of chronic injury than adding the number of 120

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segmentally glomeruli. Therefore, based on our findings, we believe that providing the number of glomeruli with periglomerular fibrosis in renal biopsy reports is justified. Although GSG+PF correlates better with interstitial fibrosis than does globally sclerotic glomeruli alone both in patients with, and in those without, diabetes, the stronger correlation between GSG+PF and renal function exists only in biopsies from patients without diabetes. In biopsies with diabetic nephropathy, adding the number of glomeruli with periglomerular fibrosis to the number of globally sclerotic glomeruli does not strengthen the correlation with renal function. The most likely explanation is that, in our material, the degree of interstitial fibrosis was significantly more prominent in biopsies with diabetic nephropathy (Table 2). Because interstitial fibrosis has the best correlation with renal function, it appears plausible that, in a biopsy with prominent interstitial fibrosis, a relatively mild change in the number of nonfunctional glomeruli will not influence the serum creatinine level. The serum creatinine level is not an accurate measurement of renal function; a modest decline in the glomerular filtration rate is not necessarily reflected Periglomerular Fibrosis—Jenkins et al

Figure 4. A, Correlation among serum creatinine levels and percentages of globally sclerotic glomeruli (GSG). B, The sum of GSG and periglomerular fibrosis (GSG+PF). C, The sum of GSG and segmentally sclerotic glomeruli (GSG+SSG). D, The percentage of renal cortical interstitial fibrosis. The strongest correlation is seen with interstitial fibrosis. Among the chronic glomerular lesions, GSG+PF shows the strongest correlation with serum creatinine levels.

by an increase in serum creatinine levels. We did not use glomerular filtration rate values in our study because accurate 24-hour urine collection was not performed in many patients. In addition, the pathogenesis of interstitial fibrosis and progressive chronic renal injury in diabetic nephropathy is probably different from nondiabetic chronic renal diseases. In diabetic nephropathy, disturbances in the renal microcirculation may be relevant (eg, severe diabetic microangiopathy with arteriolar hyalin, possible more-prominent loss of peritubular capillaries).

In nondiabetic chronic renal diseases, many, or most, glomeruli with periglomerular fibrosis probably represent nonfunctional glomeruli. Many of these glomeruli are atubular glomeruli (glomeruli with no connection to a proximal tubule) but, in selected cases, we have performed serial sectioning and proved that many of these glomeruli do have existing, but stenotic, glomerulotubular junctions. Such stenotic glomerulotubular junctions were noted by other investigators as well in chronic glomerular/renal diseases.16 Invariably, if we saw such stenotic

Table 1. Correlations of Different Patterns of Chronic Glomerular Injury With Serum Creatinine Levels and Interstitial Fibrosis in Biopsies From Patients With Diabetic Nephropathy and Other Chronic Conditions (Nondiabetic) Serum Creatinine Diabetic 2

Histologic Pattern

R

GSG PF GSG+PF GSG+SSG Interstitial fibrosis

0.09 0.0009 0.08 0.06 0.33

Interstitial Fibrosis Nondiabetic

2

P

R

.03 .82 .03 .06 ,.001

0.20 0.03 0.24 0.16 0.38

Diabetic 2

P

R

,.001 .07 ,.001 ,.001 ,.001

0.45 0.05 0.55 0.36 N/A

Nondiabetic 2

P

R

,.001 .07 ,.001 ,.001 N/A

0.35 0.07 0.46 0.34 N/A

P

,.001 .004 ,.001 ,.001 N/A

Abbreviations: GSG, globally sclerotic glomeruli; N/A, not applicable; PF, periglomerular fibrosis; SSG, segmentally sclerotic glomeruli. Arch Pathol Lab Med—Vol 135, January 2011

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Table 2.

Distribution of Examined Glomerular Patterns of Injury and Interstitial Fibrosis in Biopsies From Patients With Diabetic Nephropathy and Other Chronic Conditions (Nondiabetic) Glomeruli, %

Histologic Pattern

GSG PF SSG Interstitial fibrosis, %a

Total (n = 177)

37.2 12.0 3.5 45.6

(2.0) (1.0) (0.6) (1.8)

Diabetic (n = 59)

48.8 17.0 2.0 58.8

(3.3) (1.8) (1.1) (2.8)

Nondiabetic (n = 118)

33.4 10.3 4.3 38.8

Diabetic Versus Nondiabetic, P

(2.4) (1.1) (0.7) (1.9)

.01 .001 .07 ,.001

Abbreviations: GSG, globally sclerotic glomeruli; PF, periglomerular fibrosis; SSG, segmentally sclerotic glomeruli. a

Interstitial fibrosis is given in percentages of involved renal cortex.

connections, the proximal tubules, belonging to glomeruli with periglomerular fibrosis, were atrophic with thickened tubular basement membranes and simplified epithelium, lacking brush borders. Therefore, even if there is some degree of filtration by these glomeruli, this filtration most likely does not contribute significantly to renal function. Probably, the only relevant function of glomeruli with periglomerular fibrosis is that they maintain blood flow; therefore, through postglomerular blood flow, they contribute to the oxygen supply of the interstitium and tubules. It is not entirely clear how and why periglomerular fibrosis develops. Periglomerular fibrosis can be seen in a large variety of chronic renal diseases, including glomerular diseases, systemic diseases, and primary tubulointerstitial diseases. However, in our experience, it appears that their number in primary tubulointerstitial diseases and in diabetic nephropathy is higher than in primary glomerular diseases. It appears plausible that, in primary tubulointerstitial diseases, when repeated tubular injury results in tubular atrophy, the tubular damage somehow provides feedback to the glomerulus, which results in thickening of the Bowman capsular basement membrane and reactive periglomerular fibrosis. Kriz et al17 proposed misdirected filtration as an important pathogenetic factor for glomerular Bowman capsular thickening and tubular basement membrane thickening in patients with proteinuria. This certainly could be important in patients with diabetic nephropathy and, perhaps, in other glomerular diseases with proteinuria, such as in focal segmental glomerular sclerosis, but probably less so in primary, chronic tubulointerstitial diseases. Recent evidence suggests that the epithelium of the Bowman capsule is a very important reservoir for the regeneration of glomerular and tubular epithelial cells.18 The epithelium at the glomerulotubular junction may play a particularly important role. Therefore, if the glomerulotubular junction is injured, regeneration of both the glomerular and the proximal tubular epithelium may be hampered. In summary, based on our data, we propose to include the number of glomeruli with periglomerular fibrosis in the routine renal biopsy report. The sum of sclerotic glomeruli and glomeruli with periglomerular fibrosis can then be calculated to better estimate the number of

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