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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 5  |  Page : 885-892
Pathological interstitial vascular proliferation adjacent to glomeruli in immunoglobulin a nephropathy


1 Department of First Integrated Medicine, Division of Nephrology, Saitama Medical Center, Jichi Medical University, Saitama, Japan
2 Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan
3 University Health Center, Joetsu University of Education, Joetsu, Japan
4 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

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Date of Web Publication22-Sep-2016
 

   Abstract 

We detected an increase in small arterioles around glomeruli, particularly adjacent to tuft adhesive lesions in immunoglobulin A nephropathy (IgAN), for the 1 st time, as far as we know. We labeled these as periglomerular microarterioles (PGMAs). This study aimed to clarify the pathological significance of PGMAs. Sixty-two patients with IgAN and 19 controls with minor glomerular abnormalities without proteinuria were evaluated in this study. The number of PGMAs located between the Bowman's capsule and the adjoining tubules was counted for each glomerulus. The mean number of PGMAs per glomerulus in cases of IgAN was significantly higher than those of the controls (0.530 ± 0.477 vs. 0.240 ± 0.182, P <0.05). Serial sections showed that most of the PGMAs were in contact with adjacent glomeruli (71.8%), through tuft adhesive lesions (52.1%), or the vascular pole (19.7%). By single regression analysis, the number of PGMAs was found to be positively correlated with the incidence of glomerular tuft adhesion, glomerular sclerosis, or the area of interstitial fibrosis in IgAN. By multiple regression analysis, the incidence of glomerular tuft adhesion was found to be the only independent pathological feature to correlate with the number of PGMAs (P = 0.0006). We have noticed the existence of PGMAs around glomeruli as a pathological finding of IgAN. Furthermore, the number of PGMAs was associated with the incidence of tuft adhesive lesion in glomeruli of IgAN although there was no relationship between the presence of PGMAs and clinical parameters including urinary protein excretion or creatinine clearance in the present study.

How to cite this article:
Mori H, Nishi S, Ueno M, Imai N, Ookawara S, Mirishita Y, Narita I, Tabei K. Pathological interstitial vascular proliferation adjacent to glomeruli in immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl 2016;27:885-92

How to cite this URL:
Mori H, Nishi S, Ueno M, Imai N, Ookawara S, Mirishita Y, Narita I, Tabei K. Pathological interstitial vascular proliferation adjacent to glomeruli in immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Oct 14];27:885-92. Available from: http://www.sjkdt.org/text.asp?2016/27/5/885/190779

   Introduction Top


Several experimental models have shown that loss of peritubular capillaries is closely associated with glomerular sclerosis, tubulointerstitial injury, and deteriorating renal function. [1],[2],[3],[4],[5] In addition, peritubular capillary density was negatively correlated with interstitial volume in human kidney diseases such as chronic tubulointerstitial diseases [6] and chronic allograft nephropathy. [7] An increased number of peritubular capillaries has occasionally been reported in ischemic nephropathy [8] and renal allograft rejection. [9] Most studies regarding the interstitial vasculature of the kidney focused on the peritubular capillaries, which drain the efferent arterioles and empty into interlobular veins.

On the other hand, several studies document the changes of the vasculature other than peritubular capillaries in the interstitium. In one study using three-dimensional microcomputed tomography, the density of renal cortical vessels was shown to be significantly higher in a model of hyperlipidemia than in controls. [10] Few authors have described an increase in smaller arterioles, other than afferent or efferent arteriole, in the vascular pole with the progression of both Type 1 and 2 diabetic nephropathy, [11],[12],[13],[14] and Osterby et al labeled these as extra efferent arterioles. [11],[12],[13],[14] These findings suggest that angiogenesis may be a necessary reaction in the process of kidney injury. However, thus far, few studies have explored a potential role for interstitial angiogenic capacity in the progression of human primary glomerulonephritis.

In the present study, we report the presence of smaller sized arterioles other than afferent or efferent arterioles in the interstitium adjacent to glomeruli, which we label as periglomerular microarterioles (PGMAs), particularly in the tuft adhesive lesion in patients with immunoglobulin A nephropathy (IgAN). Although similar to the extra efferent arterioles found in diabetic nephropathy, the distribution of these PGMAs in IgAN was different from the extra efferent arterioles that are located only in the vascular pole. Therefore, the aim of the present study was to investigate the distribution of PGMAs in IgAN and to clarify their pathological significance in the progression of glomerular injury or interstitial fibrosis.


   Subjects and Methods Top


Study subjects

Subjects were selected retrospectively from 1464 renal biopsies performed on patients at Niigata University Hospital or to three affiliated hospitals between April 1993 and March 2003. The diagnosis of IgAN was based on the detection of as mesangial proliferation in light microscopy and the presence of dominant glomerular mesangial deposits of IgA by immunofluorescence histochemistry.

The eligibility criteria for inclusion in this study were the following: (1) no evidence of systemic disease that would be expected to cause glomerular change such as systemic glomeruli with sufficient circumference to be evaluated; (2) fasting blood sugar level of <110 mg/dL, or HbA1c (JDS) level of <5.6%; (3) patient's blood pressure at the time of biopsy under 140/90 mm Hg; and (4) over 20 years of age at renal biopsy.

Sixty-two patients with IgAN who met the inclusion criteria were enrolled in this study. Nineteen patients matched for age and sex and with minor glomerular abnormalities and urine protein of <0.2 g/day were used as controls. They were selected from patients with asymptomatic hematuria in donors for renal transplantation. Written informed consents were obtained from all subjects for publication of this study and accompanying images. The Ethics Committee in our facilities approved the study.

Clinical characteristics of the patients before the start of any treatment including age, gender, body height (cm), body weight (kg), blood pressure (mm Hg), urinary protein excretion (g/day), serum creatinine (mg/dL), and blood sugar (mg/dL) were retrospectively reviewed from their medical records. Glomerular filtration rate was calculated using the Cockcroft- Gault formula; [(140 - age)/serum creatinine] × body weight/72 (×0.85 if female).

Pathological examination

Histological examination was conducted to evaluate PGMAs and the size of glomeruli using seven serial tissue sections of 1.5−2.0 μm thickness each, then fixed with alcohol Bouin and stained with periodic acid methenamine silver Masson stain [Figure 1]a-c. To follow the routes of PGMAs, 70‒80 serial sections of 1.5-2.0 μm thickness each were sliced from three randomly selected cases.
Figure 1. Numerous periglomerular microarterioles (arrows), which are smaller than afferent arterioles are seen around the glomeruli (a-c, PAM-Masson, ×400). Some periglomerular microarterioles are in contact with the glomerular tuft through Bowman's capsule (arrowheads). The vascular nature of periglomerular microarterioles was determined by a positive reaction with anti-CD34 antibody (d) and antialpha smooth muscle actin antibody (e) on serial sections.

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PGMAs were defined as small vessels less than 15 μm in diameter situated within the interstitium, surrounded by the Bowman's capsule and the adjoining tubules. They consisted of an inner layer of endothelial cells (ECs), one layer of smooth muscle cells, and an outer pericytes layer and had no lamina elastica interna. Thus, we could differentiate PGMAs from the afferent and efferent arterioles, which are larger in diameter and possess lamina elastica interna. The vascular nature of PGMAs was determined by the positive reaction with anti-CD34 monoclonal mouse antibody to human ECs [Figure 1]d (clone QBEnd 10, DAKO, Glostrup, Denmark), antialpha smooth muscle actin antibody to human smooth muscle cells [Figure 1]e (Clone 1A4, DAKO, Glostrup, Denmark) on serial sections.

The number of PGMAs around each glomerulus was calculated, and the mean value per glomerulus for each case was determined as the mean number of PGMAs (mPGMAs).

Using the Image-Pro Plus software (Media Cybernetics, MD, USA), the renal glomerular size and the interstitial area were measured. The maximum glomerular area among seven serial sections was selected, and the mean size (G size) calculated as. The interstitial area with fibrous change was measured as the percentage of pale green area in Masson staining in each specimen as % Int.

Histopathological features such as glomerular global sclerosis, segmental sclerosis, tuft adhesion to Bowman's capsule, crescent formation, and mesangial matrix index were calculated from patient records as follows:

  1. %GS: Percentage of glomeruli with global sclerosis/all glomeruli
  2. %SS: Percentage of glomeruli with segmental sclerosis/evaluated glomeruli
  3. %Ad: percentage of glomeruli with tuft adhesion/evaluated glomeruli
  4. %Cres: Percentage of glomeruli with crescent formation/evaluated glomeruli
  5. Mesangial index; [(0 × n0) + (1 × n1) + (2 × n2) + (3 × n3) + (4 × n4) + (5 × n5)]/evaluated glomerular counts (n0 + n1 + …n5), where, n0: no, n1: segmental mild, n2: segmental moderate, n3: diffuse mild, n4: diffuse moderate, and n5: diffuse severe proliferation of mesangial cells.


Clinical data of the patients, evaluation of mPGMAs, G size and percentage of interstitial area with fibrosis (%Int), and other histological records were conducted independently by different researchers.


   Statistical analysis Top


Clinical data were analyzed using the unpaired t-test. The differences between glomeruli with and without PGMAs were tested by the Chisquare test. The histopathological findings in the IgAN and the control group were compared using the Mann-Whitney U-test. Single regression and multivariate analysis were performed for the respective factors that were used to determine the incidence of PGMAs. P <0.05 was considered statistically significant. StatView version 5.0 for Windows (SAS, NC, USA) was used as a statistical computer application.


   Results Top


As shown in [Figure 1]a-e, PGMAs were observed around the entire glomeruli, especially around tuft adhesive lesions. Occasionally, they were in contact with the Bowman's capsule at the tuft adhesive lesion. We rarely found PGMAs around glomerular global sclerosis.

The clinical and pathological data of patients with IgAN and controls are summarized in [Table 1]. There were no significant differences between IgAN and control groups in clinical parameters including gender, age, blood pressure, body mass index, blood sugar, and creatinine clearance.
Table 1: Clinical and pathological data of patients with immunoglobulin A nephropathy and controls.

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The mPGMAs per glomerulus (mPGMAs) in IgAN cases was significantly higher than those of the controls (IgAN; 0.530 ± 0.447, range 0.000‒2.200, controls; 0.240 ± 0.182, range 0.000‒0.733, P <0.05, [Figure 2]. [Table 2] shows the histopathological differences between glomeruli with PGMAs and those without PGMAs in a total of 562 glomeruli from 62 cases of IgAN. Glomeruli with PGMAs showed evidence of more severe injury, adhesions, crescent formation, segmental sclerosis, and collapsing lesions than those without PGMAs. In particular, adhesions were observed in 44 of 174 glomeruli with PGMAs (25.3%), and in only 5.2% of glomeruli without PGMAs.
Figure 2: The mean number of periglomerular microarterioles in each immunoglobulin A nephropathy and controls.

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Table 2: Histopathological differences between glomeruli with or without periglomerular microarterioles in immunoglobulin A nephropathy.

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We examined the route of 71 PGMAs around 49 glomeruli in 70-80 serial sections from three patients [Figure 3]. Most of the PGMAs with routes toward the glomeruli were in direct contact with the adjacent glomeruli ([Figure 3]a, 71.8%) through either tuft adhesive lesions ([Figure 3]b, 52.1%) or the vascular pole ([Figure 3]c: 19.7%). Some PGMAs penetrate into glomerular capillaries [Figure 1]a and b although their communication was unclear. A smaller percentage of PGMAs (14.1%) was found to connect either afferent or efferent arterioles in a different section. The PGMAs with routes away from the glomeruli, emptied into the peritubular capillary (42%) or followed larger small arterioles (37.7%). We were able to follow the residual PGMAs only halfway and were unable to find their final destination.
Figure 3: The route of periglomerular microarterioles. Most periglomerular microarterioles are in contact with tuft adhesive lesions (a and b).

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The mPGMAs per glomerulus in IgAN cases showed a significantly positive relationship with renal injuries such as the incidence of tuft adhesion (r = 0.540, P <0.0001), global sclerosis (r = 0.509, P <0.0001), and an area of interstitial fibrosis (r = 0.555, P <0.0001) in a single regression analysis. [Table 3] summarizes the relationship between the mPGMAs per glomerulus and the histopathological or clinical findings in multiple regression analysis. Only one adhesive lesion had a significant correlation with the mPGMAs per glomerulus (standardized coefficient: 0.532, P = 0.0006).
Table 3: The relationship of the mean number of periglomerular microarterioles with the other histopathological changes and clinical data in multiple regression analysis.

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   Discussion Top


We describe the development of PGMAs around glomeruli, especially adjacent to tuft adhesive lesions in primary glomerulonephritis. The number of PGMAs in cases of IgAN was significantly higher than those of the controls and was positively correlated with the severity of various renal lesions including the tuft adhesive lesion, global sclerosis, and interstitial fibrosis. We suspect that glomerular injuries and interstitial fibrosis might induce an increase of PGMAs.

The peculiar feature of PGMAs is their location. Serial sections of the glomeruli showed that the most frequent route of these PGMAs is that they start at the glomerular tuft adhesive lesion and end at the interstitium and vice versa. The incidence of glomerular tuft adhesion was the only pathological feature that significantly correlated with the number of PGMAs in multiple regression analysis. PGMAs share similar histological features to those found in the "extra efferent arterioles" seen in diabetic nephropathy as described by Osterby. [11],[12],[13] Both are smaller than afferent arterioles, appear around glomeruli, and increase with the progression of glomerular injuries. [11],[12],[13] However, there are some differences between the PGMAs described here and the extra efferent arterioles in diabetic nephropathy. The appearance of PGMAs significantly correlated with the presence of tuft adhesive lesions, whereas extra efferent arterioles appeared independently of these lesions. In our analysis, there was no significant correlation between the number of PGMAs and glomerular sizes, whereas the extra efferent arterioles correlated with glomerular hypertrophy in diabetics. [11],[12] We deduce that the appearance of PGMAs is not related to glomerular hyperfiltration or hypertension in IgAN.

Kriz et al demonstrated the existence of misdirected filtration from tuft adhesions to Bowman's capsule and subsequent spreading of the filtrate around the entire circumference of a glomerulus in a model of segmental glomerulosclerosis with exogenous tracers. [15],[16] Exogenous tracers accumulated at the following sites: (1) within tuft adhesions to Bowman's capsule and associated paraglomerular spaces; (2) at the glomerulotubular junction contained within extensions of the paraglomerular spaces onto the tubule; and (3) within subepithelial peritubular spaces eventually encircling the entire proximal convolution of an affected nephron. Moreover, PGMAs cannot be considered homologous with Kriz's misdirected filtrations, as PGMAs are not spaces but vessels. Kriz's misdirected filtrates are pooled in paraglomerular interstitial spaces, and the pooled filtrates are considered to cause the glomerular or interstitial injury. Filtrate may flow in the presence of PGMAs; therefore, PGMAs might be generated as an early protection against such injuries.

The tuft adhesion is the earlier change preceding cellular crescent formations, or segmental sclerosis, and could be repaired as adherent scar. [17] The repair process consists of the formation of a bridge of fibrotic scar tissue that develops from the mesangium and from the interstitium. [17] Angiogenesis is a part of the important process of tissue repair together with fibrosis, so PGMAs might appear to mediate a glomerular repair in the early stage of glomerular injuries.

New vessel formation, or angiogenesis, is also an important mechanism in inflammatory and immune responses [18],[19] Briefly, inflammatory leukocytes and their mediators cause morphologic changes of ECs, affect vascular permeability, and result in vascular injury. Leukocytes also adhere to and transmigrate through, the EC layer of the vessel wall. Several mediators may trigger the formation of new vessels such as growth factors, cytokines, extracellular molecules, and cell adhesion molecules. LeukocyteEC interaction with these factors leads to EC proliferation, migration, and angiogenesis. Thus, it is plausible that PGMAs are also the result of tuft capillary injury and intra-capillary leukocyte-EC transmigration at the tuft adhesion toward the interstitium. The outcome of PGMAs may be dependent on the equilibrium or alterations in equilibrium between angiogenic mediators and inhibitors, similar to that observed in general inflammatory processes.

Recent studies, using tracing studies, showed that it is the peripheral epithelial cells (PECs) that are responsible for the epithelial hyperplasia observed in crescentic glomeruli by in mice [20] and in human glomerulonephritis. [21] Several authors believe that cellular crescent formation begins at the PECs-podocyte adhesion, which leads to changes in both PECs and podocyte proliferation and spreading behavior, resulting in the crescent formation. [16],[22] Several plasma components and growth factors including CXCR4/stromal cell-derived factor-1 axis, [23] von Hippel-Lindau gene deletion, [23] PDGF-D, [24] and EGF [25] are associated with PECs proliferation and crescent formation. These chemokines also play a role in angiogenesis. It is possible to speculate that PGMAs are derived from several of the angiogenic mediators stimulated by PECs-podocyte interactions around the tuft adhesive lesion.


   Conclusion Top


We have discovered the existence of PGMAs around glomeruli in pathological finding of IgAN. These PGMAs are associated with the incidence of tuft adhesive lesion in glomeruli of IgAN although had no relationship with clinical parameters including urinary protein excretion and creatinine clearance in the present study.


   Acknowledgments Top


We thank Professor Shigeki Yamada (Jichi Medical University, Saitama Medical Center) for the anti-CD34 antibody and the antialpha smooth muscle actin antibody, Professor Yoshihiko Ueda (Dokkyo Medical University Koshigaya Hospital), and Professor Tetsuya Kawano (Jichi Medical University, Saitama Medical Center), for their technical assistance.

Conflict of interest: None declared.

 
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Correspondence Address:
Susumu Ookawara
Department of First Integrated Medicine, Division of Nephrology, Saitama Medical Center, Jichi Medical University, Saitama
Japan
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DOI: 10.4103/1319-2442.190779

PMID: 27751994

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