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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 6  |  Page : 1196-1201
Morphometry of non-inflammatory arteriolar changes in lupus nephritis: A study of 40 cases


1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, Ansari Nagar, New Delhi, India
2 Department of Medicine, All India Institute of Medical Sciences, New Delhi, Ansari Nagar, New Delhi, India
3 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, Ansari Nagar, New Delhi, India

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Date of Web Publication17-Nov-2012
 

   Abstract 

Vascular changes in lupus nephritis (LN) may be the cause of renal function derangement without obvious changes in activity or chronicity indices. Although a few morphological studies of renal vasculature exist, arteriolar morphometric parameters in LN have not been evaluated. For this study, 40 patients with LN and 40 age-matched patients with minimal change disease (controls) were included. Their clinical features were noted, renal biopsy changes classified according to the modified World Health Organization classification of LN and activity and chronicity indices were calculated. Arteriolar morphometric parameters were obtained using manual tracing and an image analysis software. Appropriate statistical tests were applied to assess significance of difference between various groups. Arteriolar wall thickness as well as circumference was significantly higher in all classes of LN as compared with controls (P <0.05). However, no difference was observed in the wall-to-lumen ratio between the two groups (P >0.05). An inter-class analysis of LN did not show any significant difference for any of the arteriolar morphometric parameters (P >0.05). No correlation was found between activity or chronicity indices and the various arteriolar morphometric parameters. This study demonstrates morphometric evidence of arteriolar wall changes in LN. Although no correlation was found with the histological features, further studies are required in this area.

How to cite this article:
Gupta R, Sharma A, Gupta R, Agarwal SK, Dinda AK. Morphometry of non-inflammatory arteriolar changes in lupus nephritis: A study of 40 cases. Saudi J Kidney Dis Transpl 2012;23:1196-201

How to cite this URL:
Gupta R, Sharma A, Gupta R, Agarwal SK, Dinda AK. Morphometry of non-inflammatory arteriolar changes in lupus nephritis: A study of 40 cases. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Aug 12];23:1196-201. Available from: http://www.sjkdt.org/text.asp?2012/23/6/1196/103559

   Introduction Top


Renal involvement is common in systemic lupus erythematosus (SLE). Much focus has been on the glomerular lesions, which form the basis of the modified World Health Organization (WHO) classification of lupus nephritis (LN). [1] Vascular changes in LN, other than vasculitis and fibrinoid necrosis, are often under-reported. [2] A study by Descombes et al classified the vascular changes in LN into five classes: (a) non-specific sclerotic vascular lesions, (b) immunoglobulin microvascular casts (lupus vasculopathy), (c) thrombotic microangiopathy, (d) vasculitis and (e) parietal vascular immunoglobulin deposits. [3] In their study, the authors showed that non-specific sclerotic lesions were the most frequent. However, the presence of intra-renal vascular lesions did not have a bearing on the long-term prognosis of patients with LN in their study. [3]

In the vascular network, arterioles are the main seat of vascular resistance and, hence, control the fraction of systemic blood pressure that is transmitted to the glomerular capillaries. Morphometric studies on kidneys in aging normotensive individuals and in advanced essential hypertension have shown loss of autoregulation in renal arterioles, evidenced by the dilated lumens and thinned-out muscle layer due to non-obstructive hyaline deposits. [4],[5] Morphometric studies on renal microvasculature, however, have not been extended to the inflammatory lesions. Because vascular lesions may underlie a deterioration of renal functions in LN, a systematic study of arteriolar changes by morphometric techniques may be helpful.

The present study was aimed at evaluating the morphometric parameters in arterioles in kidney biopsies from patients with LN and to compare them with control subjects. In addition, correlation of these morphometric parameters between various classes of LN as well as with the activity and chronicity indices was attempted.


   Materials and Methods Top


Study material

Forty renal biopsies from patients diagnosed as SLE with manifestations of renal involvement were included in the study. For comparison, 40 age-matched biopsies from patients diagnosed as minimal change disease were selected.

Clinical and morphological features

The clinical parameters taken into consideration included duration of renal symptoms, presence of hypertension and renal function tests at the time of biopsy. Kidney biopsies were reviewed by three independent observers (RG, AS, AKD) and cases were classified into various classes of LN according to the revised WHO classification. [1] Activity and chronicity indices were calculated using the parameters proposed by Austin et al. [6]

Morphometry

Morphometric measurements were performed on digitized images (×400 magnification) of Hematoxylin and eosin-stained sections using the ImageProPlus software (Media Cybernetics Inc., Rockeville, USA). In these images, a minimum of five arterioles with a circular crosssection were selected and their outer and inner circumference traced manually, followed by calculation of parameters including wall thickness, outer circumference and wall-to-lumen ratio [Figure 1]. Biopsies showing fibrinoid necrosis of the arteriolar wall or presence of fibrin thrombi were excluded from the morphometric analysis because the purpose of the study was to evaluate the morphometric parameters in non-inflamed arterioles.
Figure 1: Photomicrograph showing the method of tracing the inner and outer circumference of arterioles using the ImageProPlus software.

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   Statistical Analysis Top


A non-parametric test (Mann-Whitney) was applied to determine the significance between the various groups (controls vs LN as well as between various classes of LN). Spearman's rank coefficient test was used to correlate morphometric parameters with activity and chronicity indices.


   Results Top


Clinical features and morphological changes

The age range of patients with LN was 9-42 years (mean 18.5 years), which was comparable to 5-38 years in the control group (mean 16.8 years). There was a female predominance in both groups (male:female 1:9 in LN and 1:4 in controls). The mean duration of symptoms in patients with LN was 26 (±17.1) months. Hypertension (well-controlled on one or two anti-hypertensive drugs) at the time of biopsy was detected in 10 patients (25%), while impaired renal function (serum creatinine >1.5 mg/dL) was noted in 13 patients (32%). None of the patients had features of malignant hypertension. In the control group, six patients (15%) had hypertension while only two (5%) had impairment of renal function tests. There was no difference in the proportion of patients with hypertension in both the groups (P = 0.402). None of the patients with LN had circulating anti-phospholipid or anti-cardiolipin antibodies.

On light microscopy and immunofluorescence (IF), four cases of LN were classified as Class-II with mesangial proliferation and mesangial immune-complex deposits (mesangial, 10%), 12 as Class-III with focal endocapillary proliferation and capillary wall granular deposits of immunoglobulins and complement components (focal proliferative, 30%), 18 as Class-IV with diffuse endocapillary proliferation and coarse granular deposits in the capillary wall (diffuse proliferative, 45%) and six as Class-V showing diffuse thickening of peripheral glomerular basement membrane with granular deposits in the capillary wall (membranous, 15%). For statistical analysis, Classes-II and -V were grouped together (as both are primarily non-exudative classes of LN). The mean activity index was 2.75 ± 3.09 for Class-II/V, 5.00 ± 1.79 for Class-III and 8.39 ± 2.30 for Class-IV LN. The chronicity index was 1.75 ± 1.25 in Class-II/V, 2.83 ± 2.04 in Class-III and 3.22 ± 1.93 in Class-IV LN.

All the patients with LN were treated with immunosuppressive drugs (steroids ± cyclophosphamide) and followed-up regularly with renal function tests (serum urea and creatinine) and urinalysis for proteinuria, hematuria and active sediment. On follow-up, none of the patients of LN had evidence of renal dysfunction (defined as serum creatinine >1.5 mg/dL). Majority of the patients had non-nephrotic range proteinuria and microscopic hematuria at the last follow-up visit.

Morphometric parameters

The median arteriolar wall thickness was 8.68 μm in renal biopsies with minimal change disease as compared with 12.72 μm in Class-II/V LN, 11.62 μm in Class-III and 12.27 μm in Class-IV LN. The difference in median arteriolar wall thickness between controls and various classes of LN was found to be significant (P <0.05, Mann-Whitney test). However, the various classes of LN did not show a significant inter-class difference in median arteriolar wall thickness. Similar results were found for median arteriolar circumference. However, there was no significant difference in the wall-to-lumen ratio between controls and LN. These results are summarized in [Table 1] and [Table 2].
Table 1: Arteriolar parameters in lupus nephritis and controls.

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Table 2: Comparison of arteriolar morphometric parameters between lupus nephritis and controls (nonparametric tests).

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The non-parametric test (Mann-Whitney) did not reveal any correlation between the presence of hypertension or renal function impairment and the arteriolar morphometric parameters in patients with LN (P >0.05). The activity and chronicity indices were correlated with the arteriolar morphometric parameters using the Spearman's rank coefficient test. Neither the activity nor the chronicity index showed correlation with the median circumference, wall thickness or wall-lumen ratio (P >0.05).


   Discussion Top


Renal involvement in SLE (LN) is an important cause of morbidity and mortality associated with this multisystemic autoimmune inflammatory disease. [1] Studies of renal biopsies in LN have led to several classifications of renal morphologic changes, most of which are based primarily on the glomerular features. [1],[7] These classifications do correlate, to some extent, with the prognosis of LN. However, some patients experience sudden deterioration of renal function during the course of their disease that cannot be explained by the glomerular changes alone. In another subset of patients, control of inflammatory activity with immunosuppressive agents does not translate into normalization of renal functions. In such cases, vascular changes are thought to be responsible for the deterioration or persistence of renal dysfunction. [2]

Intra-renal vascular lesions in LN were described in detail by Klemperer et al in 1941, followed by a few other studies. [3],[8],[9],[10] These include uncomplicated vascular immune deposits, non-inflammatory necrotizing vasculopathy, inflammatory vasculitis, thrombotic vasculopathy and non-specific arteriosclerosis. Of these, non-specific arteriosclerosis is reported to be the most frequent, followed by uncomplicated vascular immune deposits. [3] The vasculitic changes, although infrequent, have been associated with a poorer clinical outcome. [10],[11],[12] However, the clinical significance of majority of the other vascular lesions in LN is still debatable. Hence, in routine nephropathology practice, these vascular lesions, other than vasculitis, are frequently underreported while evaluating renal biopsies from patients with LN.

Arterioles, especially afferent, are the main resistance vessels in the kidney and control the blood pressure transmitted to the glomerulus. In systemic hypertension, the arterioles show cardinal changes of hyaline arteriolosclerosis and intimal and medial thickening. [13] The changes involving small vessels are currently characterized as vascular remodeling, and are thought to involve rearrangement of the smooth muscle and intercellular matrix material. Such changes lead to an increased stiffening and reduced compliance in the resistance vessels. Experimental studies have demonstrated the efficacy of angiotensin receptor antagonists and angiotensin-converting enzyme inhibitors (ACE inhibitor) in reversing the vascular remodeling in genetically hypertensive rats. [14],[15]

Hill et al, in their studies, have demonstrated loss of auto-regulation in the renal afferent arterioles in normotensive aging kidneys as well as kidneys in essential hypertension. This loss of auto-regulation leads to higher pressures being transmitted to the glomerulus, eventually resulting in glomerular sclerosis. [4],[5] In these studies, arterioles containing non-occlusive hyaline deposits had dilated lumens with corresponding increase in width and circumference of the lumen. It was suggested that such arterioles would generate higher circumferential tension with lower ability of the smooth muscle to contract against this tension. Glomeruli of hypertrophic and focal and segmental glomerulosclerosis-type were associated with arterioles having large lumens and non-obstructive hyaline deposits in these studies. [4],[5] Although such studies have been performed in aging, hypertension and diabetes, the role of vascular remodeling in inflammatory renal lesions has not been investigated as yet.

In the present study conducted in patients with an immune-mediated inflammatory disease (SLE), the arteriolar morphometric parameters were found to differ significantly from the control subjects (minimal change disease). In various classes of LN, the outer circumference and wall thickness of the arterioles were higher compared with the controls. However, no differrence was noted in the wall-to-lumen ratio. These results suggest a degree of vascular remodeling in LN leading to thicker arterioles. The lack of any significant inter-class difference in the morphometric parameters underscores the fact that the vascular changes occur independently of the glomerular inflammatory process in this disease. Also, the morphometric alterations did not correlate with the activity and chronicity indices thus suggesting that the vascular changes do not progress concurrently with the inflammatory and healing process. At the same time, the vascular changes in our study could not be (entirely) attributed to the hypertension, as the presence of hypertension did not correlate with the arteriolar morphometric parameters in patients with LN.

In conclusion, the present study shows objective morphometric evidence of vascular remodeling in renal microvasculature in LN. Our results show that these vascular changes occur independently of the inflammatory activity and chronicity of LN. More extensive studies are required to validate and further evaluate these vascular changes.


   Acknowledgment Top


The authors wish to acknowledge Dr. Sompal Singh for his assistance in statistical analysis. Dr. Ruchika Gupta and Dr. Alok Sharma acknowledge CSIR for research grant support as research associates.

 
   References Top

1.Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-50.  Back to cited text no. 1
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2.Rothfield NF, McCluskey RT, Baldwin DS. Renal disease in systemic lupus erythematosus. N Engl J Med 1963;269:12-5.  Back to cited text no. 2
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3.Descombes E, Droz D, Drouet L, Grunfeld JP, Lesavre P. Renal vascular lesions in lupus nephritis. Medicine 1997;76:355-68.  Back to cited text no. 3
    
4.Hill GS, Heudes D, Jacquot C, Gauthier E, Bariety J. Morphometric evidence for impairment of renal autoregulation in advanced essential hypertension. Kidney Int 2006;69: 823-31.  Back to cited text no. 4
    
5.Hill GS, Heudes D, Bariety J. Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation. Kidney Int 2003;63:1027-36.  Back to cited text no. 5
    
6.Austin HA III, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis: Contributions of clinical and histologic data. Kidney Int 1994;45:544-50.  Back to cited text no. 6
    
7.Churg J, Bernstein J, Glassock RJ. Renal disease: Classification and Atlas of Glomerular Disease, 2 nd ed, Tokyo, Japan, Igaku-Shoin, 1995. p. 20.  Back to cited text no. 7
    
8.Bhathena DB, Sobel BJ, Migdal SD. Non-inflammatory renal microangiopathy of systemic lupus erythematosus ("lupus vasculitis"). Am J Nephrol 1981;1:144-59.  Back to cited text no. 8
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9.Klemperer P, Pollack AD, Baehr G. Pathology of disseminated lupus erythematosus. Arch Pathol 1941;32:569-631.  Back to cited text no. 9
    
10.Tsumagari T, Fukumoto S, Kinjo M, Tanaka K. Incidence and significance of intrarenal vasculopathies in patients with systemic lupus erythematosus. Hum Pathol 1985;16:43-9.  Back to cited text no. 10
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11.Appel GB, Pirani CL, D'Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994;4:1499-515.  Back to cited text no. 11
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12.Banfi G, Bertani T, Boeri V, et al. Renal vascular lesions as a marker of poor prognosis in patients with lupus nephritis. Am J Kidney Dis 1991;18:240-8.  Back to cited text no. 12
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13.Irving RJ, Walker BR. Blood vessel structure in hypertension. Saudi J Kidney Dis Transpl 1999;10:257-66.  Back to cited text no. 13
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14.Ledingham JM, Laverty R. Renal afferent arteriolar structure in the genetically hypertensive (GH) rat and the ability of losartan and enalapril to cause structural remodelling. J Hypertens 1998;16(12 Pt 2):1945-52.  Back to cited text no. 14
    
15.Notoya M, Nakamura M, Mizojiri K. Effects of lisinopril on the structure of renal arterioles. Hypertension 1996;27:364-70.  Back to cited text no. 15
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Correspondence Address:
Amit Kumar Dinda
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110029
India
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DOI: 10.4103/1319-2442.103559

PMID: 23168848

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