Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
Advanced search 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 3019 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 

Table of Contents   
Year : 2019  |  Volume : 30  |  Issue : 3  |  Page : 726-734
Manifest interstitial and vascular pathology in anti-neutrophil cytoplasmic antibody-associated renal disease

1 Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Click here for correspondence address and email

Date of Submission01-May-2018
Date of Decision08-Aug-2018
Date of Acceptance13-Aug-2018
Date of Web Publication26-Jun-2019


Rapidly progressive renal failure in anti-neutrophil cytoplasmic antibody (ANCA)- associated renal disease customarily implies crescentic glomerulonephritis with approximately 50% of the glomeruli will have crescents. The tubulointerstitial inflammation is often proportionate to the glomerular inflammation and may have granulomatous pattern adjacent to the glomeruli or an inflamed vessel. A 77-year-old male with rapidly progressive renal failure was myeloperoxidase-ANCA positive, and renal histopathology revealed thrombotic microangio-pathy, significant interstitial inflammation, interstitial granulomas, and arteritis. Pathology is unique for the paucity of the classical crescents and the myriad of extraglomerular features. His renal function improved and stabilized after induction with cyclophosphamide and maintenance with azathioprine.

How to cite this article:
Haridasan S, Ganesh RN, Parameswaran S, Priyamvada P S. Manifest interstitial and vascular pathology in anti-neutrophil cytoplasmic antibody-associated renal disease. Saudi J Kidney Dis Transpl 2019;30:726-34

How to cite this URL:
Haridasan S, Ganesh RN, Parameswaran S, Priyamvada P S. Manifest interstitial and vascular pathology in anti-neutrophil cytoplasmic antibody-associated renal disease. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 May 26];30:726-34. Available from: http://www.sjkdt.org/text.asp?2019/30/3/726/261359

   Introduction Top

The primary renal site for anti-neutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis is the glomeruli with the characteristic pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis. The distinctive pathological features are the glomerular crescents, necrosis of the capillary loops and the paucity of immune deposits with or without nonspecific peri-glomerular and interstitial infiltrates, and necrotizing arteritis.[1] All lesions are posited to be secondary to respiratory burst of ANCA-induced activation of primed neutrophils. Herein, we present a case of myeloperoxidase (MPO)-ANCA vas-culitis with pure tubulointerstitial nephritis, renal arteritis, and interstitial granulomatous reaction lacking the characteristic glomerular crescent or necrosis. The histopathology spectrum is singular for the prominent interstitial and vascular pathology overriding the glome-rular lesions.

   Case report Top

Informed consent was obtained from the patient before reporting the case.

Patient is a 77-year-old male who was in his usual health until two months back when he developed easy fatigability, loss of appetite, significant loss of weight, and body pains. He had no associated abdominal pain, vomiting, fever, rash, or joint pains. He had lost 5–6 kg of weight over this time and had generalized aches and pains. One month before admission, he started having pedal edema which was bilateral, pitting, and painless. There was no history of facial puffiness, decreased urine output, frothing of urine, hematuria, or noc-turia. He had no history of shortness of breath, chest pain, palpitations, syncope, joint pains, skin rash, or oral ulcers. The patient denied inadvertent consumption of analgesics or indigenous medicines.

He had a long-standing history of bronchial asthma for which he had received inhalational bronchodilators and indigenous medicines, and the same had been discontinued two years ago. There was no past history of diabetes mellitus, hypertension, or jaundice and no family history of cancer, immunodeficiency, or autoimmune diseases.

At admission, the patient was conscious and oriented. His height was 155 cm, weight 68 kg, blood pressure 140/80 mm Hg, pulse rate 84/ min, respiratory rate 18/min, and temperature 36.8°C. There was no pallor, icterus, edema or rash, and no organomegaly, ascites, or focal neurological deficits. Cardiovascular system and respiratory system looked unremarkable on examination. Investigations revealed normo-cytic normochromic anemia, significant azo-temia, and hyponatremia [Table 1].
Table 1: Laboratory parameters.

Click here to view

Renal biopsy showed 9 glomeruli, of which few showed capillaries occluded by fibrinous material, subendothelial expansion, and mesan-giolysis consistent with thrombotic micro-angiopathy (TMA) [Figure 1], [Figure 2]. There was no increase in glomerular cellularity. Tubules showed mild tubular necrosis and neutrophilic tubular casts and mild tubular atrophy. No other tubular lesions were noted. Interstitium showed diffuse inflammation by sheets of plasma cells, lymphocytes, and occasional aggregates of histiocytes forming ill-defined granuloma. Medium-sized artery showed extensive segmental transmural arteritis with leukocytoclasia [Figure 3], [Figure 4]. Immunofluore-scence of three glomeruli was negative for all immunoglobulin and complement components. Altogether, histopathology had interstitial granuloma, arteritis, and TMA. There was no evidence of peripheral microangiopathy. On further evaluation, his Mantoux test was negative, chest X-ray was normal, serum and urine protein electrophoresis were unremarkable, and pulmonary function test revealed severe obstructive physiology with no bron-chodilator reversibility.
Figure 1: 3 glomeruli with normal cellularity and interstitium showing dense infiltration by lymphocytes and plasma cells (H&E, ×40).

Click here to view
Figure 2: Glomerulus with capillaries occluded by fibrinous material (arrow), subendothelial expansion, and mesangiolysis morphologically consistent with thrombotic microangiopathy (H&E, ×400).

Click here to view
Figure 3: Renal cortex with fibrinoid necrosis and infiltration of lymphocytes and histiocytes in a medium-sized artery (arrow). A small aggregate of epithelioid histiocytes forming an ill-formed granuloma with lymphocyte cuffing is seen on the top of the artery (H&E, Eosin ×200).

Click here to view
Figure 4: Destruction of arterial wall and fibrinoid necrosis surrounded by histiocytic and lymphocytic infiltration (arrow) (Periodic acid Schiff stain, ×200).

Click here to view

With a clinicopathological diagnosis of acute interstitial nephritis and unidentified small vessel vasculitis, he was treated with pulse methylprednisolone for three doses followed by 1 mg/kg of oral steroids.

Later, assays were found to be negative for cANCA by immunofluorescence while pANCA was positive. By ELISA, MPO-ANCA was positive in significant titers. Duly, he was initiated on intravenous cyclophosphamide monthly pulse therapy at a dose of 10 mg/kg/ dose with mesna. After six doses of pulse cyclophosphamide, he was maintained on low-dose steroids (5 mg/day) and azathioprine (2 mg/kg/day), and at last follow-up, 24 months after the disease onset, serum creatinine is 3.7 mg/dL.

   Discussion Top

From the neutrophilic capillaritis and segmental glomerular necrosis of microscopic polyangiitis and granulomatosis with poly-angiitis (GPA) to the larger necrotizing lesions of GPA and eosinophilic GPA, there is marked variation in histology of ANCA-associated vasculitis. On an average, in a given renal biopsy specimen of ANCA-associated vascu-litis, 45%–55% of glomeruli have crescents, and 20%–25% of glomeruli have fibrinoid necrosis accompanied by crescent formation.[2] Vasculitis affecting the glomerular capillaries, arterioles, interlobular, and arcuate arteries is not uncommon. Fibrin thrombi often are present in glomerular capillaries adjacent to the necrotic zones. However, arteritis and tubulo-interstitial nephritis without glomerular cre-scents or necrosis is exceptional.[3],[4],[5]

Tubulointerstitial inflammation and fibrosis are usually commensurate with the degree of active glomerular lesions and glomerulo-sclerosis, respectively. The tubulointerstitial inflammation more pronounced with MPO- ANCA than with PR3-ANCA is associated with acute or chronic tubular changes and prevails next to a severely inflamed glomerulus or vessel.[4] Less common is an interstitial necrotizing granulomatous inflammation not centering on the glomeruli and characterized by a central zone of necrosis surrounded by an infiltrate of mononuclear leukocytes, neutro-phils and scattered multinucleated giant cells. Tubulointerstitial nephritis or granuloma in the absence of glomerulonephritis is extremely rare. In 232 renal biopsy specimens with ANCA-positive pauci-immune renal disease analyzed at the University of North Carolina Nephropathology Laboratory, only 1% had isolated tubulointerstitial inflammation.[6] A metaanalysis of 349 patients with Wegener’s granulomatosis (1979–1997) had vasculitis of the renal interstitial arteries and arterioles in almost 20%, whereas renal granulomas were seen in seven biopsy specimens.[7] In yet another retrospective analysis, interstitial inflammation was present in 94% of pauci-immune glomerulonephritis, of which 33% were graded to be severe and two cases had interstitial granulomas.[8]

Granulomatosis presumably arise from a T- cell-mediated (Type IV) adaptive immune response specific for PR3 or MPO or by an antigen-independent innate response of macrophages. Primed neutrophils stationed in the extravascular tissue due to unknown triggers gets activated by ANCA IgG in the interstitial fluid of a patient with circulating ANCAs. Activated neutrophils and the attendant alternative complement pathway induce microabscess culminating in a granulomatous reaction walling off the zone of necrosis.[9] ANCA-activated monocytes release pro-inflammatory cytokines, ad rem, and monocyte chemoattractant protein-1 which could facilitate transition from a predominantly neutrophil-rich inflammation to a monocyte and/or macrophage-rich inflammation, including granulomatous inflammation. Later stages of granulomatosis contain amorphous necrotic debris that is walled off by a well-defined band of epithelioid macrophages and more of lymphoid cells including effector T cells, memory T cells, B cells, dendritic cells, and plasma cells.[10]

In addition, there are unique cases of ANCA- positive acute tubulointerstitial nephritis without renal or systemic vasculitis, and renal graft granulomatous arteritis sine crescents.[11],[12] The index case here is MPO-ANCA positive with renal interstitial granuloma, leukocyto-clastic vasculitis, and glomerular TMA with paucity of the characteristic glomerular pathology and has been in partial remission for two years with the standard immunosuppressive regimen.

   Conclusion Top

Hallmark histology of ANCA-associated renal disease entitled as pauci-immune crescentic glomerulonephritis overlooks the extraglome-rular damages incurred in the process. Rarely, the pathophysiology may get confined to the interstitium and/or the vessels, manifesting as isolated vasculitis or granulomatous inflammation. This brings into question, whether the pathology of renal disease in ANCA commences in the interstitium and eventually affects the glomerulus or vice versa.

Conflict of interest: None declared.

   References Top

Jennette JC, Thomas DB. Pauci-immune and antineutrophil cytoplasmic autoantibody-mediated crescentic glomerulonephritis and vasculitis. In: Heptinstall Pathology of the Kidney. 7th ed., Ch. 16. Philadelphia, PA: Lippincott Williams & Wilkins, 2007 p. 69170.  Back to cited text no. 1
Hauer HA, Bajema IM, van Houwelingen HC, et al. Renal histology in ANCA-associated vasculitis: Differences between diagnostic and serologic subgroups. Kidney Int 2002;61:80-9.  Back to cited text no. 2
Chen M, Yu F, Wang SX, et al. Renal histology in Chinese patients with anti-myelo-peroxidase autoantibody-positive Wegener’s granulomatosis. Nephrol Dial Transplant 2007; 22:139-45.  Back to cited text no. 3
Vizjak A, Rott T, Koselj-Kajtna M, Rozman B, Kaplan-Pavlovcic S, Ferluga D. Histologic and immunohistologic study and clinical presen-tation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity. Am J Kidney Dis 2003;41:539-49.  Back to cited text no. 4
Yamagata K, Usui J, Saito C, et al. ANCA- associated systemic vasculitis in Japan: Clinical features and prognostic changes. Clin Exp Nephrol 2012;16:580-8.  Back to cited text no. 5
D’Agati V, Jennette JC, Silva FG. Non-Neoplastic Renal Disease. Washington: American Registry of Pathology; 2005. p. 385.  Back to cited text no. 6
Bajema IM, Hagen EC, van der Woude FJ, Bruijn JA. Wegener’s granulomatosis: A meta-analysis of 349 literary case reports. J Lab Clin Med 1997;129:17-22.  Back to cited text no. 7
Minz RW, Chhabra S, Joshi K, et al. Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study. Indian J Pathol Microbiol 2012;55:28-32.  Back to cited text no. 8
  [Full text]  
Mark EJ, Matsubara O, Tan-Liu NS, Fienberg R. The pulmonary biopsy in the early diagnosis of Wegener’s (pathergic) granulomatosis: A study based on 35 open lung biopsies. Hum Pathol 1988;19:1065-71.  Back to cited text no. 9
Jennette JC, Falk RJ. Pathogenesis of antineu-trophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 2014;10:463-73.  Back to cited text no. 10
Nakabayashi K, Sumiishi A, Sano K, et al. Tubulointerstitial nephritis without glomerular lesions in three patients with myeloperoxidase-ANCA-associated vasculitis. Clin Exp Nephrol 2009;13:605-13.  Back to cited text no. 11
Farris AB, Ellis CL, Rogers TE, Chon WJ, Chang A, Meehan SM. Renal allograft granulomatous interstitial nephritis: Observations of an uncommon injury pattern in 22 transplant recipients. Clin Kidney J 2017;10:240-8.  Back to cited text no. 12

Correspondence Address:
P S Priyamvada
Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
Login to access the Email id

DOI: 10.4103/1319-2442.261359

PMID: 31249242

Rights and Permissions


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  

   Case report
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded103    
    Comments [Add]    

Recommend this journal