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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1420-1426
Rare renal pathologic manifestation of antineutrophil cytoplasmic antibodies associated vasculitis as suppurative interstitial nephritis: A case report and review of the literature

1 Department of Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
2 Department of Pathology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
3 Department of Rheumatology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey

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Date of Web Publication29-Jan-2021


A 69-year old male patient attended our clinic with fatigue, fever, anuria, nephritic syndrome and severe renal failure. Kidney biopsy showed pauci-immune crescentic glomerulonephritis with an unusual association of suppurative interstitial nephritis. Though most patients with renal involvement linked to antineutrophil cytoplasmic antibodies associated vasculitis (AAV) have pauci-immune glomerulonephritis, only a few patients were identified to have atypical renal pathology. In most cases, mononuclear tubulointerstitial infiltrate may be a feature of AAV, suppurative interstitial nephritis is very rare. In the literature, we found only one case reported associated with suppurative interstitial nephritis without glomerulonephritis who later developed classic pauci-immune necrotizing glomerulonephritis. Here, we report a case diagnosed as AAV, presenting with pauci-immune crescentic glomerulonephritis and suppurative interstitial nephritis. It is not clear whether suppurative interstitial nephritis is a severe disease variant in AAV-associated renal disease. As described in the first case the lack of improvement in renal functions in spite of intense immunosuppressive treatment leads to the conclusion that suppurative interstitial nephritis is a marker of poor prognosis.

How to cite this article:
Ozkurt S, Acikalin MF, Mengus C, Bilge N, Yalcin AU. Rare renal pathologic manifestation of antineutrophil cytoplasmic antibodies associated vasculitis as suppurative interstitial nephritis: A case report and review of the literature. Saudi J Kidney Dis Transpl 2020;31:1420-6

How to cite this URL:
Ozkurt S, Acikalin MF, Mengus C, Bilge N, Yalcin AU. Rare renal pathologic manifestation of antineutrophil cytoplasmic antibodies associated vasculitis as suppurative interstitial nephritis: A case report and review of the literature. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Oct 18];31:1420-6. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1420/308362

   Introduction Top

Renal involvement in antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) is characterized by extra capillary proliferation and crescent formation with excessively variable density, along with focal and segmental necrotizing glomerulonephritis. The analysis of crescentic glomerulonephritis linked to different causes shows significant increase in granulocytes and monocytes in glomerular infiltrate, with T lymphocytes and monocytes forming primarily in interstitial infiltrate.[1],[2] However, there are some exceptions to this rule, and some vasculitis patients may have atypical pathologic features. We had a 69-year old male patient attending our clinic with nephritic syndrome and severe renal failure whose kidney biopsy showed pauciimmune crescentic glomerulonephritis with an unusual association of suppurative interstitial nephritis. Although most patients with renal involvement linked to antineutrophil cytoplasmic antibodies associated vasculitis (AAV) have pauci-immune glomerulonephritis, a few patients are identified to have atypical renal pathology. Our aim in this article is to enlighten readers of a rare pathologic manifestation that may occur in patients with vasculitis.

With this in mind, we searched websites such as PubMed, Web of Science, Scopus, and Google Scholar using key words such as “ANCA-associated vasculitis and tubulo-interstitial nephritis; pauci-immune crescentic glomerulonephritis and tubulointerstitial nephritis; ANCA-associated vasculitis and suppurative interstitial nephritis; pauci-immune crescentic glomerulonephritis and suppurative interstitial nephritis; tubulointerstitial nephritis” published between 1980 and 2019. English and non-English literature which included English abstract was selected for the review. Cases who have AAV and had isolated mono-nuclear tubulointerstitial nephritis or suppurative interstitial nephritis were included to the study.

   Case Report Top

In February 2019, a 69-year old male patient, without a history of chronic disease or continuous medication use, attended with pretibial edema, anuria, nephritic syndrome and severe renal failure. His history included fever, fatigue and 4 kg of weight loss in the last two weeks. Kidney function tests performed at a different health center two weeks ago were normal. At time of admission, physical examination found blood pressure 120/80 mm Hg, fever 38.5°C, pretibial edema (+2), and 50 mL/day urine output. Chest X-ray and abdominal ultrasonography were normal. In laboratory examination, blood urea nitrogen level was 109 (8–23) mg/dL, creatinine 8.3 (0.7–1.2) mg/dL, Na 127 (135–150) mEq/L, K 8 (3.5–5.1) mEq/L, Ca 7.68 (8.6–10.2) mg/dL, P 6.1 (2.7–4.5) mg/dL, total protein 5.7 (6.4–8.3) g/dL, albumin 2.3 (3.5–5.2) g/dL, hemoglobin 9.5 (13.3–17.2) g/dL, leukocyte 24.1 103/uL (3.7–9.7 103/uL), and platelets were 440 103/uL (179–373 103/uL), respectively. Liver function tests were normal. Urine analysis identified protein (+2), erythrocyte 6/HPF, leukocyte 7/HPF, in spot urine protein/ creatinine ratio was 1599 mg/day. C reactive protein: 214 (0–5) mg/L, procalcitonin: 2.02 (0–0.5) ng/mL, parathormone: 128.2 (15–65) pg/mL, ferritin 235 (30–400) ng/mL, vitamin B12: 362 (191–663) pg/mL and folate: 13.59 (4.6–18.7) ng/mL. Peripheral blood distribution tended toward the left and neutrophils had no pathologic finding apart from toxic granulation. After samples for blood and urine cultures were taken, imipenem and vanco-mycin therapy were begun. Even repeated blood and urine cultures were sterile, the patient’s fever continued. Using broad-spectrum antibiotics, the patient had continuous high fever without identification of infection focus and was assessed as having disease fever. The patient had hemodialysis and kidney biopsy was performed. Hepatitis B surface antigen, hepatitis C antibody, HIV antibody, antinuclear antibody, anti-double Stranded DNA tests were all negative, complement C3 and C4 levels were normal, serum Ig G level was 1910 (751–1560), IgA 135 (82–453), IgM 55.7 (46–304) and serum protein electrophoresis showed no monoclonal peak. With the ELISA method pANCA was negative and c-ANCA was positive (formalin-resistant). With no necrotizing granulomatous lesion identified on paranasal computed tomography, high-resolution computed tomography (HRCT) and abdominal computed tomography of the patient did not identify vasculitic involvement, infective pathology, and findings in favor of malignancy. Renal biopsy observed cellular crescents in five of 12 glomeruli (40%) [Figure 1], fibrinoid necrosis and inflammatory cells in the artery walls in the area stained with trichrome stain (necrotizing arteritis) [Figure 2], severe interstitial inflammation formed mainly of plasma cells and neutrophils, neutrophil clusters in the style of micro abscess on a necrotic background in focal areas [Figure 3], with some lymphocytes identified between some tubule epithelium cells (tubulitis) and negative immunofluorescence staining. Considered to have pauci-immune crescentic glomerulonephritis, the patient received 1000 mg rituximab and 1000 mg IV methylprednisolone (3 days), then transferred to 1 mg/kg maintenance oral methylpredni-solone and plasmapheresis was performed. The patient did not have a focus for infection but his fever continued, as he received rituximab therapy trimethoprim sulfameta-xozol was added on the 10th day of imipenem and vancomycin. On the 5th day of immuno-suppressive treatment, the patient developed hemoptysis and repeated HRCT identified widespread alveolar hemorrhage and vasculitic involvement, but there was no sign of infection. Daily plasmapheresis was started for alveolar hemorrhage. He needed respiratory support because of carbon dioxide retention and hypoxia on the 9th day of immuno-suppressive treatment. A 2nd dose of rituximab was administered with 15 days’ interval. After factor 7a and 14-day plasmapheresis treatment, alveolar hemorrhage ameliorated; however, on the 10 days of respiratory support with mechanical ventilator (4 days after the 2nd dose of rituximab therapy) Acinetobacter baumanii was detected in both blood and sputum cultures (imipenem resistant and colistin sensitive). Hence, imipenem was replaced with colistin. On the 30th day of immunosup-pressive treatment, while the patient still had anuria and continued to require hemodialysis. He died on the 12th day of colistin therapy from sepsis due to A. baumanii pneumonia. Important clinical events and treatment are summarized in [Table 1].
Figure 1: Cellular crescent formation in two out of three glomeruli (methenamine silver, ×100).

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Figure 2: Necrotizing arteritis with fibrinoid necrosis highlighted in red with Masson trichrome stain (arrow) (×100).

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Figure 3: Focus of neutrophilic interstitial inflammation with necrotic debris (H and E, ×200).

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Table 1: Important clinical features and treatment.

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The author obtained all appropriate consent forms from the patient’s relative for the publication of the case report.

   Discussion Top

Although the pathogenesis of ANCA associated vasculitis has still not been fully explained, the presence of ANCA indicates an autoimmune background. Diseases linked to the immune mechanism, generally affect glomeruli along with secondary involvement of tubules and interstitium. Systemic vasculitis associated with ANCA is shown to be characterized by pauci-immune necrotizing glome-rulonephritis in characteristic renal lesions.[3] Glomerular involvement is frequently accompanied with mononuclear tubulointerstitial infiltrate with or without granuloma formation and this mononuclear tubulointerstitial infiltrate is always described along with glome-rulitis.[3]

In addition, some renal biopsy samples of patients with diseases associated with ANCA reported only mononuclear tubulointerstitial infiltration without glomerular lesions.[4],[5],[6] Interstitial nephritis as the only manifestation of vasculitis is attributed to interstitial inflammation and peritubular capillaritis causing preservation of larger veins and glomeruli.[7] The presence of these renal biopsy findings which are not expected without crescent and vasculitis severe clinical findings may be considered to be a good prognostic marker in patients with severe clinical findings. In the literature, idiopathic ANCA-associated pure tubulointerstitial nephritis cases are characterized by mononuclear interstitial infiltration and are reported to have improved kidney functions after immunosuppressive treatment.[4],[5],[6] However, the study by Lockwood of four patients with ANCA-associated isolated TIN reported that two patients with mononuclear infiltration and two patients with neutrophil dominant interstitial infiltration spontaneously improved. However, this study has some limitations; detailed clinical information about ANCA types and patients was not given and additionally spontaneous resolution of ANCA associated renal disease is not an expected situation. [Table 2] summarizes the clinical and pathologic features of AAV patients presenting with TIN.[8],[9],[10] Some studies have proposed pauci-immune glomerulonephritis is a delayed type hypersensitivity disease due to clear infiltration of T cells and cell-mediated immunity is considered the most important injury mediator.[11],[12],[13] The initial event mediated by a variety of cytokines is a complex interaction between antigen-presenting mono-nuclear phagocytes and dominant T-helper cells and results in proliferation and activation of T lymphocytes. Oxygen radicals and nitric oxide play an important role in initiation and growth of this process. In addition, after beginning the inflammatory process, secondary activation of monocytes cannot be ignored. This may form a direct cellular contact route between T cells and monocytes. The role of neutrophils in the initiation of renal injury in AAV is not clear.[14] In recent times, it was shown that ANCA-mediated neutrophil activation may play an important role in pauci-immune vasculitis or nephritis pathogenesis. Activated neutrophils releasing lysosomal enzymes and oxygen radicals are shown to contribute to direct cell-mediated injury of not just the affected glomeruli but also interstitium and other glomeruli.[14],[15]
Table 2: Clinical and pathologic features of antineutrophil cytoplasmic antibodies associated vasculitis patients presenting with tubulointerstitial nephritis.

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In renal biopsy samples of AAV patients, leukocyte subgroups found inflammatory cell infiltrate in glomeruli and interstitium and their effect on renal prognosis have not been fully researched. The study by Brouwer et al found a strong positive correlation between the degree of renal failure and active neutrophil numbers within the kidney showing active neutrophils contribute to the pathogenesis of renal lesions in granulomatosis with polyangiitis.[15] Weidner et al found a significant correlation between serum creatinine concentration at the time of biopsy and glomerular infiltration of CD68-positive macrophages in addition to interstitial tissue, the authors underlined the important role of monocytes in addition to neutrophils in tissue injury in AAV.[14]

In our case, the inconsistent feature according to AAV pathogenesis is neutrophils found in tubulointerstitium not in glomerular capillaries. The effect of suppurative interstitial nephritis with or without pauci-immune cre-scentic glomerulonephritis on renal prognosis is not clear in AAV-associated vasculitis. Banerjee et al identified suppurative interstitial nephritis on the first renal biopsy and identified pauci-immune crescentic glomerulo-nephritis on a second biopsy after no response to pyelonephritis treatment when reporting a case who remained anuric with renal functions not improving after intense immunosup-pressive treatment. They proposed that suppurative interstitial nephritis may represent an early event in the natural progression of vasculitis.[16] Our case presented with constitutional symptoms of vasculitis and anuria, and renal biopsy identified association of necrotizing arteritis, pauci-immune crescentic glomerulonephritis and suppurative interstitial nephritis. Severe pyelonephritis together with pauci-immune crescentic glomerulonephritis may make some people think that AAV developed after infection. However, the patient had no signs of urinary tract infection, repeated blood and urinary cultures were sterile and were unresponsive to antibiotic therapy which makes difficult to believe in this hypothesis. Cytoplasmic ANCA positivity and severe pulmonary involvement is consisted with granulomatosis with Polyangiitis. In spite of intense immunosuppressive treatment and plasmapheresis, renal function did not improve and he had poor prognosis progressing to mortality due to alveolar hemorrhage and pulmonary infection. The possibility of treatment response to AAV-associated renal diseases reaching the stage needing dialysis is less compared to those presenting in the early stage.[17] Our patient presented late in the stage needing dialysis; however, acute changes were present on renal biopsy indicating the possibility of treatment response. It may be noted that Wen et al reported that even the patients presenting in the dialysis requiring stage with isolated mononuclear interstitial nephritis on kidney biopsy favorably responded to immuno-suppressive treatment.[4]

In conclusion, suppurative interstitial nephritis is a situation that may be observed with AAV associated vasculitis and it is not clear whether it is a severe disease variant. There is a need for more studies to determine the immunologic mechanisms, distribution model, and effect on prognosis of renal leukocyte infiltration.

Conflict of interest: None declared.

   References Top

Hooke DH, Gee DC, Atkins RC. Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int 1987;31:964-72.  Back to cited text no. 1
Stachura I, Si L, Whiteside TL. Mononuclear-cell subsets in human idiopathic crescentic glomerulonephritis (ICGN): Analysis in tissue sections with monoclonal antibodies. J Clin Immunol 1984;4:202-8.  Back to cited text no. 2
Jennette JC. Renal involvement in systemic vasculitis. In: Jennette JC, Olson JL, Schwartz MM, editors. Heptinstall’sPathology of the Kidney. Philadelphia: Lippincott-Raven; 1998. p.1059-95.  Back to cited text no. 3
Wen YK, Chen ML. Transformation from tubulointerstitial nephritis to crescentic glomerulonephritis: An unusual presentation of ANCA-associated renal vasculitis. Ren Fail 2006;28:189-91.  Back to cited text no. 4
Ernam D, Atikcan S, Yilmaz A, et al. An unusual renal presentation of wegener’s granulomatosis. TuberkToraks 2003;51:193-6.  Back to cited text no. 5
Fannin SW, Hagley MT, Seibert JD, Koenig TJ. Bronchocentric granulomatosis, acute renal failure, and high titer antineutrophil cyto-plasmic antibodies: Possible variants of Wegener’s granulomatosis. J Rheumatol 1993;20:507-9.  Back to cited text no. 6
American Society of Nephrology, National Kidney Foundation, American College of Physicians. Medical Knowledge Self Assessment Program in Nephrology and Hypertension Syllabus; 1994. pp. 109.  Back to cited text no. 7
Lockwood CM. Antineutrophil cytoplasmic autoantibodies: The nephrologist’s perspective. Am J Kidney Dis 1991;18:171-4.  Back to cited text no. 8
Sanavi S, Afshar R. An unusual presentation of antineutrophil cytoplasmic antibody-associated vasculitis: Discrepancy between histopatho-logy and clinical presentation. Iran J Kidney Dis 2011;5:347-50.  Back to cited text no. 9
Montoliu J, Amoedo ML, Panadés MJ, Ramos J. Lessons to be learned from patients with vasculitis. Nephrol Dial Transplant 1997;12: 2781-6.  Back to cited text no. 10
Cameron JS. New horizons in renal vasculitis. KlinWochenschr 1991;69:536-51.  Back to cited text no. 11
Cunningham MA, Huang XR, Dowling JP, Tipping PG, Holdsworth SR. Prominence of cell-mediated immunity effectors in “pauci-immune” glomerulonephritis. J Am Soc Nephrol 1999;10:499-506.  Back to cited text no. 12
Aasarod K, Bostad L, Hammerstrom J, Jorstad S, Iversen BM. Wegener’s granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies – a clinico-pathological study. Scand J UrolNephrol 2001;35:401-10.  Back to cited text no. 13
Weidner S, Carl M, Riess R, Rupprecht HD. Histologic analysis of renal leukocyte infiltration in antineutrophil cytoplasmic antibody-associated vasculitis: Importance of monocyte and neutrophil infiltration in tissue damage. Arthritis Rheum 2004;50:3651-7.  Back to cited text no. 14
Brouwer E, Huitema MG, Mulder AH, et al. Neutrophil activation in vitro and in vivo in wegener’s granulomatosis. Kidney Int 1994;45: 1120-31.  Back to cited text no. 15
Banerjee A, McKane W, Thiru S, Farrington K. Wegener’s granulomatosis presenting as acute suppurative interstitial nephritis. J ClinPathol 2001;54:787-9.  Back to cited text no. 16
KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012;2 Suppl 2:233-9.  Back to cited text no. 17

Correspondence Address:
Sultan Ozkurt
Department of Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir
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DOI: 10.4103/1319-2442.308362

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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