Abstract
Background
Hematuria is common in myeloperoxidase anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-MPO). Previous studies have mainly focused on urinary dysmorphic red blood cells and few have reported the clinical significance of isomorphic urinary red blood cells. Therefore, the main aim of this study was to assess the predictive yield of urinary isomorphic red blood cells for disease severity and renal outcomes in patients with ANCA-MPO associated vasculitis.
Methods
A total of 191 patients with ANCA-MPO associated vasculitis with hematuria were retrospectively selected and were divided into two groups (with isomorphic red blood cells versus dysmorphic red blood cells) according to the percentage of isomorphic red blood cells on urinary sediment analysis. Clinical, biological and pathological data at diagnosis were compared. Patients were followed up for a median of 25 months and progression to end-stage kidney disease and death were regarded as main outcome events. Additionally, univariate and multivariate Cox regression models were used to estimate the risk factors for end-stage kidney disease.
Results
Out of 191 patients, 115 (60%) had ≥ 70% and 76 (40%) had < 30% urine isomorphic red blood cells. Compared with patients in the dysmorphic red blood cell group, patients in the isomorphic red blood cell group had a significantly lower estimated glomerular filtration rate (eGFR) [10.41 mL/min (IQR 5.84–17.06) versus 12.53 (6.81–29.26); P = 0.026], higher Birmingham Vasculitis Activity Score [16 (IQR 12–18) versus 14 (10–18); P = 0.005] and more often received plasma exchange [40.0% versus 23.7% (P = 0.019)] at diagnosis. Kidney biopsies revealed a higher proportion of patients with glomerular basement membrane fracture in the isomorphic red blood cell group [46.3% versus 22.9% (P = 0.033)]. Furthermore, patients with predominant urinary isomorphic red blood cells were more likely to progress to end-stage kidney disease [63.5% versus 47.4% (P = 0.028)] and had a higher risk of death [31.3% versus 19.7% (P = 0.077)]. The end-stage kidney disease-free survival was lower in patients in the isomorphic red blood cell group (P = 0.024). However, urine isomorphic red blood cells ≥ 70% could not predict the presence of end-stage kidney disease in multivariate Cox analysis.
Conclusion
Myeloperoxidase-anti-neutrophil cytoplasmic antibody associated vasculitis patients with predominant urinary isomorphic red blood cells at diagnosis had more severe clinical manifestations and a higher risk of poor renal outcomes. In this respect, urinary isomorphic red blood cells could be viewed as a promising biomarker of ANCA_MPO vasculitis severity and progression.
Graphical abstract

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Data availability
The datasets used during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AAV:
-
Antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis
- MPO:
-
Myeloperoxidase
- PR3:
-
Proteinase 3
- iRBCs:
-
Isomorphic red blood cells
- dRBCs:
-
Dysmorphic red blood cells
- IF:
-
Immunofluorescence
- ELISA:
-
Enzyme-linked immunosorbent assay
- HPF:
-
High-power field
- WBC:
-
White blood cell
- RBC:
-
Red blood cell
- HB:
-
Hemoglobin
- sC3:
-
Serum C3 levels
- sC4:
-
Serum C4 levels
- sIgA:
-
Serum IgA levels
- sIgG:
-
Serum IgG levels
- sIgM:
-
Serum IgM levels
- CRP:
-
C-reactive protein
- ESR:
-
Erythrocyte sedimentation rate
- UACR:
-
Urinary albumin to creatinine ratio
- eGFR:
-
Estimated glomerular filtration rate
- BVAS:
-
Birmingham vasculitis activity score
- GBM:
-
Glomerular basement membrane
- IC:
-
Immune-complex
- PE:
-
Plasma exchange
- ESRD:
-
End-stage renal disease
- KRT:
-
Kidney replacement therapy
References
Cornec D, Cornec-Le Gall E, Fervenza FC, Specks U (2016) ANCA-associated vasculitis—clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol 12(10):570–579
Kitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, Kullman J, Lyons PA, Merkel PA, Savage COS, Specks U, Kain R (2020) ANCA-associated vasculitis. Nat Rev Dis Primers 6(1):71
Geetha D, Jefferson JA (2020) ANCA-associated vasculitis: core curriculum 2020. Am J Kidney Dis 75(1):124–137
Van Daalen EE, Neeskens P, Zandbergen M, Harper L, Karras A, Vaglio A, de Zoysa J, Bruijn JA, Bajema IM (2019) Podocytes and proteinuria in ANCA-associated glomerulonephritis: a case-control study. Front Immunol 26(10):1405
Córdova-Sánchez BM, MejÃa-Vilet JM, Morales-Buenrostro LE, Loyola-RodrÃguez G, Uribe-Uribe NO, Correa-Rotter R (2016) Clinical presentation and outcome prediction of clinical, serological, and histopathological classification schemes in ANCA-associated vasculitis with renal involvement. Clin Rheumatol 35(7):1805–1816
Liang H, Xin M, Zhao L, Wang L, Sun M, Wang J (2017) Serum creatinine level and ESR values associated to clinical pathology types and prognosis of patients with renal injury caused by ANCA-associated vasculitis. Exp Ther Med 14(6):6059–6063
Rhee RL, Davis JC, Ding L, Fervenza FC, Hoffman GS, Kallenberg CGM, Langford CA, McCune WJ, Monach PA, Seo P, Spiera R, St Clair EW, Specks U, Stone JH, Merkel PA (2018) The utility of urinalysis in determining the risk of renal relapse in ANCA-associated vasculitis. Clin J Am Soc Nephrol 13(2):251–257
Chen TK, Murakami C, Manno RL, Geetha D (2014) Hematuria duration does not predict kidney function at 1 year in ANCA-associated glomerulonephritis. Semin Arthritis Rheum 44(2):198–201
Jalalah SM, Alzahrani IH, Furness PN (2002) Glomerular changes in microscopic haematuria, studied by quantitative immunoelectron microscopy and in situ zymography. Nephrol Dial Transplant 17(9):1586–1593
Collar JE, Ladva S, Cairns TD, Cattell V (2001) Red cell traverse through thin glomerular basement membranes. Kidney Int 59(6):2069–2072
Rogers PW, Kurtzman NA, Bunn SM Jr, White MG (1973) Familial benign essential hematuria. Arch Intern Med 131(2):257–262
Perry GJ, George CR, Field MJ, Collett PV, Kalowski S, Wyndham RN, Newland RC, Lin BP, Kneale KL, Lawrence JR (1989) Thin-membrane nephropathy—a common cause of glomerular haematuria. Med J Aust 151(11–12):638–42
Schifferli J, Rees AJ, Pearse E (1979) Haematuria: glomerular or non-glomerular? Lancet 2(8150):1014
Tesser Poloni JA, Bosan IB, Garigali G, Fogazzi GB (2012) Urinary red blood cells: not only glomerular or nonglomerular. Nephron Clin Pract 120(1):c36-41 (Discussion c41)
Van Iseghem P, Hauglustaine D, Bollens W, Michielsen P (1983) Urinary erythrocyte morphology in acute glomerulonephritis. Br Med J (Clin Res Ed) 287(6400):1183
Serra A, Torguet P, Romero R, Bonal J, Caralps A (1991) Normal urinary red blood cell morphology in segmental necrotizing glomerulonephritis. Nephron 59(2):351–352
Favaro S, Bonfante L, D’Angelo A, Giacomini A, Normanno M, Caló L, Bordin V, Vianello D, Meani A, Antonello A, Borsatti A (1997) Is the red cell morphology really useful to detect the source of hematuria? Am J Nephrol 17(2):172–175
Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D (1994) Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 87(11):671–678
Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, Flossmann O, Hall C, Hollywood J, Jayne D, Jones R, Lanyon P, Muir A, Scott D, Young L, Luqmani RA (2009) Modification and validation of the Birmingham vasculitis activity score (version 3). Ann Rheum Dis 68(12):1827–1832
Suppiah R, Mukhtyar C, Flossmann O, Alberici F, Baslund B, Batra R, Brown D, Holle J, Hruskova Z, Jayne DR, Judge A, Little MA, Palmisano A, Stegeman C, Tesar V, Vaglio A, Westman K, Luqmani R (2011) A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis. Rheumatology (Oxford) 50(5):899–905
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA (2013) 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65(1):1–11
Hagen EC, Andrassy K, Chernok E, Daha MR, Gaskin G, Gross W, Lesavre P, Lüdemann J, Pusey CD, Rasmussen N et al (1993) The value of indirect immunofluorescence and solid phase techniques for ANCA detection. A report on the first phase of an international cooperative study on the standardization of ANCA assays. EEC/BCR Group for ANCA Assay Standardization. J Immunol Methods 159(12):1–16
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J (2009) CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–12
Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, Waldherr R, Bruijn JA, Bajema IM (2010) Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 21(10):1628–1636
Hamadah AM, Gharaibeh K, Mara KC, Thompson KA, Lieske JC, Said S, Nasr SH, Leung N (2018) Urinalysis for the diagnosis of glomerulonephritis: role of dysmorphic red blood cells. Nephrol Dial Transplant 33(8):1397–1403
Koo KC, Lee KS, Choi AR, Rha KH, Hong SJ, Chung BH (2016) Diagnostic impact of dysmorphic red blood cells on evaluating microscopic hematuria: the urologist’s perspective. Int Urol Nephrol 48(7):1021–1027
Crop MJ, de Rijke YB, Verhagen PC, Cransberg K, Zietse R (2010) Diagnostic value of urinary dysmorphic erythrocytes in clinical practice. Nephron Clin Pract 115(3):c203–c212
Pollock C, Liu PL, Györy AZ, Grigg R, Gallery ED, Caterson R, Ibels L, Mahony J, Waugh D (1989) Dysmorphism of urinary red blood cells–value in diagnosis. Kidney Int 36(6):1045–1049
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C (2016) EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 75(9):1583–1594
Ahn SS, Yoon T, Song JJ, Park YB, Lee SW (2022) Serum albumin, prealbumin, and ischemia-modified albumin levels in patients with ANCA-associated vasculitis: a prospective cohort study. PLoS One 17(7):e0271055
Zeng T, Tian Y, Tan L, Wu Y, Yu J, Huang J, Pei Z (2019) Inflammation level and renal function injury in antineutrophil cytoplasmic antibody-associated vasculitis: a correlation with low albumin and high-density lipoprotein. Biomark Med 13(7):557–565
Harper L, Savage CO (2005) ANCA-associated renal vasculitis at the end of the twentieth century—a disease of older patients. Rheumatology (Oxford) 44(4):495–501
Bakoush O, Segelmark M, Torffvit O, Ohlsson S, Tencer J (2006) Urine IgM excretion predicts outcome in ANCA-associated renal vasculitis. Nephrol Dial Transplant 21(5):1263–1269
Marchesi VT (1966) Mechanisms of cell migration and macromolecule transport across the walls of blood vessels. Gastroenterology 51(5):875–892
Ghim M, Alpresa P, Yang SW, Braakman ST, Gray SG, Sherwin SJ, van Reeuwijk M, Weinberg PD (2017) Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow. Am J Physiol Heart Circ Physiol 313(5):H959–H973
Deen WM, Bohrer MP, Brenner BM (1979) Macromolecule transport across glomerular capillaries: application of pore theory. Kidney Int 16(3):353–365
Vuononvirta J, Marelli-Berg FM, Poobalasingam T (2021) Metabolic regulation of T lymphocyte motility and migration. Mol Aspects Med 77:100888
O’Sullivan KM, Lo CY, Summers SA, Elgass KD, McMillan PJ, Longano A, Ford SL, Gan PY, Kerr PG, Kitching AR, Holdsworth SR (2015) Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Kidney Int 88(5):1030–1046
Aendekerk JP, Jiemy WF, Raveling-Eelsing E, Bijnens N, Abdul-Hamid MA, Strating IM, Dekkema GJ, Sanders JF, Stegeman CA, Damoiseaux JGMC, Little MA, Heeringa P, van Paassen P (2022) CD163 and CD206 expression define distinct macrophage subsets involved in active ANCA-associated glomerulonephritis. J Autoimmun 29(133):102914
Chen A, Lee K, Guan T, He JC, Schlondorff D (2020) Role of CD8+ T cells in crescentic glomerulonephritis. Nephrol Dial Transplant 35(4):564–572
Tofik R, Torffvit O, Rippe B, Bakoush O (2012) Urine IgM-excretion as a prognostic marker for progression of type 2 diabetic nephropathy. Diabetes Res Clin Pract 95(1):139–144
Fogazzi GB, Ferrari B, Garigali G, Simonini P, Consonni D (2012) Urinary sediment findings in acute interstitial nephritis. Am J Kidney Dis 60(2):330–332
Funding
This research was supported by the National Natural Science Foundation of China (81270786), Natural Science Foundation of Hunan Province (2020JJ4887), and Clinical Medical Technology Innovation Guidance Program of Hunan Province (2020SK53701).
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All authors have made substantial contributions to the completion of the work. Research idea and study design: FW, XL; Data acquisition: FW, YJ, FZ, LL, JT, LH, ZL, YJ, LD, HG, DS, GX; Statistical analysis and manuscript writing: FW, LL; Supervision: XL, JF, XH. All authors reviewed and approved the article.
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This study was approved by the medical ethics committee of Xiangya Hospital of Central South University (2019030598).
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Wang, F., Jin, Y., Zhou, F. et al. Urinary isomorphic red blood cells for the prediction of disease severity and renal outcomes in MPO-ANCA-associated vasculitis: a retrospective cohort study. J Nephrol 36, 2295–2304 (2023). https://doi.org/10.1007/s40620-023-01663-3
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DOI: https://doi.org/10.1007/s40620-023-01663-3