Interstitial ANCA-Associated Vasculitis Associates with Severe Kidney Injury Independent of Glomerulonephritis

Background: SLE, a pan-systemic inflammatory disease, can have a deleterious effect on renal function. Timely detection and management of renal dysfunction is highly desirable, since many patients develop disease at an early age and inflammatory nephropathies can be relentlessly progressive. Methods: We developed a Raman spectroscopic technology (Rametrix ® molecular urinalysis) to detect SLE systemic/renal effects by analysis of patient urine. It is based on chemometric analysis of the Raman spectrum of urine and detects metabolomic differences. The technology is not designed specifically to detect cell degradation products (DP), such as nucleic acid DPs, but can be harnessed to probe and quantify these. We hypothesized that SLE would alter urine composition and that Rametrix® analysis could detect renal dysfunction via urine molecular ‘fingerprinting’. We applied Rametrix® analysis on 587 urine specimens collected from 82 patients with biopsy-proven (80/82) and/or laboratory-validated SLE markers. Patients were 8-21 years of age (median age 14.5) and 77.5% female. Most patients were African-American (183/587), Latino (162/587) or Caucasian (129/587). Serial longitudinal urine samples were obtained on multiple individuals. A renal SLEDAI-2K score was correlated to Rametrix® findings. Using chemometric analysis of urine Raman spectra, we compared SLE urine spectra with urine spectra from urine of healthy controls (203), patients with CKD (20), COVID19 patients (118), bladder cancer patients (19) and Lyme disease patients (20). Results: Rametrix ® molecular urinalysis distinguished SLE-associated changes in urine composition with predictive metrics (accuracy, sensitivity, specificity, PPV, and NPV) ranging between 73-97%. A correlation between changes in urine Raman spectra and physician assessment of disease (SLEDAI-2K) was also found through computational analysis. Urine spectra from SLE and COVID19 patients showed notable Raman spectral similarities, suggesting common inflammatory pathways (interferonopathies). Conclusions: Raman molecular urinalysis can be useful to detect and manage SLE and renal dysfunction.


Background:
We proposed the IgMPC-TIN disease concept in 2017, and this disease concept is gradually gaining recognition in Japan.However, there are no clear diagnostic criteria for diagnosing IgMPC-TIN.We attempted to develop diagnostic criteria for IgMPC-TIN from both clinical and histological parameters or from only clinical parameters using cases collected from multiple institutions.
Methods: A total of 118 renal biopsy samples were collected from 61 patients with suspected IgMPC-TIN and 57 patients with other interstitial lesions from our hospital and national collaborating centers, and we performed double staining (IgM and CD138) using the immunoenzymatic method.Patients with M protein in their blood or urine and patients with diabetes mellitus were established as exclusion criteria.Then several nephrologists classified each case that did not meet the exclusion criteria from +3 (typical IgMPC-TIN) to −3 (not IgMPC-TIN at all).Based on 49 cases judged as +3 and 56 cases judged as −3, a decision tree-based diagnostic algorithm was created in JMP.Finally, the sensitivity and specificity of the diagnostic criteria created were calculated.
Results: In the diagnostic criteria consisting of histological and clinical parameters, the most important requirement was a maximum IgMPC infiltration count of ≥20/high magnification field of view (7400 µm 2 ).The next most important requirement was the presence of urinary sugar, and the next requirement was the presence of primary biliary cholangitis (PBC).For diagnostic criteria consisting only of clinical parameters, the most important requirement was a serum IgM level of 267 or higher, followed by the presence of Fanconi syndrome.Sensitivity and specificity of each diagnostic criterion were 97.9 and 100% for histological and clinical parameters and only for clinical parameters.Although we consider diagnostic criteria that include histological parameters to be the gold standard, diagnostic criteria based solely on clinical parameters are also sufficiently accurate.

Conclusions:
We analyze the clinical characteristics of IgMPC-TIN cases and develop criteria for the diagnosis of IgMPC-TIN based on histological and clinical parameters.

TH-PO795 Poster Thursday
Pathology and Lab Medicine -I Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgG4-related disease (IgG4-RD) are immune disorders with distinctions in pathogenesis, prognosis, and management, that can share clinical and laboratory features.While ANCA positivity excludes IgG4-RD in the 2019 ACR/EULAR classification, this criterion is not uniformly applied, and AAV can form inflammatory masses in various organs and show increase in IgG4+ plasma cells, similar to IgG4-RD.This case highlights challenges in AAV and IgG4-RD diagnoses in a child.

ANCA-Associated
Case Description: A 5-year-old female with previously normal kidney function presents with nausea, diarrhea and acute kidney injury with hematuria and proteinuria.Her only medical history is of a left orbital mass a year ago, diagnosed as IgG4-RD based on elevated serum IgG (1270 mg/dL) and biopsy with sclerosing fibrosis with IgG4+ plasma cells and eosinophils, and treated with steroids with complete mass resolution.On this admission, she has a positive MPO ANCA (1:80) with pertinent negatives of normal serum C3, C4, total IgG, and IgG4, and negative ANA and anti-dsDNA.A kidney biopsy shows chronic active pauci-immune crescentic glomerulonephritis and acute tubulointerstitial nephritis with up to 14 IgG4+ plasma cells/40X field, IgG4+/ IgG+ plasma cell ratio up to 25%, and focal tubular basement membrane (TBM) deposits (Image).She is treated with pulse steroids and rituximab with no kidney function improvement, in contrast to most cases of IgG4-RD.
Discussion: Pauci-immune crescentic GN with positive ANCA are characteristic for kidney AAV, and in retrospect, suggest the orbital mass may have represented the initial manifestation of AAV despite orbital mass histology with increased IgG4+ plasma cells and elevated serum IgG4 at diagnosis.The additional features of TBM deposits and increased IgG4+ plasma cells in the kidney biopsy highlight further potential for confounding morphologic overlap between AAV and IgG4-RD, for which correlation with ANCA testing is essential.

TH-PO796 Poster Thursday
Pathology and Lab Medicine -I Interstitial ANCA-Associated Vasculitis Associates with Severe Kidney Injury Independent of Glomerulonephritis Bjoern Tampe.Universitatsmedizin Gottingen, Gottingen, Germany.
Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney.Although crescentic ANCA glomerulonephritis (GN) is a common histological finding reflecting glomerular small vessel vasculitis, it is reasonable that manifestation of AAV could also contribute to interstitial small vessel vasculitis.Therefore, we here aimed to expand our current knowledge focusing on interstitial vasculitis in ANCA GN by systematic histological scoring of vascular lesions analogous to Banff.
Methods: A total number of 49 kidney biopsies with confirmed renal involvement of AAV at the University Medical Center Göttingen were retrospectively included between 2015 till 2020.A renal pathologist evaluated all biopsies and was blinded to clinical data collection and analysis.
Results: Since previous studies established that crescentic ANCA GN associates with severe kidney injury and acute deterioration of kidney function in AAV, we first systematically scored interstitial vasculitis in association with requirement of renal replacement therapy (RRT).Among all active and chronic tubulointerstitial lesions analogous to the Banff scoring system, the only association between severe kidney injury requiring RRT was observed for interstitial vasculitis in AAV reflected by peritubular capillaritis (ptc, p=0.0002) and arteritis (v, p=0.0069), affecting 5/49 (10.2%) and 11/49 (22.4%) of renal biopsies, respectively.Interestingly, no association between interstitial vasculitis (ptc and v correlating with severe kidney injury) and any glomerular lesion in ANCA GN (also correlating with severe kidney injury) was observed, thereby confirming that interstitial vasculitis contributes to severe kidney injury independent of ANCA GN.By contrast, short-term renal recovery from RRT was equal in both groups, suggesting a distinct association with acute decline of kidney function at disease onset.
Conclusions: Taken together, by using the Banff scoring system we here expand our current knowledge of renal interstitial lesions in AAV revealing peritubular capillaritis and arteritis as important histological alterations associated with severe kidney injury in a considerable subset of AAV.