# A Clinicopathological Description of Kidney Features in VEXAS Syndrome

Martin Mathurin, Pierre Hirsch, Vincent Jachiet, Jérôme Hadjadj, Guillaume Le Guenno, Mael Heiblig, Solenne Pelletier, Alexis Mathian, Cyril Garrouste, Aurélie Lavergne, et al.

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Martin Mathurin, Pierre Hirsch, Vincent Jachiet, Jérôme Hadjadj, Guillaume Le Guenno, et al. A Clinicopathological Description of Kidney Features in VEXAS Syndrome. Kidney International Reports, 2024, 10 (1), pp.260 - 264. 10.1016/j.ekir.2024.10.026. hal-05096159

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# A Clinicopathological Description of Kidney Features in VEXAS Syndrome

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Martin Mathurin¹, Pierre Hirsch²,³, Vincent Jachiet⁴, Jérôme Hadjadj⁴,
Guillaume Le Guenno⁵, Mael Heiblig⁶, Solenne Pelletier⁷, Alexis Mathian⁸, Cyril Garrouste⁹,
Aurélie Lavergne¹⁰, Samuel Ardois¹¹, Joanne Flejeo¹², Ingrid Masson¹³,
Zakaria Boukerroucha¹⁴, François Perrin¹⁵, Marion Magnol¹⁶, Arnaud Constantin¹⁶,
Jérémie Dion¹⁶, Thibault Comont¹⁶, Antoine Huart¹⁷, Jean-Louis Kemeny¹⁸, Cécile Picard¹⁹,
Magali Colombat²⁰, Cécile Le Naoures²¹, Laurent Benard²², Aurélie Sannier²³,
François Vrtovsnik²⁴, Isabelle Brocheriou²⁵, Cedric Pastoret²⁶, Pierre Sujobert²⁷,
Eric Delabesse²⁸, Olivier Kosmider²⁹, François Delhommeau²,³, Arsène Mekinian⁴,
Sophie Georgin-Lavialle¹, David Buob³⁰ and Khalil El Karoui³¹; and on behalf of the
FRENVEX Group³¹

¹Médecine Interne, Hôpital Tenon, Sorbonne Université, Paris, France; ²Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Siric Curamus, Paris, France; ³Hôpital Saint-Antoine, Service d'Hématologie Biologique, Sorbonne Université, Paris, France; ⁴Médecine Interne, Hôpital Saint-Antoine, Sorbonne Université, Paris, France; ⁵Médecine Interne, Hôpital Estaing, Clermont-Ferrand, France; ⁶Hématologie, Hôpital Lyon Sud-HCL, Lyon, France; ⁷Néphrologie, CHU Lyon-HCL, Lyon, France; ⁸Médecine Interne 2, Hôpital Pitié-Salpétrière, Paris, France; ⁹Néphrologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France; ¹⁰Néphrologie, CHU de Rennes, Rennes, France; ¹¹Médecine Interne, CHU de Rennes, Rennes, France; ¹²Néphrologie, GHT d'Armor, Saint-Brieuc, France; ¹³Néphrologie, Centre Hospitalier de St Etienne, France; ¹⁴Néphrologie, Centre Hospitalier de Saint-Nazaire, Saint-Nazaire, France; ¹⁵Médecine Interne, Centre Hospitalier de Saint-Nazaire, Saint-Nazaire, France; ¹⁶Médecine Interne, IUCT-Oncopole, Toulouse, France; ¹⁷Néphrologie, Hôpital de Rangueil, Toulouse, France; ¹⁸Anatomopathologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France; ¹⁹Anatomopathologie, Hospices Civils de Lyon, Lyon, France; ²⁰Anatomopathologie, CHU de Toulouse, Toulouse, France; ²¹Anatomopathologie, CHU de Rennes, Rennes, France; ²²Anatomopathologie, Centre Hospitalier de Saint-Nazaire, Saint-Nazaire, France; ²³Anatomopathologie, Hôpital Bichat - Claude-Bernard, Paris, France; ²⁴Néphrologie, Hôpital Bichat - Claude-Bernard, Paris, France; ²⁵Anatomopathologie, Hôpital Pitié-Salpétrière, Paris, France; ²⁶Hématologie - Biologie Moléculaire, CHU Pontchaillou, Rennes, France; ²⁷Hématologie Biologique, Hospices Civils de Lyon, Hôpital Lyon Sud, Lyon, France; ²⁸Hématologie Biologique, Institut Universitaire de Cancérologie de Toulouse site Oncopôle, Toulouse, France; ²⁹Hématologie Biologique, Institut Cochin, Paris, France; ³⁰Anatomopathologie, Hôpital Tenon, Sorbonne Université, Paris, France; and ³¹Néphrologie, Hôpital Tenon, Sorbonne Université, Paris, France

**Correspondence:** Khalil El Karoui, Nephrology Department, Hôpital Tenon, Paris, France. E-mail: khalil.el-karoui@aphp.fr

³¹Members of the FRENVEX Group are listed in the Appendix.

**Received 16 October 2024; accepted 21 October 2024; published online 28 October 2024**

Kidney Int Rep (2025) 10, 260–264; https://doi.org/10.1016/j.ekir.2024.10.026

KEYWORDS: acute kidney injury; chronic kidney disease; inflammation; kidney biopsy; UBA1; VEXAS

© 2024 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## INTRODUCTION

VEXAS (Vacuoles, enzyme E3, X-linked, Autoinflammatory, Somatic) is a recently reported late-onset autoinflammatory syndrome characterized by myeloid lineage-restricted somatic mutations in the ubiquitin-activating E1 (UBA1) gene.¹ The estimated prevalence of disease-causing UBA1 variants was 1 in 4269 men aged >50 years in 163.096 exome data from a US regional health system.² The main clinical features of VEXAS include skin lesions (83%, mostly neutrophilic dermatosis), fever (64%), lung involvement (50%), and ocular inflammation (39%).¹,³ Myelodysplastic syndrome is identified in about 50% cases. Interestingly, direct

organ infiltration by immature clonal cells could have a critical role in disease pathophysiology.⁴,⁵ To date, renal lesions of patients with VEXAS have been poorly characterized, on the basis of single case reports only, and include interstitial nephritis, AA amyloidosis, or pauci-immune vasculitis.⁶⁻⁹ In the present work, we aimed to describe the clinico-pathological findings and molecular characterization of patients with VEXAS who underwent a kidney biopsy.

## RESULTS

Among 303 patients with VEXAS with somatic pathogenic UBA1 variants, we identified 11 patients with
<table><caption>Table 1. Clinical and biological characteristics at kidney biopsy</caption><thead><tr><th>Patient<sup>a</sup></th><th>Age</th><th>AKI</th><th>CKD</th><th>Systemic symptoms</th><th>Treatment at KB</th><th>sCreatinine (µmol/l)</th><th>eGFR (ml/min per 1.73 m<sup>2</sup>)</th><th>Albuminemia (g/l)</th><th>Pu (g/d)</th><th>Albuminuria (% of proteinuria)</th><th>Hematuria</th><th>Leucocyturia</th><th>Hb (g/dl)</th><th>MCV (µ<sup>3</sup>)</th><th>CRP (mg/l)</th><th>Monoclonal gammopathy</th><th>Associated MDS</th><th>Autoimmunity</th></tr></thead><tbody><tr><td>1</td><td>61</td><td>0</td><td>1</td><td>HLA B27+, U, IBD, RP, S (ND), sclerosing panniculitis, possible SS</td><td>Steroids 30mg/d + Aza</td><td>70</td><td>110</td><td>NA</td><td>0.12</td><td>NA</td><td>+</td><td>NA</td><td>8.9</td><td>108</td><td>75</td><td>IgM Kappa</td><td>Yes</td><td>Type II cryoglobulinemia</td></tr><tr><td>2</td><td>72</td><td>1</td><td>0</td><td>L, S (vasculitis), IBD, RP</td><td>0</td><td>1300</td><td>0</td><td>2.1</td><td>1.8</td><td>NA</td><td>+</td><td>+</td><td>6.2</td><td>97</td><td>291</td><td>0</td><td>Yes</td><td>AAN 1/320</td></tr><tr><td>3</td><td>69</td><td>1</td><td>0</td><td>A, S, IBD, IS, CI, L, SS, RP, E</td><td>Hydro-cortisone 30mg/j</td><td>169</td><td>35</td><td>3.5</td><td>0.7</td><td>22%</td><td>+</td><td>0</td><td>10.4</td><td>99</td><td>37</td><td>0</td><td>NA</td><td>AAN 1/640</td></tr><tr><td>4</td><td>69</td><td>0</td><td>0</td><td>E, A, VTE, S(ND), orchitis, L</td><td>Steroids 20mg/d</td><td>72</td><td>90</td><td>2.3</td><td>5.6</td><td>NA</td><td>+</td><td>0</td><td>8.5</td><td>102</td><td>160</td><td>0</td><td>Yes</td><td>0</td></tr><tr><td>5</td><td>73</td><td>1</td><td>0</td><td>A, S (ND), IBD</td><td>Steroids 25mg/d</td><td>980</td><td>NA</td><td>2.5</td><td>6.3</td><td>NA</td><td>+</td><td>+</td><td>9.0</td><td>118</td><td>137</td><td>IgM kappa and IgM lambda</td><td>Yes</td><td>0</td></tr><tr><td>6</td><td>67</td><td>0</td><td>0</td><td>E, RP, S(vasculitis)</td><td>Steroids 50mg/d</td><td>43</td><td>113</td><td>NA</td><td>3.0</td><td>NA</td><td>NA</td><td>+</td><td>6.6</td><td>NA</td><td>175</td><td>IgM lambda</td><td>Yes</td><td>NA</td></tr><tr><td>7</td><td>73</td><td>1</td><td>1</td><td>S (vasculitis), A, U</td><td>Steroids 50mg/d</td><td>296</td><td>NA</td><td>3.4</td><td>1.2</td><td>NA</td><td>0</td><td>+</td><td>8.7</td><td>95</td><td>92</td><td>IgM lambda, IgG lambda</td><td>Yes</td><td>0</td></tr><tr><td>8</td><td>77</td><td>0</td><td>1</td><td>S (ND), A, RP</td><td>Steroids 3mg/d (+ Upadacitinib)</td><td>191</td><td>29</td><td>NA</td><td>4.3</td><td>72%</td><td>0</td><td>+</td><td>11.0</td><td>NA</td><td>37</td><td>0</td><td>Yes</td><td>NA</td></tr><tr><td>9</td><td>73</td><td>1</td><td>1</td><td>S(ND), peripheral neuropathy, meningitis, VTE</td><td>Steroids &lt;10mg/d + Ruxo</td><td>239</td><td>22</td><td>NA</td><td>0.3</td><td>NA</td><td>0</td><td>0</td><td>9.1</td><td>102</td><td>26</td><td>IgG lambda</td><td>NA</td><td>NA</td></tr><tr><td>10</td><td>59</td><td>0</td><td>1</td><td>A, S, RP</td><td>Steroids</td><td>427</td><td>12</td><td>NA</td><td>9.0</td><td>NA</td><td>NA</td><td>NA</td><td>8.13</td><td>107</td><td>97</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>11</td><td>78</td><td>1</td><td>0</td><td>S (vasculitis + ND), A,</td><td>Steroids 7mg/d</td><td>207</td><td>26</td><td>NA</td><td>3.8</td><td>NA</td><td>+</td><td>NA</td><td>9.90</td><td>NA</td><td>237</td><td>IgM Kappa</td><td>No</td><td>0</td></tr></tbody></table>

A, arthritis; AKI, acute kidney injury; AS, ankylosing spondylitis; Aza, azathioprine; CI, cardiac infarction; CKD, chronic kidney disease; CRP, C-reactive protein; E, episcleritis; Hb, hemoglobin; Hu, hematuria; IBD, intestinal bowel disease; IS, ischemic stroke; KB, kidney biopsy; L, lung involvement; Lu, leukocyturia; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; NA, non available; ND, neutrophilic dermatosis; NS, nephrotic syndrome; Pu, proteinuria; RP, relapsing polychondritis; Ruxo, ruxolitinib; S, skin; SS, Sicca syndrome; U, uveitis; VTE, venous thromboembolism.

<footnote>ªPatients 1, 2 and 10 were previously reported on.⁵,⁷,⁹</footnote>
kidney biopsy. Three patients were reported on pre-
viously.⁶,⁷,⁹ Renal biopsy was performed between
2012 and 2023 (with retrospective molecular diag-
nosis in 8 patients). Clinical characteristics of renal
biopsy are presented in Table 1. All patients were
male, mean (minimum–maximum) age was 70 (59–
78) years, hemoglobin was 8.77 (6.2–11) g/dl, mean
corpuscular volume was 104 (95–118) µ³, and C-
reactive protein was elevated in all patients. Renal
presentation included progressive chronic kidney
disease in 5 patients and acute kidney injury in 6,
including two patients (patients 7 and 9) needing
renal replacement therapy. All patients presented
with extrarenal manifestations (Table 1). Interest-
ingly, acute kidney injury episodes were chrono-
logically linked with VEXAS flares in 3 patients
(patients 2, 3, and 11). Most patients (n = 10/11,
90%) were already exposed to steroids or immu-
nomodulators at renal biopsy. Nephrotic range
proteinuria was observed in 5 patients. Mean
serum creatinine was 363 µmol/l; leukocyturia and
hematuria were present in 5 and 6 patients
respectively. Seven patients presented with an
associated myelodysplastic syndrome. Monoclonal
gammopathy of undetermined significance was
identified in 6 patients, with IgM circulating clones
in 5 of 6 patients. Renal function evolution was
usually favorable after treatment with corticoste-
roids and various immunosuppressants, despite
frequent infectious complications (Supplementary
Table S1).

Histopathological findings are depicted in Supplementary Tables S2 and S3. Primary diagnoses included acute interstitial nephritis (n = 4), antineutrophil cytoplasmic autoantibody negative pauci-immune vasculitis (n = 1), IgA nephropathy superimposed with minimal change disease (n = 1), IgA nephropathy (n = 1), diabetic nephropathy with extensive fibrosis (n = 1), acute tubular necrosis (n = 2), and AA amyloidosis (n = 1). No patients had monotypic deposits. Interestingly, interstitial inflammatory infiltration was noticed in 8 of 11 cases, whatever the primary diagnosis (Figure 1). Immunohistochemical characterization of interstitial inflammatory cells demonstrated the presence of lymphocytes and plasma cells, admixed with macrophages and neutrophil cells. Myeloperoxidase and CD68 immunostaining was positive in all cases, with a variable degree of expression (Supplementary Table S2 and Figure S1). Notably, 4 cases showed infiltrative cells expressing both myeloperoxidase and CD68, suggesting the presence of immature clonal cells of the myeloid lineage. In line with this observation, to identify the presence of UBA1-mutated clone in kidney samples, we performed

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Renal biopsy: severe interstitial inflammatory infiltration with presence of lymphocytes and plasma cells, admixed with macrophages and neutrophil cells. (HES, ×20).</figcaption></figure>

molecular analysis of DNA extracted from the 8 avail-
able frozen samples by next generation sequencing us-
ing a panel of 65 genes implied in myeloid malignancies
(including UBA1). UBA1 variation was detected in 7 of 8
samples, with variant allele frequency ranging from 2%
to 17% of total kidney DNA (Supplementary Table S2),
with other associated clones in only 2 of 8 kidney
samples (Supplementary Table S2).

DISCUSSION

In this work, we report the first series focusing on
clinicopathological and molecular renal features of
patients with VEXAS. We show that clinical and
histological presentation is diverse, and that UBA1
clone is detected within the kidney in most cases
(88%).

The number of patients who experienced renal
biopsy among the large cohort of the French
VEXAS network (11/303 patients, ~3.6%) may
suggest that renal disease associated with VEXAS is
rare. However, renal injury is probably under-
diagnosed in this population with a high risk of
postbiopsy complications, due to altered general
condition and frequent thrombocytopenia. In
addition, the improvement of renal dysfunction
after steroid increase in some patients may also
have limited kidney biopsy indications.

The different clinical and histological presentations
(acute interstitial nephritis, pauci-immune vasculitis,
IgA-dependent diseases, minimum change disease, or
AA amyloidosis) are in line with previous single case
reports, or diagnoses observed in myelodysplastic
syndrome context⁵¹ and other autoinflammatory dis-
eases.⁵² Notably, interstitial infiltration appears as a
frequent hallmark of renal biopsies of patients with
VEXAS, despite frequent treatment with various im-
munomodulators. Moreover, the favorable evolution of
acute kidney injury after steroid treatment suggests
that renal disease could represent a manifestation of
VEXAS flare. Our systematic analysis of all renal biopsies within the French VEXAS cohort also reveals diagnoses with no direct link with VEXAS, such as postsepsis acute tubular necrosis or diabetic nephropathy. Consequently, histological analysis appears essential to characterize renal involvement in elderly men with autoinflammatory symptoms suggestive of VEXAS syndrome.

In this work, we provide a molecular analysis of clones of the myeloid lineage (including UBA1) in renal biopsy, suggesting the frequent presence of UBA1 clones within the kidney. The variant allele frequency of the UBA1 clones (until 17% of whole kidney DNA) suggests the presence of clonal cells within the kidney, rather than a nonspecific contamination by circulating clonal cells. Thus, UBA1 clones could infiltrate solid organ tissues (such as kidney or skin, as previously reported⁵), although no definitive conclusion regarding their pathophysiological role could be drawn from this small, retrospective cohort. Interestingly, kidney infiltrates frequently showed both myeloperoxidase and CD68 expression suggestive of pathogenic clonal cells, as previously described in neutrophilic dermatoses associated with VEXAS.⁵ This supports a similar mechanism of clonal infiltration leading to kidney and skin involvement. However, the demonstration of the pathophysiological impact of UBA1 clones in kidney injury would need specific experiments in a murine model bearing myeloid UBA1 variant, as previously shown for clonal hematopoiesis of indeterminate potential.⁵³ Interestingly, UBA1 clones were even detected within kidney samples with extensive inflammatory fibrosis, suggesting that the proinflammatory clones may also favor fibrosis induction, as previously reported.⁵³,⁵⁴

The limitations of this study are inherent in its retrospective nature. The low number of patients limits the generalizability of these data. Similarly, the absence of concomitant kidney and blood evaluation of UBA1 variant allele frequency prevents the comparison of kidney and peripheral variant allele frequency. However, our detailed pathological, immunohistochemical, and molecular data provide a unique characterization of kidney lesions in VEXAS syndrome.

In conclusion, this series highlights the heterogeneous clinical and histological presentation of VEXAS-associated kidney disease. The molecular analysis of kidney tissue along with the frequent histological finding of interstitial infiltration may suggest a specific involvement of clonal cells directly targeting the kidney during VEXAS, thereby expanding the characterization of renal diseases associated with myeloid clones.

# APPENDIX

## List of the FRENVEX Group

Jérôme Hadjadj, Yann Nguyen, Rim Bourguiba, Mael Heiblig, Chloé Mc Avoy, Valentin Lacombe, Samuel Ardois, Thibault Comont, Estibaliz Lazaro, Francois Lifermann, Guillaume Le Guenno, Herve Lobbes, Vincent Grobost, Roderau Outh, Yvan Jamilloux, Alexis Mathian, Jonathan Broner, Thomas Moulinet, Achille Aouba, François Chasset, Laurent Arnaud, Pierre Sujobert, Pierre Hirsch, Noémie Abisror, Pierre Fenaux, Olivier Kosmider, Vincent Jachiet, Olivier Fain, Benjamin Terrier, Sophie Georgin-Lavialle, and Arsène Mekinian.

# DISCLOSURE

All the authors declared no competing interests.

# DATA AVAILABILITY STATEMENT

The data in this study were extracted from confidential medical records. French legislation does not authorize their free use and transfer. This data cannot be made freely available. Data may be shared as part of a collaborative project, subject to further validation by an institutional review board and patient consent.

# SUPPLEMENTARY MATERIAL

## Supplementary File (PDF)

## Supplementary Methods.

## Supplementary References.

**Figure S1.** Representative CD68 (A 40X, C 20X) and MPO (B 40X, D 20X) immunostaining.

**Table S1.** Evolution at last follow-up.

**Table S2.** Histological, immunohistochemical and molecular characteristics.

**Table S3.** Detailed histological description.
STROBE Statement.

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