<figure><img src="image_1.png" /></figure>

HAL
open science

# Kidney involvement in myelodysplastic syndromes

Marie-Camille Lafargue, Jean-Paul Duong van Huyen, Helmut G Rennke, Marie Essig, Mickaël Bobot, Noémie Jourde-Chiche, Hamza Sakhi, Alexandre Karras, Idris Boudhabhay, Philippe Brunet, et al.

<figure><img src="image_2.png" /></figure>

## To cite this version:

Marie-Camille Lafargue, Jean-Paul Duong van Huyen, Helmut G Rennke, Marie Essig, Mickaël Bobot, et al.. Kidney involvement in myelodysplastic syndromes. Clinical Kidney Journal, 2024, 17 (8), pp.sfae185. 10.1093/ckj/sfae185. hal-04870530

HAL Id: hal-04870530

https://hal.science/hal-04870530v1

Submitted on 7 Jan 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_3.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_4.png" /></figure>

ORIGINAL ARTICLE

# Kidney involvement in myelodysplastic syndromes

Marie-Camille Lafargue<fnref n="1" />, Jean-Paul Duong Van Huyen², Helmut G. Rennke³, Marie Essig ID⁴, Mickaël Bobot ID⁵, Noémie Jourde-Chiche ID⁵, Hamza Sakhi⁶, Alexandre KARRAS⁷, Idris Boudhabhay ID⁶, Philippe Brunet⁵, Hugoline Boulay⁸, Vincent Grobost⁹, Carole Philipponnet ID¹⁰, Juliette Jeannel¹¹, Jonathan Chemouny ID¹², Jean-Jacques Boffa¹³, Dorra Braham-Stambouli¹⁴, Umut Selamet¹⁵, Leonardo V. Riella¹⁶, Olivier Fain¹⁷, Lionel Adès¹⁸, Pierre Fenaux¹⁸, Camille Cohen¹⁹,* and Arsène Mekinian¹⁷,*

On behalf of MINHEMON, GFM and French VEXAS group

<footnote n="1">¹Department of Nephrology, Tenon's Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France, ²Department of Pathology, Université Paris Cité, Necker's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, ³Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, ⁴Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne-Billancourt, Université Paris-Saclay, Paris, France, ⁵Centre de Néphrologie et Transplantation Rénale, AP-HM, Hôpital de la Conception, CHU de la Conception, Marseille, France, ⁶Department of Nephrology, Necker's Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France, ⁷Department of Nephrology, CHU HEGP, Paris, France, ⁸University of Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR_S 1085, Rennes, France, ⁹CHU Estaing, Médecine interne, Clermont-Ferrand, France, ¹⁰Nephrology, Dialysis and Transplantation Department, University Hospital, Clermont-Ferrand, France, ¹¹Internal Medicine Department, Strasbourg University Hospital, Strasbourg, France, ¹²Transplant Unit, Department of Nephrology, University Hospital, Rennes, France, ¹³Department of Nephrology, Sorbonne University, Tenon's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, ¹⁴Department of Hematology, University Hospital, Rennes, France, ¹⁵Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA, ¹⁶Center for Transplantation Sciences, Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, ¹⁷Sorbonne Université, Hôpital Saint-Antoine, Service de Médecine Interne et de l'Inflammation-(DHU i2B), Assistance Publique-Hôpitaux de Paris, Paris, France, ¹⁸Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France and ¹⁹Service de Néphrologie Hémodialyse, Hôpital Bichat - Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France</footnote>

<footnote>*Co-senior authors.</footnote>

<footnote>Correspondence to: Arsène Mekinian; E-mail : arsene.mekinian@aphp.fr</footnote>
ABSTRACT

**Introduction.** The objective of this study was to describe kidney involvement in patients with myelodysplastic syndromes (MDS), their treatments, and outcomes.

**Methods.** We conducted a multicenter retrospective study in seven centers, identifying MDS patients with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities.

**Results.** Fifteen patients developed a kidney disease 3 months after MDS diagnosis. Median urine protein-to-creatinine ratio was 1.9 g/g, and median serum creatinine was 3.2 mg/dL. Ten patients had AKI at presentation, and 12 had extra-renal symptoms. The renal diagnoses included anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), ANCA negative vasculitis, C3 glomerulonephritis, immune complex-mediated glomerulonephritis, polyarteritis nodosa, and IgA vasculitis. All patients but one received a specific treatment for the MDS-associated kidney injury. The effect of MDS treatment on kidney injury could be assessed in six patients treated with azacitidine, and renal function evolution was heterogenous. After a median follow-up of 14 months, four patients had CKD stage 3, five had CKD stage 4, and three had end stage kidney disease. On the other hand, three evolved to an acute myeloid leukemia and three died. Compared to 84 MDS controls, patients who had kidney involvement were younger, had a higher number of dysplasia lineages, and were more eligible to receive hypomethylating agents, but no survival difference was seen between the two groups. Compared to 265 AAV without MDS, the ten with MDS-associated pauci-immune vasculitis were older, ANCA serology was more frequently negative, and more cutaneous lesions were seen.

**Conclusion.** The spectrum of kidney injuries associated with MDS is mostly represented by vasculitis with glomerular involvement, and especially AAV.

**Keywords:** acute kidney injury, ANCA-associated vasculitis, auto-immunity, myelodysplastic syndromes, myeloid neoplasms

KEY LEARNING POINTS

What was known:

* Hematologic malignancies can be associated with renal complications.

* Renal complications associated with myeloid neoplasms are less described, which is why we studied the clinical and histological presentation of patients with renal impairment during myelodysplastic syndromes.

This study adds:

* The kidney, along with other organs, is target of auto-immunity in the setting of myelodysplastic syndromes.

* The spectrum of kidney injuries associated with myelodysplastic syndromes is mostly represented by vasculitis with glomerular involvement, and especially ANCA-associated vasculitis.

Potential impact:

* A diagnosis of ANCA-associated vasculitis, in a patient with cytopenias, other than inflammatory anemia, should lead to the research of a possible myelodysplastic syndrome.

INTRODUCTION

Hematologic malignancies can be associated with renal com-
plications. In the last few years, the concept of monoclonal
gammopathy of renal significance (MGRS) has allowed a bet-
ter characterization of kidney diseases related to monoclonal
gammopathies [1]. Nevertheless, renal complications associated
with myeloid neoplasms are less described.

Myeloid neoplasms encompass myeloid leukemia, myelo-
proliferative neoplasms (MPN), myelodysplastic syndromes
(MDS), and overlapping syndromes MPN/MDS [2]. MDS are char-
acterized by clonal proliferation of hematopoietic stem cells,
recurrent genetic abnormalities, ineffective hematopoiesis,
and myelodysplastic features resulting in peripheral
cytopenias [3].

MDS can be associated in 10%–25% with systemic in-
flammatory and auto-immune diseases, among them neu-
trophilic diseases, connective tissue disorders, arthritis, and
vasculitis [4–7]. In two previously retrospective cohorts, the
estimated prevalence of glomerulopathies during MDS was

between 0.4% and 2.4% [8, 9]. Previous case reports published
in the literature mentioned that membranous nephropathy,
immunoglobulin-mediated membrano-proliferative glomeru-
lonephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-
associated vasculitis (AAV) could be observed among patients
with MDS [10–14]. The predominant kidney pathological fea-
ture described in a recent series of 19 patients was tubu-
lointerstitial nephritis, which was present in 37% of cases,
followed by 16% of ANCA negative vasculitis and 10% of mem-
branous nephropathies [15]. For the remaining patients, the di-
agnoses were IgA nephropathy, IgA vasculitis, immunoglobulin-
associated membrano-proliferative glomerulonephritis type I,
crescentic C3 glomerulopathy, fibrillary glomerulonephritis,
minimal change disease, and polyarteritis nodosa [15].

The objective of this work was to study the clinical and his-
tological presentation of patients with renal impairment dur-
ing MDS, as well as their therapeutic management. Furthermore,
two analyses were performed: (i) comparison of the hematolog-
ical phenotype of patients with a kidney injury occurring during
MDS with MDS control patients, and (ii) comparison of the renal phenotype of AAV associated with MDS with AAV without MDS.

# MATERIALS AND METHODS

## Patients' selection

We included patients from three different sources (Supplementary Fig. 1). The first group of patients were recruited at the Brigham and Women's Hospital, and the Massachusetts General Hospital, at Boston, where we screened-in all consecutive patients with a diagnosis of MDS with a kidney biopsy in the last 20 years. The second one included patients with a renal injury related with a diagnosis of vasculitis associated with MDS, from a French multicenter retrospective study by Roupie et al. who enrolled patients from different databases conducted by the "Groupe Francophone des Myélodysplasies" (GFM), and "French Network of Dysimmune Disorders Associated with Hemopathies" (MINHEMON) groups [16]. Finally, we reached out to various French scientific societies ("Société Nationale Française de Médecine Interne," and "Société Francophone de Néphrologie Dialyse et Transplantation") to do a retrospective collection of patients cases that fitted our inclusion criteria.

Controls with MDS without any kidney injury were extracted from GFM prospective nationwide database. Controls with AAV without any MDS diagnosis come from a French study who included patients with a kidney biopsy analyzed at the Paris Cité Nephropathology unit at Necker hospital [17].

## MDS definitions

Diagnosis criteria for MDS were based on the WHO classification revised in 2016: MDS with single lineage dysplasia (MDS-SLD), MDS with multilineage dysplasia (MDS-MLD), MDS with ring sideroblasts (MDS-RS), MDS-RS with single lineage dysplasia (MDS-RS-SLD), MDS-RS with multilineage dysplasia (MDS-RS-MLD), MDS with isolated del(5q), MDS with excess of blasts (MDS-EB), and unclassifiable MDS (MDS-U) [2]. We excluded patients with MDS secondary to an immunosuppressive treatment or radiotherapy (therapy-related MDS), and MDS secondary to infections, and toxic causes. Cytogenetic analysis and molecular findings were collected when available.

## Definition of kidney diseases

We included adult patients (>18 years old) diagnosed with MDS and a kidney disease. We excluded patients with kidney disease diagnosed before MDS, and remaining stable after the myeloid neoplasm diagnosis.

According to the National Kidney Foundation's Kidney Disease Outcome and Quality Initiative (KDOQI) guidelines, CKD (chronic kidney disease) is defined as either a decreased GFR (glomerular filtration rate <60 ml/min/1.73 m²), or markers of kidney damage: albuminuria with an albumin creatinine ratio ≥30 mg/g, urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders and abnormalities detected by histology among other things [18]. eGFR (estimated glomerular filtration rate) was calculated according to the CKD-EPI formula [19]. Acute kidney injury (AKI) is defined according to the Kidney Disease: Improving Global Outcomes as follows: increase in serum creatinine by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours, or increase in serum creatinine to ≥1.5 times baseline, or urine volume <0.5 ml/kg/hour for

6 hours. Kidney biopsies were locally reviewed in each pathology center.

## Clinical data

Clinical and biological data were retrospectively collected from the patients' charts. Clinical data included were gender, age at the time of the hematological and renal diagnosis, history of hypertension, and diabetes mellitus. Extra-renal organ involvement was recorded if it was directly attributable to systemic manifestations of the MDS.

Biological data, at the time of hematological and renal diagnosis, included blood cell counts, serum creatinine, eGFR, urinary protein-to-creatinine ratio, and urine sediment.

Regarding underlying MDS, data collection included bone marrow cytology and cytogenetic analyses, revised-International Prognosis Scoring System-Revised (IPSS-R) scales and its components, treatments, and the evolution to acute myeloid leukemia (AML). The presence and the type of somatic mutations by next-generation sequencing were recorded when available.

At the time of the renal diagnosis, we collected: antinuclear antibodies and titer, ANCA testing by IF and/or enzyme-linked immunosorbent assay, serum albumin, C-reactive protein (CRP), C3/C4 levels, and the type of treatment.

## Follow-up

During follow-up, events such as dialysis, kidney transplantation, occurrence of AML, or patient death were collected. Evaluation of renal function with proteinuria and serum creatinine was performed at the diagnosis of MDS, at the time of kidney disease, and at last follow-up.

## Statistics

The descriptive data of the patients were expressed in number (frequency) for the binary variables and in median (interquartile range, IQR) for the continuous variables. Owing to non-normal distribution of the values, we used nonparametric tests. Comparisons of continuous variables between two groups were made using the Mann-Whitney test, and those of binary variables were made using the Chi-square test. A Kaplan-Meier method was used to estimate overall survival. The significance level was $P < .05$.

Statistical analyses were performed using GraphPad Prism v.8.00 for MacOS (GraphPad Software, La Jolla, CA, USA).

## Ethics

This study was conducted according to the Declaration of Helsinki and fulfilled the recommendations of the French "Commission Nationale Informatique & Libertés" CNIL. According to its policy, this study was approved by the Institutional Review Board of the Brigham and Women's Hospital (protocol number 2019P003787), who validated a waiver of consent.

# RESULTS

## Characteristics of the patients

Overall, 15 patients [male gender, n = 9; median age 76 years 71-80)] with a kidney disease associated with MDS were included in this study.
## Hematological characteristics

The MDS subtypes were MDS-MLD (n = 7, 50%), MDS-EB-2 (n = 4, 28%), MDS-SLD (n = 1, 7%), MDS with isolated del(5q) (n = 1, 7%), and MDS-U (n = 1, 7%) (Table 1). Median neutrophils count at admission to the renal unit was 2.3 G/l [1.8–3.2]. Median hemoglobin was 9.3 g/dl [7.5–9.8], and median platelets count was 90 G/l [44–219]. Karyotype was available in nine patients, and five had abnormalities including monosomy 7, trisomy 8, and 20q deletion in patient BWH-01; Y chromosome duplication and trisomy 8 in patient FRA-30; del(5q14q35), monosomy 12, add(16), add(17) in patient VAS-03; del(5q) in patient VAS-04; and del(7q) in patient VAS-07. Myeloid somatic mutation analysis was available for two patients: GATA2, DNMT3A, STAG2 (patient MGH-02), WT1 (patient VAS-07). There was no UBA1 mutation in our cohort. Eighty-six percent of the patients had an IPSS-R inferior or equal to 3.5, which was equivalent to very low or low for each of those patients.

## Kidney and systemic presentations

Kidney disease was diagnosed following MDS in eight cases [median time 3 months (0–22)], and concomitantly in six cases. Patients mainly presented with a rapidly progressive glomerulonephritis (n = 10, 71.4%), a nephrotic syndrome (n = 2, 14.3%), isolated microscopic hematuria in one patient, acute kidney injury associated with proteinuria in one patient, and isolated proteinuria in one patient. Median urine protein-to-creatinine ratio was 1.88 g/g (0.6–3.1) (Table 1). Median serum albumin was 3.2 g/dl (2.7–3.6). Eleven patients presented with a microscopic hematuria. Median serum creatinine was 3.2 mg/dl (1.15–4.56). Ten (66.7%) patients presented with AKI, and three (17.6%) required hemodialysis at diagnosis. Three patients had a previous diagnosis of CKD of unspecified cause with an eGFR between 43 and 51 ml/min/1.73 m².

Auto-immunity was detected in 11 of the 14 tested patients (antinuclear antibodies n = 4, and ANCA n = 9 with anti-myeloperoxidase (MPO) in five patients, anti-proteinase 3 (PR3) in three patients and no specificity in one case). Out of the six patients with an analysis of the complement, four (66.6%) had a normal serum complement C3, and five (83.3%) a normal serum C4. One patient had a type II cryoglobulinemia. Median CRP was 51 mg/l [15–73.5]. In 12 (80%) cases, extra-renal symptoms were associated; fever and altered condition (n = 5, 42%), cutaneous lesions (n = 6, 50%), and lung manifestations (n = 5, 42%) were the most prevalent.

## Renal diagnoses and histological features of MDS patients

Kidney biopsy was performed in nine (60%) out of the 15 patients. For the other patients, the diagnosis was made according to the clinical and biological data, or based on another organ biopsy, because of kidney biopsy's contraindications (Supplementary Table S1).

For the nine patients who underwent a kidney biopsy, all patients displayed a glomerular involvement, the histological diagnoses were: C3 glomerulonephritis (n = 2), immune complex-mediated glomerulonephritis (n = 1), microscopic polyangiitis (n = 3), pauci-immune necrotizing and crescentic glomerulonephritis (n = 1) (Fig. 1), granulomatosis with polyangiitis (n = 1), and IgA vasculitis (n = 1). The features of light microscopy and immunofluorescence analyses of the kidney biopsies are listed in Table 2.

For the patients who did not have a kidney biopsy, two had a diagnosis of microscopic polyangiitis based on the clinical and biological data confirming the ANCA positivity with a MPO specificity, one had an ANCA negative vasculitis with a diagnosis based on an association between AKI, pulmonary involvement, and purpura lesions, one had a granulomatosis with polyangiitis with an ANCA positivity specific to PR3, and one a polyarteritis nodosa based on the imaging (Supplementary Table S1).

Regarding the three patients with a C3 glomerulonephritis, and an immune complex-mediated glomerulonephritis, serum complement C3 and C4 levels were normal. The only patient with a type II cryoglobulinemia had a granulomatosis with polyangiitis.

## Outcomes

At admission, one out of the nine patients with a previous diagnosis of MDS was started on a hematological disease-modifying therapy (azacitidine) 2 months before the renal diagnosis was made. Following the identification of MDS-associated kidney disease, treatment was started or modified in five patients (33.3%), and consisted in azacitidine (n = 5), a switch for one patient from lenalidomide to azacitidine, and an allogenic stem cell transplantation (SCT) for another patient (Table 3). Among the six patients with a diagnosis of MDS concomitant or less than two months after renal involvement, three received azacitidine, one underwent an allogenic SCT and one had a withdrawal of azacitidine because of severe infections. After a median follow-up of 14 months (6.6–74.3), three evolved to AML. Hematologic malignancy was considered as stable in seven (46.7%) patients. Three patients died at last follow-up (survival rate 80%).

All patients but one received a specific treatment for the MDS-associated kidney injury including steroids. The immunosuppressive regimen details are listed in Table 3. Three patients received plasma exchanges, nine had an induction treatment with rituximab, whereas three had cyclophosphamide. After treatment, data on renal function was available for 13 patients. Renal function improved in eight patients (53%), and worsened in three (20%). Among the three patients who underwent renal replacement therapy (hemodialysis) at diagnosis, none recovered any renal function.

## Comparison to AAV without MDS

MDS-associated AAV (n = 10) were compared with a cohort of AAV without MDS (n = 265) (Table 4). Patients with MDS-associated AAV were older than patients with AAV without MDS (76 vs 63 years old; P = .025). The serum creatinine at diagnosis was similar between the two groups (2.5 mg/dl in AAV patients without MDS, and 3.6 mg/dl with MDS; P = .781). According to the Berden classification, there was one sclerotic type in the MDS-associated AAV group compared to the AAV without MDS group (n = 107, 40.4%). There was no difference in the renal risk score between the two groups (P = .523). There is a tendency of a higher frequency of ANCA negative AAV in the MDS-associated AAV group (n = 2 vs 11, P = .075). Regarding organ involvement, skin was the most prevalent systemic manifestations in patients with MDS-associated AAV, compared with controls AAV (40% vs 9.1%; P = .012). In terms of induction regimen, MDS-associated AAV patients were more likely to be treated with rituximab than cyclophosphamide (60% vs 22.3%; P = .013 and 30% vs 74.7%; P = .005, respectively). It must be noted that the median year at AAV diagnosis was 2018 (2011–2020) for MDS-associated AAV and 2012 (2009–2016) for AAV. The median follow-up for
<table><caption>Table 1: Hematologic and renal characteristics of 15 patients with kidney involvement and MDS.</caption><thead><tr><th>Pt</th><th>Gender<br>Age (y)</th><th>MDS type<br>Karyotype<br>Mutations</th><th>Hb (g/dl)<br>Plt (G/l)<br>Neutrophils (G/l)</th><th>Delay<br>(mo)</th><th>SCr<br>(mg/dl)</th><th>UPCR<br>(g/g)</th><th>Hu</th><th>Renal<br>diagnosis</th><th>Extra-renal<br>manifestations</th></tr></thead><tbody><tr><td>BWH-01</td><td>M, 63</td><td>MDS-U<br>monosomy 7, trisomy 8 and 20q deletion</td><td>7.5<br>273<br>3.81</td><td>180</td><td>3.5</td><td>0.7</td><td>+</td><td>C3 GN</td><td>Hemoptysis</td></tr><tr><td>BWH-02</td><td>M, 70</td><td>MDS-MLD<br>Normal</td><td>6.4<br>90<br>3</td><td>31</td><td>1.8</td><td>9</td><td>+</td><td>Immune complex-mediated<br>GN</td><td>NA</td></tr><tr><td>FRA-07</td><td>F, 76</td><td>MDS-MLD<br>Normal</td><td>9.6<br>386<br>8.4</td><td>0</td><td>4.6</td><td>11</td><td>+</td><td>MPA</td><td>Demineralization of both nasal<br>turbinates and septum</td></tr><tr><td>FRA-10</td><td>M, 77</td><td>MDS-MLD</td><td>10.3<br>23<br>1.97</td><td>-1</td><td>5.5/HD</td><td>3</td><td>+</td><td>MPA</td><td>Alveolar hemorrhage</td></tr><tr><td>FRA-15</td><td>F, 79</td><td>MDS-EB</td><td>7.5<br>47<br>0.7</td><td>1</td><td>4.8</td><td>0.5</td><td>+</td><td>ANCA negative vasculitis</td><td>NA</td></tr><tr><td>FRA-29</td><td>M, 85</td><td>MDS-MLD</td><td>10.5<br>61<br>NA</td><td>0</td><td>5.2/HD</td><td>NA</td><td>+</td><td>GPA</td><td>Right lower limb purpura</td></tr><tr><td>FRA-30</td><td>M, 75</td><td>MDS-EB<br>Y chromosome duplication and trisomy 8</td><td>7.4<br>40<br>2.7</td><td>14</td><td>4.6</td><td>2.14</td><td>+</td><td>MPA</td><td>NA</td></tr><tr><td>FRA-31</td><td>F, 59</td><td>MDS-EB<br>Normal</td><td>9.7<br>107<br>NA</td><td>9</td><td>0.6</td><td>0.15</td><td>+</td><td>MPA</td><td>Alveolar hemorrhage</td></tr><tr><td>FRA-33</td><td>F, 78</td><td>MDS-MLD</td><td>NA</td><td>30</td><td>3</td><td>3</td><td>+</td><td>MPA</td><td>Lower limbs necrotic purpura</td></tr><tr><td>MGH-02</td><td>M, 28</td><td>Mono-MAC syndrome<br>GATA2, DNMT3A, STAG2</td><td>9.3<br>165<br>1.36</td><td>0</td><td>0.8</td><td>3.43</td><td>-</td><td>ANCA negative vasculitis</td><td>Pancreatitis</td></tr><tr><td>VAS-01</td><td>M, 48</td><td>MDS-MLD</td><td>NA</td><td>47</td><td>HD</td><td>NA</td><td>+</td><td>PAN</td><td>Subcutaneous knots</td></tr><tr><td>VAS-03</td><td>M, 73</td><td>MDS-EB<br>del5q14q35, monosomy 12, add(16), add(17)</td><td>NA</td><td>0</td><td>NA</td><td>3</td><td>+</td><td>C3 GN</td><td>NA</td></tr><tr><td>VAS-04</td><td>F, 82</td><td>MDS-del(5q)<br>del5q</td><td>8.3<br>334<br>1.9</td><td>3</td><td>NA</td><td>1.14</td><td>NA</td><td>IgA vasculitis</td><td>Purpura, gastric ulcer, and<br>pericarditis</td></tr><tr><td>VAS-05</td><td>M, 69</td><td>MDS-MLD<br>Normal</td><td>10<br>16<br>NA</td><td>7</td><td>1.6</td><td>0.33</td><td>NA</td><td>GPA</td><td>Purpura, chondritis, scleritis,<br>pericarditis and arthralgia</td></tr><tr><td>VAS-07</td><td>F, 85</td><td>MDS-MLD<br>del7q<br>WT1</td><td>NA</td><td>-100</td><td>2.1</td><td>1.61</td><td>NA</td><td>MPA</td><td>Cough</td></tr></tbody></table>

Abbreviations: F, female; GN, glomerulonephritis; GPA, granulomatosis with polyangiitis; Hb, hemoglobin; HD, hemodialysis; Hu, hematuria; M, male; Mo, months; Mono-MAC syndrome, monocytopenia and mycobacterial infection syndrome; MPA, microscopic polyangiitis; NA, not applicable; PAN, polyarteritis nodosa; Plt, platelets; Pt, patient; SCr, serum creatinine; UPCR, urine protein-to-creatinine ratio; Y, years. 'Except altered condition.
<figure><img src="image_5.png" /><figcaption>**Figure 1:** Kidney biopsy of a 28-year-old man with a history of mono-MAC syndrome (monocytopenia and mycobacterial infection syndrome) and MDS referred to renal clinic for evaluation of a nephrotic syndrome with hematuria. Focal proliferative and crescentic glomerulonephritis, pauci-immune cellular crescents and fibrocellular or fibrous crescents with segmental scarring (hematoxylin and eosin staining, magnification ×177). Courtesy of Helmut G Rennke.</figcaption></figure>

MDS-associated with AAV was 8.5 months (4.8–22), and 46 months (18–98) in AAV controls ($P < 0.001$). Overall survival was significantly decreased in the MDS-associated AAV [median survival not reached in both groups, $P = .019$, odds ratio: 4.43 (95% CI 0.28–76)] (Fig. 2a). Median creatinine at last follow-up was 1.3 mg/dl in the AAV without MDS group, and 1.9 in the AAV with MDS ($P = .191$).

## Comparison between MDS with and without kidney injuries

There were 84 MDS patients without a kidney injury. Compared to these controls, patients who had a kidney involvement were younger (78 vs 75 years, respectively, $P = .048$) (Table 5). Even if there was no difference in prognosis scores (IPSS-R > 3.5 14.3% and 14.3%, $P = 1$), MDS patients with kidney injury had a higher number of dysplastic lineages (two dysplasia, $P = .044$; three dysplasia, $P = .005$). MDS patients with kidney injury were more eligible to receive a specific hematologic treatment with hypomethylating agents (60% and 26.2% in the control MDS group, $P = .003$). The median follow-up from MDS diagnosis was 23 months (12–35) in patients without a kidney injury, and 8 months [3–39] in patients with a kidney injury ($P = .277$). Patients with MDS-associated kidney injury tended to progress more frequently to AML (8.3% and 30%, respectively, $P = .071$). The median survival was 66, and 225 months in MDS with and without kidney injury, respectively [$P = 0.7309$, odd ratio: 0.71 (95% CI 0.24–2.11)] (Fig. 2b).

## DISCUSSION

Even if the knowledge about kidney injuries associated with hematological malignancies has increased recently with the

concept of MGRS, data about renal complications associated with myeloid neoplasms are scarce, especially in patients with MDS.

In our study, the development of kidney disease tended to be early after MDS diagnosis (3 months), and was concomitant in 40%. This was earlier than in previous large cohort [15]. We identified vasculitis as the most frequent kidney disease associated with MDS, with a high prevalence of AAV. Systemic vasculitis associated with MDS were already described in the literature. However, a recent study reported different patterns of kidney lesions: Schwotzer et al. documented the spectrum of kidney diseases from MDS patients with kidney biopsies, and reported that acute tubulointerstitial nephritis was the predominant kidney injury [15]. Yet, tubulointerstitial nephritis is mainly reported in chronic myelomonocytic leukemia, a hematological disorder at the frontier between MDS and myeloproliferative disorders. The fact that we have mostly identified glomerular diseases and systemic vasculitis can be explained by the recruitment of our patients. Indeed, some of our patients were included from a cohort of vasculitis associated with MDS/CMML [16]. Furthermore, in a large cohort studying 123 patients with systemic and auto-immune manifestations associated with MDS/CMML, 32% of the manifestations were systemic vasculitis [6]. Our analysis comparing AAV with and without MDS highlights the fact that we should look for MDS among elderly AAV patients, or with a cutaneous manifestation at AAV diagnosis. In such cases, a bone marrow biopsy should be performed if cytopenia is present.

Even if most of the cases published to date are from small series and case reports, it has also been described that extra-renal vasculitis can be associated with MDS, arguing for the association MDS-crescent glomerulonephritis that we observe here [16]. Whether the mechanisms of lesion development are shared
<table><caption>Table 2: Renal pathology description of nine patients with MDS-associated kidney injury.</caption><thead><tr><th>Patients</th><th>Glomeruli</th><th>Tubules</th><th>Interstitium</th><th>Vessels</th><th>IF</th><th>Diagnosis</th></tr></thead><tbody><tr><td>BWH-01</td><td>37 (9 sclerotic)<br/>Rare double contours<br/>Inflammatory cells in capillary loops<br/>Mesangium hypercellularity</td><td>Tubular atrophy<br/>Epithelial cell<br/>vacuolization</td><td>Mild inflammation<br/>Infiltrate of mononuclear cells<br/>with rare eosinophils and plasma cells<br/>Fibrosis 30%</td><td>Severe arterial and<br/>hyaline arteriolar<br/>sclerosis</td><td>C3 (3+) in the mesangium<br/>Fine granular reactivity for IgA</td><td>C3<br/>glomerulonephritis</td></tr><tr><td>BWH-02</td><td>30 (6 sclerotic).<br/>Membrano-proliferative<br/>Diffuse proliferative, and focal<br/>crescentic pattern of glomerular<br/>injury<br/>Active cellular crescents are present<br/>in 10 of 24 viable glomeruli</td><td>Acute tubular injury<br/>with focal tubular<br/>necrosis</td><td>Moderate interstitial inflammation<br/>in areas of atrophy, composed of<br/>mononuclear cells, few plasma<br/>cells, and rare eosinophils<br/>Fibrosis 10-15%</td><td>Mild to moderate<br/>arterial and arteriolar<br/>sclerosis</td><td>Granular and smudgy<br/>reactivity for IgG (2+), IgA (3+),<br/>IgM (1+), C3 (2+), kappa LC (3+)<br/>and lambda LC (3+) both along<br/>the capillaries and in the<br/>mesangium</td><td>Immune<br/>complex-mediated<br/>glomerulonephritis</td></tr><tr><td>FRA-07</td><td>11 (4 sclerotic)<br/>Mesangium hypercellularity<br/>Focal segmental extra-capillary<br/>proliferation in 1 glomerulus<br/>Segmental fibrous lesions with<br/>flocculo-capsular synechia in 4<br/>glomeruli</td><td>Acute tubular injury<br/>with epithelial cell<br/>vacuolization</td><td>Mild to moderate fibrosis<br/>Infiltrate of mononuclear cells</td><td>Mild to moderate<br/>arterial and arteriolar<br/>sclerosis</td><td>IgG (3+) along capillary loops.<br/>IgG2 (2+), IgG4 (2+), kappa LC<br/>(2+) and lambda LC (2+)</td><td>Microscopic<br/>polyangiitis</td></tr><tr><td>FRA-29</td><td>18 (3 sclerotic)<br/>Cellular crescents in 4 glomeruli<br/>Fibrous crescents in 3 glomeruli<br/>Bowman's capsule rupture in 1<br/>glomerulus<br/>No granuloma</td><td>Tubular atrophy 10%</td><td>Moderate interstitial<br/>inflammation, composed of<br/>lymphocytes, and few plasma cells<br/>Fibrosis 20%</td><td>Moderate arterial and<br/>arteriolar sclerosis</td><td>No significant deposits</td><td>Granulomatosis<br/>with polyangiitis</td></tr></tbody></table>
<table><caption>Table 2: Continued</caption><thead><tr><th>Patients</th><th>Glomeruli</th><th>Tubules</th><th>Interstitium</th><th>Vessels</th><th>IF</th><th>Diagnosis</th></tr></thead><tbody><tr><td>FRA-31</td><td>14 (1 sclerotic)<br>Endo-capillary proliferation<br>Thickening of Bowman's capsule<br>in 1 glomerulus with a segmental<br>lesion associated with a loss of<br>capillary loop lumen</td><td>Normal epithelium</td><td>No inflammation<br>Fibrosis 10%</td><td>Mild to moderate<br>arterial and arteriolar<br>sclerosis</td><td>Granular and segmental reactivity<br>for IgM (1+) on the Bowman's<br>capsule</td><td>Microscopic polyangiitis</td></tr><tr><td>MGH-02</td><td>Focal proliferative and crescentic<br>glomerulonephritis,<br>pauci-immune cellular crescents<br>are present in 2 of 35 viable<br>glomeruli, and fibrocellular or<br>fibrous crescents are present in 4<br>glomeruli with segmental scarring</td><td>Acute tubular injury<br>with focal tubular<br>necrosis</td><td>Chronic-active interstitial<br>nephritis, severe, most likely<br>drug-induced (TMP-SMX)<br>Fibrosis 30%</td><td>Mild arterial and<br>arteriolar sclerosis</td><td>Fibrin deposits (3+)<br>IgG (2+), kappa LC (2+) and lambda<br>LC (2+) along the capillaries</td><td>Pauci-immune<br>necrotizing and<br>crescentic<br>glomerulonephritis</td></tr><tr><td>VAS-03</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>C3 glomerulonephritis</td></tr><tr><td>VAS-04</td><td>26 (0 sclerotic)<br>Mostly segmental endocapillary<br>proliferation in almost all the<br>glomeruli<br>No extra-capillary proliferation</td><td>NA</td><td>Moderate edema<br>Mild fibrosis<br>No inflammatory infiltrate</td><td>Important arterial and<br>arteriolar sclerosis</td><td>Subendothelial reactivity for IgA<br>(1+) and IgM (3+)</td><td>IgA vasculitis</td></tr><tr><td>VAS-07</td><td>8 (0 sclerotic)<br>Cellular crescents in 6 glomeruli</td><td>Acute tubular injury</td><td>Mild fibrosis</td><td>Mild arterial and<br>arteriolar sclerosis</td><td>No significant deposits</td><td>Microscopic polyangiitis</td></tr></tbody></table>

Abbreviations: IF, immunofluorescence; LC, light chain; NA, Detailed report non-available; TMP-SMX, trimethoprim-sulfamethoxazole.
<table><caption>Table 3: Treatments and outcomes of 15 patients with MDS and kidney involvement.</caption><thead><tr><th rowspan="2">Malignancy</th><th colspan="2">Hematologic treatments</th><th rowspan="2">Follow-up (months)</th><th colspan="2">Renal</th><th colspan="4">Outcomes</th></tr><tr><th>At diagnosis of the kidney disease</th><th>After</th><th>Diagnosis</th><th>Treatment</th><th>eGFR at last follow-up</th><th>GFR change</th><th>Malignancy</th><th>Overall</th></tr></thead><tbody><tr><td>MDS-U</td><td>No</td><td>No</td><td>45.4</td><td>C3 GN</td><td>Steroids</td><td>25</td><td>8</td><td>AML</td><td>Death</td></tr><tr><td>MDS-MLD</td><td>No</td><td>No</td><td>2.7</td><td>MPGN</td><td>Steroids, rituximab, IVIg</td><td>30</td><td>-7</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>No</td><td>No</td><td>4.9</td><td>MPA</td><td>Steroids, rituximab</td><td>26</td><td>14</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>No</td><td>Azacitidine</td><td>3.6</td><td>MPA</td><td>PLEX, steroids, rituximab</td><td>Dialysis</td><td>Dialysis</td><td>AML</td><td>Alive</td></tr><tr><td>MDS-EB</td><td>Azacitidine</td><td>Azacitidine</td><td>NA</td><td>PiNCG</td><td>None<sup>b</sup></td><td>27</td><td>16</td><td>NA</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>No</td><td>No</td><td>0.8</td><td>GPA</td><td>PLEX, steroids, rituximab</td><td>Dialysis</td><td>Dialysis</td><td>Failure</td><td>Death</td></tr><tr><td>MDS-EB</td><td>No</td><td>No</td><td>20.2</td><td>MPA</td><td>Steroids, cyclophosphamide</td><td>27</td><td>14</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS-EB</td><td>No</td><td>No</td><td>8.4</td><td>MPA</td><td>Steroids, rituximab</td><td>47</td><td>-49</td><td>Stable</td><td>Death</td></tr><tr><td>MDS-SLD</td><td>No</td><td>No</td><td>9.3</td><td>MPA</td><td>Steroids, rituximab</td><td>40</td><td>26</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS<sup>a</sup></td><td>No</td><td>Allogeneic SCT</td><td>8</td><td>PiNCG</td><td>Steroids</td><td>83</td><td>9</td><td>CR</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>No</td><td>Azacitidine</td><td>181.9</td><td>PAN</td><td>cyclophosphamide, MMF, rituximab</td><td>Dialysis</td><td>Dialysis</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS-EB</td><td>Azacitidine</td><td>No</td><td>8.3</td><td>C3 GN</td><td>Steroids, rituximab, eculizumab</td><td>NA</td><td>NA</td><td>HI</td><td>Alive</td></tr><tr><td>MDS-del(5q)</td><td>Lenalidomide</td><td>Azacitidine</td><td>14.4</td><td>IgA vasculitis</td><td>Steroids, MMF</td><td>NA</td><td>NA</td><td>HI</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>Azacitidine</td><td>Azacitidine</td><td>45.6</td><td>GPA</td><td>Steroids, rituximab</td><td>44</td><td>-29</td><td>Stable</td><td>Alive</td></tr><tr><td>MDS-MLD</td><td>Azacitidine</td><td>Azacitidine</td><td>103.1</td><td>MPA</td><td>PLEX, steroids, cyclophosphamide</td><td>27</td><td>15</td><td>AML</td><td>Alive</td></tr></tbody></table>

Abbreviations: AML, acute myeloid leukemia; CR, complete remission; GN, glomerulonephritis; GPA, granulomatosis with polyangiitis; HU, hematologic improvement; IVIg, intravenous immunoglobulins; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; MPGN, membrano-proliferative glomerulonephritis; NA, not applicable; PAN, polyarteritis nodosa; PiNCG, pauci-immune necrotizing and crescentic glomerulonephritis; PLEX, plasma exchange; SCT, stem cell transplantation.

<footnote>a Mono-MAC syndrome.</footnote>

<footnote>b None: the patient only received azacitidine for the MDS-associated kidney injury.</footnote>
<table><caption>Table 4: Characteristics of ANCA-associated vasculitis according to the presence/absence of MDS.</caption><thead><tr><th>Variable</th><th>Total (n = 275)</th><th>ANCA-associated vasculitis<br>without MDS (n = 265)</th><th>ANCA-associated vasculitis<br>with MDS (n = 10)</th><th>P</th></tr></thead><tbody><tr><td>Age (years)</td><td>64 [53-74]</td><td>63 [53-73]</td><td>76 [67-80]</td><td>.025</td></tr><tr><td>Male</td><td>137 (50%)</td><td>131 (49.4)</td><td>6 (60)</td><td>.540</td></tr><tr><td>Hypertension</td><td>106 (38.8)</td><td>102 (38.5)</td><td>4 (50)<sup>a</sup></td><td>.715</td></tr><tr><td>Diabetes</td><td>29 (10.3)</td><td>25 (9.4)</td><td>3 (37.5)<sup>a</sup></td><td>.0382</td></tr><tr><td>ANCA specificity</td><td></td><td></td><td></td><td></td></tr><tr><td>Proteinase 3</td><td>85 (31)</td><td>83 (31.3)</td><td>2 (25)</td><td>1.000</td></tr><tr><td>Myeloperoxidase</td><td>177 (64.6)</td><td>172 (64.9)</td><td>5 (55.6)</td><td>.725</td></tr><tr><td>None</td><td>14 (4.7)</td><td>11 (4.2)</td><td>2 (20)</td><td>.075</td></tr><tr><td>CRP (mg/l)</td><td>46 [11-127]</td><td>46 [10-130]</td><td>51 [15-86.5]<sup>a</sup></td><td>.969</td></tr><tr><td>Hemoglobin level (g/dl)</td><td>9.7 [8.8-11]</td><td>9.7 [8.8-11]</td><td>9.7 [9.3-10.3]<sup>a</sup></td><td>.836</td></tr><tr><td>Serum albumin (g/dl)</td><td>3 [2.5-3.4]</td><td>2.9 [2.5-3.4]</td><td>3.2 [2.7-4]<sup>a</sup></td><td>.24</td></tr><tr><td>Renal function</td><td></td><td></td><td></td><td></td></tr><tr><td>Serum creatinine (mg/dl)</td><td>2.6 [1.4-4.5]</td><td>2.5 [1.4-4.5]</td><td>3.6 [1.2-4.8]</td><td>.781</td></tr><tr><td>eGFR (ml/min per 1.73 m<sup>2</sup>)</td><td>23 [11-47]</td><td>24 [11-46]</td><td>14 [12-73]</td><td>.846</td></tr><tr><td>Dialysis</td><td>44 (16)</td><td>42 (15.8)</td><td>2 (20)</td><td>.664</td></tr><tr><td>UPCR (g/g)</td><td>1.5 [0.9-2.5]</td><td>1.5 [0.9-2.5]</td><td>2.1 [1.0-3.2]<sup>a</sup></td><td>.278</td></tr><tr><td>Positive hematuria</td><td>260 (94.5)</td><td>254 (95.8)</td><td>6 (85.7)<sup>a</sup></td><td>.274</td></tr><tr><td>Renal pathology</td><td></td><td></td><td></td><td></td></tr><tr><td>Total number of glomeruli</td><td>20 [14-25]</td><td>20 [14-25]</td><td>14 [10-27]<sup>a</sup></td><td>.242</td></tr><tr><td>Normal glomeruli &lt;10%</td><td>74 (27)</td><td>74 (27.9)</td><td>0 (0)<sup>a</sup></td><td>.327</td></tr><tr><td>Normal glomeruli 10-25%</td><td>39 (14.2)</td><td>37 (14)</td><td>2 (40)<sup>a</sup></td><td>.153</td></tr><tr><td>Normal glomeruli &gt;25%</td><td>157 (57.1)</td><td>154 (58.1)</td><td>3 (37.5)<sup>a</sup></td><td>.291</td></tr><tr><td>IF/TA ≥25%</td><td>107 (38.9)</td><td>105 (39.6)</td><td>2 (40)<sup>a</sup></td><td>1.000</td></tr><tr><td>Berden classification</td><td>94 (34.2)</td><td>92 (34.7)</td><td>2 (40)<sup>a</sup></td><td>.652</td></tr><tr><td>Focal</td><td>53 (19.3)</td><td>52 (19.6)</td><td>1 (20)<sup>a</sup></td><td></td></tr><tr><td>Crescentic</td><td>64 (23.3)</td><td>62 (23.4)</td><td>2 (40)<sup>a</sup></td><td></td></tr><tr><td>Mixed</td><td>59 (21.5)</td><td>59 (22.3)</td><td>0 (0)<sup>a</sup></td><td></td></tr><tr><td>Sclerotic</td><td>108 (39.3)</td><td>107 (40.4)</td><td>1 (20)<sup>a</sup></td><td></td></tr><tr><td>ANCA Renal Risk Score</td><td>84 (30.5)</td><td>81 (30.6)</td><td>3 (60)<sup>a</sup></td><td>.523</td></tr><tr><td>Low</td><td>78 (28.4)</td><td>77 (29)</td><td>1 (20)<sup>a</sup></td><td></td></tr><tr><td>Moderate</td><td></td><td></td><td></td><td></td></tr><tr><td>High</td><td></td><td></td><td></td><td></td></tr><tr><td>Organ involvement</td><td></td><td></td><td></td><td></td></tr><tr><td>Renal Limited Vasculitis</td><td>56 (20.4)</td><td>55 (20.8)</td><td>1 (10)</td><td>.693</td></tr><tr><td>Pulmonary involvement</td><td>140 (50.9)</td><td>136 (51.3)</td><td>4 (40)</td><td>.535</td></tr><tr><td>Cutaneous involvement</td><td>28 (10.2)</td><td>24 (9.1)</td><td>4 (40)</td><td>.012</td></tr><tr><td>Ophthalmologic involvement</td><td>20 (7.3)</td><td>19 (7.2)</td><td>1 (10)</td><td>.536</td></tr><tr><td>Ears, nose, and throat</td><td>84 (30.5)</td><td>82 (30.9)</td><td>2 (20)</td><td>.728</td></tr><tr><td>Cardiac involvement</td><td>12 (4.4)</td><td>11 (4.2)</td><td>1 (10)</td><td>.365</td></tr><tr><td>Gastrointestinal involvement</td><td>9 (3.2)</td><td>8 (3.0)</td><td>1 (10)</td><td>.287</td></tr><tr><td>Peripheral nervous system</td><td>44 (16)</td><td>43 (16.2)</td><td>1 (10)</td><td>1.000</td></tr><tr><td>Central nervous system</td><td>6 (2.2)</td><td>6 (2.3)</td><td>0 (0)</td><td>1.000</td></tr><tr><td>Induction therapy</td><td></td><td></td><td></td><td></td></tr><tr><td>Cyclophosphamide</td><td>201 (73.1)</td><td>198 (74.7)</td><td>3 (30)</td><td>.005</td></tr><tr><td>Rituximab</td><td>65 (23.6)</td><td>59 (22.3)</td><td>6 (60)</td><td>.013</td></tr><tr><td>Plasma exchange</td><td>50 (18.2)</td><td>47 (17.7)</td><td>3 (30)</td><td>.396</td></tr><tr><td>Follow-up (months)</td><td>45 [17-94.5]</td><td>46 [18-98]</td><td>8.5 [4.8-22]</td><td>&lt;.001</td></tr><tr><td>Relapse during follow-up</td><td>57 (20.7)</td><td>56 (32.6)</td><td>1 (10)</td><td>.693</td></tr><tr><td>Creatinine at last follow-up (mg/dl)</td><td>1.4 [1-2]</td><td>1.3 [1-2]</td><td>1.9 [1.5-2.3]</td><td>.191</td></tr><tr><td>Dialysis or kidney transplantation</td><td>64 (23.3)</td><td>62 (24.7)</td><td>2 (20)</td><td>1.000</td></tr><tr><td>Severe infection</td><td>60 (21.8)</td><td>58 (23.1)</td><td>2 (20)</td><td>1.000</td></tr></tbody></table>

Abbreviations: IF/TA, interstitial fibrosis/tubular atrophy; UPCR, urine protein-to-creatinine ratio; Quantitative data are presented as median [interquartile range] or mean (±SD) and qualitative data as n (%), as appropriate.

between MDS or classical crescent glomerulonephritis should be explored in a dedicated study.

Hence, auto-immunity seems to be a cornerstone in the setting of kidney injuries related to MDS. Extra-renal manifestations were almost systematically present when the renal disease occurred (80%). Skin (50%) and lungs (42%) were the most

prevalent organs involved, with alveolar hemorrhage, purpura, and skin eruption, which was concordant with the Schwotzer et al. study in which half of the patients presented extra-renal manifestations [15].

In our study, auto-antibodies were detected in 11 patients, with nine patients having ANCA. Even if antinuclear

<footnote>ªMissing data.</footnote>
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Figure 2:** (a) Kaplan-Meier curve for the overall survival according to AAV with and without MDS. AAV with MDS group (n = 10). AAV without MDS group (n = 265). Last follow-up at 5 years. P = .0190, log rank test. (b) Kaplan-Meier curve for the overall survival according to MDS with and without kidney injury. MDS with kidney injury (n = 15). MDS without kidney injury (n = 84). Last follow-up at 5 years. P = .7309, log rank test.</figcaption></figure>

antibodies were present in 23% of the patients with systemic and auto-immune manifestations related with MDS/CMML in the Mekinian et al. study, there was no statistically significant difference in the frequencies of various auto-antibodies in MDS/CMML patients with and without associated auto-immune disorders, except for anti-DNA antibodies [6, 20]. Contrary to CMML patients, MDS patients with auto-immune disorders did not have higher ANCA positivity [20].

In our study, the mortality rate was 20%, with three transformations toward AML, which was similar to another large cohort [15]. Among patients treated with azacitidine, two improved their renal function, and three worsened it, among whom two stayed on long-term hemodialysis. Overall, for the 13 patients with data after the renal treatment, renal function improved in eight patients (53%) and worsened in three (20%). Among the three patients who underwent renal replacement therapy (hemodialysis) at diagnosis, none recovered any renal function. Our results were similar to those of Schwotzer et al., with 10 patients evolving to CKD 3 or 4, and 5 to end stage kidney disease at last follow-up. Thus, which patients with renal complications of MDS would benefit from hypomethylating

agents remains to be determined. A prospective phase 2 study sponsored by the GFM assessed azacitidine efficacy and tolerance in patients with MDS and steroids dependent or refractory systemic inflammatory and auto-immune manifestations (SAID) [21]. In this prospective trial, 66% of MDS/CMML patients with SAID obtained SAID complete or partial response after six cycles of azacitidine. Thus, azacitidine may represent an interesting treatment for MDS/CMML patients with associated SAID, acting on both hematological disease and systemic inflammation.

The most represented subtypes of MDS were MDS-MLD and MDS-EB, two subgroups at high risk of transformation toward AML. Nevertheless, our analysis comparing MDS patients with and without kidney injury did not reveal a statistically significant difference in terms of prognosis and overall survival, this may be due to the difference of follow-up between the two groups. However, we noted that patients with a kidney injury tented to be more treated with a hypomethylating agent. Mekinian et al. showed in their study enrolling 123 patients, that MDS/CMML associated with systemic inflammatory and auto-immune disorders had worse baseline
<table><caption>Table 5: Characteristics of MDS according to the presence/absence of a kidney injury.</caption><thead><tr><th>Variable</th><th>Total (n = 99)</th><th>MDS without kidney injury (n = 84)</th><th>MDS with kidney injury (n = 15)<sup>a</sup></th><th>P</th></tr></thead><tbody><tr><td>Age (years)</td><td>78 [74-83]</td><td>78 [74-84]</td><td>75 [63-79]</td><td>.048</td></tr><tr><td>Male</td><td>61 (61.6%)</td><td>52 (61.9)</td><td>9 (60)</td><td>1.000</td></tr><tr><td>MDS type</td><td></td><td></td><td></td><td></td></tr><tr><td>MDS-SLD</td><td>16 (16.2)</td><td>15 (17.9)</td><td>1 (7.1)</td><td>.455</td></tr><tr><td>MDS-MLD</td><td>39 (39.4)</td><td>32 (38.1)</td><td>7 (50)</td><td>.803</td></tr><tr><td>MDS-SLD-RS</td><td>8 (8.1)</td><td>8 (9.5)</td><td>0 (0)</td><td>.597</td></tr><tr><td>MDS-MLD-RS</td><td>5 (5)</td><td>5 (6)</td><td>0 (0)</td><td>1.000</td></tr><tr><td>MDS-EB</td><td>18 (18.2)</td><td>14 (16.7)</td><td>4 (28.6)</td><td>.282</td></tr><tr><td>MDS-5q-</td><td>5 (5)</td><td>4 (4.8)</td><td>1 (7.1)</td><td>.545</td></tr><tr><td>MDS-U</td><td>8 (8.1)</td><td>7 (8.3)</td><td>1 (7.1)</td><td>1.000</td></tr><tr><td>Dysplasia lineage number</td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>54 (58.1)</td><td>54 (64.3)</td><td>0 (0)</td><td>&lt;.001</td></tr><tr><td>1</td><td>18 (19.4)</td><td>16 (19)</td><td>2 (22.2)</td><td>1.000</td></tr><tr><td>2</td><td>16 (17.2)</td><td>12 (14.3)</td><td>4 (44.4)</td><td>.044</td></tr><tr><td>3</td><td>5 (5.4)</td><td>2 (2.4)</td><td>3 (33.3)</td><td>.005</td></tr><tr><td>Blasts (%)</td><td>3 [1-4]</td><td>3 [1-4]</td><td>12 [0.5-17.5]</td><td>.111</td></tr><tr><td>Abnormal karyotype</td><td>36 (38.7)</td><td>32 (38.1)</td><td>4 (44.4)</td><td>.731</td></tr><tr><td>Neutrophils count (G/L)</td><td>2.5 [1.2-4.4]</td><td>2.6 [1.4-4.4]</td><td>2 [0.68-4.4]</td><td>.404</td></tr><tr><td>Hemoglobin (g/dL)</td><td>10 [9-11.7]</td><td>10.1 [9.2-11.8]</td><td>9.3 [7.8-10.4]</td><td>.044</td></tr><tr><td>Platelets (G/L)</td><td>139 [98-241]</td><td>137 [99-236]</td><td>184 [83-317]</td><td>.920</td></tr><tr><td>IPSS-R</td><td>2 [2-3]</td><td>2 [2-3]</td><td>2.3 [1.8-4]</td><td>.985</td></tr><tr><td>IPSS-R &gt;3.5</td><td>13 (14.3)</td><td>12 (14.3)</td><td>1 (14.3)</td><td>1.000</td></tr><tr><td>Specific hematologic treatment</td><td>28 (30)</td><td>22 (26.2)</td><td>6 (60)</td><td>.003</td></tr><tr><td>Transformation toward AML</td><td>10 (10.6)</td><td>7 (8.3)</td><td>3 (30)</td><td>.071</td></tr><tr><td>Time between MDS and AML (months)</td><td>10 [4.5-20.8]</td><td>10 [7-26]</td><td>0 [0-19]</td><td>.258</td></tr><tr><td>Follow-up (months)</td><td>23 [11-35]</td><td>23 [12-35]</td><td>8 [3-39]</td><td>.277</td></tr></tbody></table>

Abbreviations: AML, acute myeloid leukemia; IPSS-R, International Prognosis Scoring System-Revised; MDS-5q-, myelodysplastic syndrome with deletion 5q; MDS-EB, MDS with excess of blasts; MDS-MLD, multilineage dysplasia; MDS-RS, MDS with ring sideroblasts; MDS-SLD, single lineage dysplasia; MDS-U, undetermined.

prognostic factors than control MDS/CMML, but with a similar overall survival [6].

Limitations of this work are mainly due to its retrospective design and the small size of the cohort, even though this is the second largest published study to date. That is why it is not possible to completely rule out the hypothesis of a fortuitous association of renal diseases with MDS. To push the analysis further, the next objectives will be to collect kidney biopsies samples to characterize the pathological and molecular features of the kidney injuries associated with MDS.

The present study clearly indicates that the kidney, along with other organs, is target of auto-immunity in the setting of MDS. MDS are associated with systemic vasculitis, especially with a glomerular involvement such as AAV. A diagnosis of AAV in a patient with cytopenias, other than inflammatory anemia, should lead to research into a possible MDS.

## SUPPLEMENTARY DATA

Supplementary data is available at *Clinical Kidney Journal* online.

## FUNDING

None.

## DATA AVAILABILITY STATEMENT

The data underlying this article will be shared on reasonable request to the corresponding author.

## CONFLICT OF INTEREST STATEMENT

A.M. is investigator of CELGENE, ROCHE, CHUGAI funded trials with APHP, and Hôpital 15-20 promotion; A.M. received several fees for congress travels and expert use from LFB, SANOFI, SHIRE, and CELGENE.

## REFERENCES

1. Leung N, Bridoux F, Batuman V et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol 2019;15:45-59.

2. Arber DA, Orazi A, Hasserjian R et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405. https://doi.org/10.1182/blood-2016-03-643544

3. Cazzola M. Myelodysplastic syndromes. N Engl J Med 2020;383:1358-74. https://doi.org/10.1056/NEJMra1904794

4. Fain O, Braun T, Stirnemann J et al. Manifestations systémiques et auto-immunes des syndromes myélodysplasiques. La Revue de Médecine Interne 2011;32:552-9. https://doi.org/10.1016/j.revmed.2010.08.005

5. Grignano E, Mekinian A, Braun T et al. Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: a series of 26 cases and literature review. Leuk Res 2016;47:136-41. https://doi.org/10.1016/j.leukres.2016.05.013

6. Mekinian A, Grignano E, Braun T et al. Systemic inflammatory and autoimmune manifestations associated with

<footnote>ªMissing data.</footnote>
myelodysplastic syndromes and chronic myelomonocytic
leukaemia: a French multicentre retrospective study.
*Rheumatology (Oxford)* 2016;55:291-300. https://doi.org/10.
1093/rheumatology/kev294

7. Wesner N, Drevon L, Guedon A et al. Gastrointestinal Behcet's-like disease with myelodysplastic neoplasms with trisomy 8: a French case series and literature review. *Leuk Lymphoma* 2019;60:1782-8.

8. Morschhauser F, Wattel E, Pagniez D et al. Glomerular injury in chronic myelomonocytic leukemia. *Leuk Lymphoma* 1995;18:479-83.

9. Saitoh T, Murakami H, Uchiumi H et al. Myelodysplastic syndromes with nephrotic syndrome. Am. J. Hematol 1999;60:200-4. https://doi.org/10.1002/(SICI)1096-8652(199903)60:3%3c200::AID-AJH6%3e3.0.CO;2-0

10. Paydas S, Paydas S, Tuncer I et al. A case with membranous glomerulonephritis and myelodysplastic syndrome. *Nephron* 1992;62:231-2.

11. Enright H, Jacob HS, Vercellotti G et al. Paraneoplastic autoimmune phenomena in patients with myelodysplastic syndromes: response to immunosuppressive therapy. Br J Haematol 1995;91:403-8. https://doi.org/10.1111/j.1365-2141.1995.tb05310.x

12. Apostolou T, Sotsiou F, Pappas C et al. Atheroembolic renal disease and membranous nephropathy, in a patient with myelodysplastic syndrome, eosinophilia, and trisomy 8. *Nephrol Dial Transplant* 2002;17:1336-8. https://doi.org/10.1093/ndt/17.7.1336

13. Ko KI, Lee MJ, Doh FM et al. Membranous glomerulonephritis in a patient with myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia. *Kidney Res Clin Pract* 2013;32:134-7. https://doi.org/10.1016/j.krcp.2013.06.001

14. Komatsuda A, Miura I, Ohtani H et al. Crescentic glomerulonephritis accompanied by myeloperoxidase-antineutrophil cytoplasmic antibodies in a patient having

myelodysplastic syndrome with trisomy 7. *Am J Kidney Dis* 1998;31:336-40. https://doi.org/10.1053/ajkd.1998.v31.pm9469507

15. Schwotzer N, Provot F, Ville S et al. Spectrum of kidney involvement in patients with myelodysplastic syndromes. *Kidney Intl Rep* 2021;6:746-54. https://doi.org/10.1016/j.ekir.2020.12.030

16. Roupie AL, Guedon A, Terrier B et al. Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study. *Semin Arthritis Rheum* 2020;50:879-84. https://doi.org/10.1016/j.semarthrit.2020.07.002

17. Boudhabhay I, Delestre F, Coutance G et al. Reappraisal of renal arteritis in ANCA-associated Vasculitis: clinical characteristics, pathology, and outcome. JASN 2021;32:2362-74. https://doi.org/10.1681/ASN.2020071074

18. Inker LA, Astor BC, Fox CH et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014;63:713-35. https://doi.org/10.1053/j.ajkd.2014.01.416

19. Levin A, Stevens PE. Summary of KDIGO 2012 CKD Guideline: behind the scenes, need for guidance, and a framework for moving forward. *Kidney Int* 2014;85:49-61. https://doi.org/10.1038/ki.2013.444

20. Fraison JB, Grignano E, Braun T et al. Autoantibodies in myelodysplastic syndromes and chronic myelomonocytic leukemia. *Leuk Lymphoma* 2019;60:2594-6.

21. Mekinian A, Zhao LP, Chevret S et al. A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML. *Leukemia* 2022;36:2739-42. https://doi.org/10.1038/s41375-022-01698-8