LAUSR

To the Editor: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/ myeloproliferative (MP) overlap neoplasm (MDS/MPN), characterized by sustained peripheral blood monocytosis (absolute monocyte count≥0.5 10/L, with monocytes comprising ≥10% of the white blood cell [WBC] differential) and an inherent risk for acute myeloid leukemia (AML) transformation. CMML occurs in aging individuals (median age: 73–75 years), arising on a background of clonal hematopoiesis, with TET2 and SRSF2 mutations being early driver events. Based on presenting WBC counts CMML can be further classified into MP and myelodysplastic subtypes (MD), with the former defined by a WBC ≥13 10/L. Unlike other MPN and MDS/MPN overlap neoplasms, CMML is associated with significant monocytosis which results in a unique spectrum of end-organ damage. Prominent amongst this is a higher incidence of acute kidney injury (AKI-34.9%) and chronic kidney disease (CKD-7.6%), with this impact being statistically higher in patients with MP-CMML versus MD-CMML [AKI 40% vs. 27.8% and CKD 10% vs. 4.2%]. Further, the prevalence of AKI and CKD has been shown to correlate with peak WBC counts and absolute monocyte counts. While the mechanisms of AKI and CKD remain multifactorial, monocytic neoplasms are associated with the overproduction of lysozyme (muramidase), a low-molecular weight (15 000 Da), freely filtered protein that can accumulate in proximal tubular cells resulting in a proximal tubulopathy and subsequent kidney injury (lysozyme-induced nephropathy-LIN). Additional mechanisms of kidney injury include direct infiltration of myelomonocytic cells into tubules, presence of extramedullary hematopoiesis (EMH), hyperuricemia-associated nephropathy, autoimmune and paraneoplastic manifestations, and rarely obstructive nephropathy secondary to enlarged lymph nodes and severe hepatosplenomegaly. We carried out this study to assess the spectrum of renal pathological findings in CMML patients that underwent kidney biopsies at our institution. The study was carried out after Mayo Clinic IRB approval. The CMML institutional database was queried for patients with an established diagnosis of CMML (World Health Organization and International Consensus Classification 2022) that underwent kidney biopsies at Mayo Clinic. The pathology slides were re-reviewed by an expert nephropathologist (MPA). The needle biopsy samples were evaluated by light microscopy, immunofluorescence, and electron microscopy, as previously described. Biopsy specimens that only included the renal medulla were excluded for review. LIN was defined by the following pathological criteria: (a) proximal tubular cells having hypereosinophilic granular cytoplasm owing to the presence of abundant intracytoplasmic, PAS (Periodic Acid Schiff)-positive granules, with the absence of atypical crystalline inclusions, (b) ultrastructural evidence of increased number and size of lysosomes, many of which may contain clumped, electron-dense, degenerating cellular organellar debris, in the distribution of the proximal tubular cell cytoplasm and (c) strong diffuse cytoplasmic positivity for lysozyme in abnormal proximal tubules. Clinical, molecular and survival data points were retrospectively abstracted. Correlation with serum lysozyme levels was carried out where possible. Descriptive statistical analysis was carried out. Fourteen patients met the criteria for inclusion in the study: median age 67 years (range 47–85), with a male preponderance (70%). The time range for kidney biopsies for these 14 patients was 1999–2022. Twelve (85%) patients met the criteria for MP-CMML, while 12 (85%) patients were classified as having CMML-1 by the 5th edition of the WHO and the 2022 ICC criteria for CMML (Table 1). Somatic mutations were assessed in 11 patients, with all 11 (100%) having ASXL1 mutations and with 8 (71%) having oncogenic RAS pathway mutations (CBL-4, NRAS-3, KRAS-1). Indications for kidney biopsies included AKI, CKD, and proteinuria: AKI (n = 4: median serum creatinine 3.4 mg/dl; range 2.12–5.13 mg/dl) and CKD (n = 8: median serum creatinine 1.98 mg/dl; range 1.4–4.01 mg/dl) were common indications and while proteinuria (>150 mg/24-h urine collection) was noted in 6 (46%) assessable patients, 4 (30%) met criteria for nephrotic range proteinuria (>3.5 g/24-h urine collection). The urine sediment analysis was notable for granular and/or hyaline casts in 8 (61.5%) analyzable patients, while red cell casts were not detected. Cumulatively, glomerular sclerosis was seen in a median of 18.5% (range; 0–75%) of analyzed glomeruli, while tubular atrophy was seen in a median of 20% (range; 0–60%) of analyzed tubules. Lysozyme-induced nephropathy was diagnosed in 6 (42.8%) patients, 4 (66%) males. All 6 (100%) patients had MP-CMML and the median WBC at diagnosis of LIN was 21.7 10/L (range; 13.2– 60.1), while the median serum creatinine at the time of kidney biopsy was 2.12 mg/dl (range; 1.77–5.13 mg/dl). All 5 (100%) assessable (#6 did not have somatic mutational profiling) patients had ASXL1 mutations, while 4 (80%) had oncogenic RAS pathway mutations. Two (33%) patients presented with AKI, while 4 (66%) patients presented with CKD, and only 2 (33%) patients had subnephrotic proteinuria (urine protein levels were not increased in the remaining 4 patients with LIN). Serum lysozyme levels were markedly elevated in 4 (100%) of 4 assessable patients. The findings on light microscopy were Received: 15 January 2023 Revised: 25 February 2023 Accepted: 2 March 2023