Clonal monocytosis of renal significance

Abstract

Clonal monocytosis reflects a preneoplastic or neoplastic sustained increase in the absolute monocyte count in the absence of reactive causes. Causes of clonal monocytosis include clonal cytopenias with monocytosis and acute and chronic myeloid neoplasms. Chronic myelomonocytic leukemia is a prototypical myelodysplastic/myeloproliferative overlap neoplasm in adults, characterized by sustained peripheral blood monocytosis. Kidney abnormalities, including acute kidney injury and chronic kidney disease, are frequent in patients with chronic myelomonocytic leukemia and are predictors of worse outcomes. In addition, acute kidney injury/chronic kidney disease often limits eligibility for allogeneic stem cell transplantation or enrollment in clinical trials. In this review, we highlight clonal monocytosis-related etiologies that give rise to acute kidney injury and chronic kidney disease, with special emphasis on chronic myelomonocytic leukemia and lysozyme-induced nephropathy. Monocytes produce lysozyme, which, in excess, can accumulate in and damage the proximal renal tubular epithelium. Early identification of this etiology and a timely reduction in monocyte counts can salvage kidney function. Other etiologies of kidney injury associated with clonal monocytosis include direct renal infiltration by monocytes, renal extramedullary hematopoiesis, myeloproliferative neoplasm-associated glomerulopathy, autoimmune (membranous nephropathy, minimal change disease) and paraneoplastic manifestations, thrombotic microangiopathy, obstructive nephropathy due to myeloproliferation, and urate nephropathy due to tumor lysis syndrome. We propose to group these mechanistic etiologies of kidney injury as clonal monocytosis of renal significance and provide guidance on their diagnosis and management.

Keywords: chronic myelomonocytic leukemia; kidney diseases; lysozyme-induced nephropathy; monocytosis; renal abnormalities.

Figure 1:

Mechanisms and pathology of clonal monocytosis of renal significance. The mechanisms of renal toxicity from clonal monocytosis are shown in Panel A. Lysozyme-induced nephropathy is caused by the excessive production of lysozyme by tumor cells in the setting of clonal monocytosis. The excess filtered lysozyme is reabsorbed by the proximal tubules. Due to the high lysozyme burden, tubular epithelial cells demonstrate characteristic injury. A sequela of clonal monocytosis is aberrant immune T and B-cell reactions, which favor an underlying autoimmune milieu. This may lead to possible immune dysregulation that may contribute to, or exacerbate an associated glomerular disease. Clonal monocytes are responsible for excess production of TGF, a platelet-derived growth factor, with resultant mesangial sclerosis. Platelet aggregation with hyperviscosity due to the high and sluggish flow of intracapillary monocytes leads to endothelial injury. These contribute towards myeloproliferative neoplasm-related glomerulopathy. The hyperviscosity of blood flow with platelet aggregates also leads to endothelial injury and thrombus formation, leading to thrombotic microangiopathy. Tumor lysis syndrome results in hyperuricemia, which contributes to urate tophi and nephrocalcinosis. This can lead to obstructive uropathy. Marrow infiltration by tumor cells often leads to hepatosplenomegaly as a result of extramedullary hematopoiesis. Extramedullary hematopoiesis also occurs in the kidneys. Myelomonocytic tumor cells can directly infiltrate the renal parenchyma and cause interstitial aggregates. Some of them infiltrate the Bowman’s space and cause pseudo-crescents. Panel B shows the localization of clonal monocytosis-related renal lesions.

Figure 2:

Lysozyme-induced nephropathy (LyN) is characterized by proximal tubular epithelial cell injury. (A) The proximal tubular epithelial cells are swollen with a hypereosinophilic granular cytoplasm (hematoxylin and eosin, 200X). (B) The granules are refractile and non-argyrophilic (Jones methenamine silver stain, 200X) with (C) fuchsinophilic droplets (Masson’s trichrome, 200X). Immunohistochemical stain for lysozyme (D) is positive in the tubular epithelium and demonstrates both diffuse and strong staining in tubular epithelium, with some tubules exhibiting a more variegated and patchy staining pattern (immunoperoxidase, original magnification 200X). Ultrastructural studies show that tubules contain intracytoplasmic inclusions that may have a more uniform electron density (E; original magnification 8000), or a more granular, mottled membrane-bound appearance (F; original magnification 8000X).

Figure 3:

Myelomonocytic interstitial infiltrates (arrows) can be focal and therefore easily missed, or at other times, they can form large, mass-like lesions (A). They may occur along with other CMML-related pathology, such as LyN (hematoxylin and eosin, 200X), or (B) with mild tubular injury (hematoxylin and eosin, 100X). (C) CD163 is useful in confirming the monocytic lineage (immunoperoxidase, original magnification 100X). (D) Renal extra-medullary hematopoiesis is characterized by trilineage hematopoiesis (hematoxylin and eosin, 100X). (E) The infiltrate includes variable admixtures of myeloid cells, which are detected with MPO stains (immunoperoxidase, original magnification 100X). (F) Erythroid cells are often seen in islands and in small clusters (arrow; hematoxylin and eosin, 200X). They are characterized by homogenous dark nuclei and are identified by glycophorin (G; immunoperoxidase, original magnification 200X). Megakaryocytes are more infrequent and are recognized by hyperlobated nuclei (H) (black arrow; hematoxylin and eosin, 200X), which are detected with CD61 (I; immunoperoxidase, original magnification 100X). Abbreviations: CMML, chronic myelomonocytic leukemia; LyN, lysozyme-induced nephropathy MPO, myeloperoxidase

Figure 4:

(A) Myeloproliferative neoplasm-associated glomerulopathy is a form of glomerular injury that is characterized by mesangial sclerosis and increased intracapillary infiltration by hematopoietic cells (hematoxylin and eosin, 400X). (B) The silver stains highlight endothelial injury with double contours (arrow; Jones methenamine silver stain, 200X). (C, D) Ultrastructural evaluation is helpful in demonstrating the spectrum of features identified in myeloproliferative neoplasm-related glomerulopathy, namely mesangial sclerosis (C, D), endothelial injury (black arrows), and intracapillary infiltration with hematopoietic cells (white arrow).