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A glomerulus showing moderate global mesangial sclerosis and mild mesangial hypercellularity. The glomerular basement membrane appears mildly thickened and shows rare double contours (periodic acid-Schiff, × 400).
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Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders that can produce an undefined glomerulopathy. To better characterize the glomerular disease associated with myeloproliferative neoplasms, we evaluated features of 11 patients with myeloproliferative neoplasm-related glomerulopathy that included 8 patients with primary myelofi...
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Context 1
... mean of 37% of glomeruli were globally sclerotic (Table 2). All cases showed some degree mesangial sclerosis and hypercellularity ( Figure 1). Mesangial sclerosis was mild in six cases and moderate in five, whereas mesangial cell hypercellularity was mild in three cases, moderate in four, and marked in four. ...
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Background:
Polycythemia vera (PV) is a common type of Philadelphia chromosome-negative chronic myeloproliferative disorder. PV-associated kidney disease is rarely reported and remains poorly understood. It has been observed that chronic kidney disease could be a risk factor for poor prognosis in PV.
Methods:
We retrospectively analyzed the clin...
Citations
... Patients with essential thrombocythemia can experience impaired renal function [3], and chronic kidney disease can also contribute to an increased risk of thrombosis for these patients [4]. However, determining the exact cause of renal dysfunction in patients receiving anagrelide can be challenging due to underlying factors. ...
A 62-year-old female patient with essential thrombocythemia experienced rapid renal dysfunction and was subsequently referred to our hospital. Further investigations did not reveal any significant abnormalities except for a slight increase in urinary β2-microglobulin levels. A renal biopsy was performed to investigate the cause of her renal dysfunction, revealing acute tubular necrosis, interstitial edema, and arteriosclerosis. No significant glomerular lesions were observed. Immunofluorescence staining and electron microscopy showed no abnormalities. She had been using anagrelide for 4 years, and her dosage was increased from 2.0 to 3.0 mg/day 10 months before her initial admission. Her renal function began to deteriorate 2 months after the anagrelide dosage increase. Although 0.625 mg of bisoprolol was initiated for tachycardia 3 months after the anagrelide dosage adjustment, we suspected that the acute tubular necrosis was associated with anagrelide administration. After transitioning from anagrelide to hydroxyurea and discontinuing bisoprolol, her renal function improved. This case suggests the importance of considering anagrelide as a potential cause of renal dysfunction in patients using this medication. Therefore, renal biopsy, combined with a comprehensive medical history, is crucial for evaluating the etiology of renal injury in such cases.
... Few studies have found Focal segmental glomerulosclerosis (FSGS) and mesangial sclerosis with myeloproliferative disorder. 4 In 2011, Said et al. 5 described the term myeloproliferative disorder-related glomerulopathy (MDRG). Other lesions such as extramedullary hematopoiesis have also been described in primary myelofibrosis. ...
... 9 Renal involvement in primary myelofibrosis is generally secondary to hyperuricemia and renal vein thrombosis, with rare involvement of the glomerular compartment with mesangial proliferation, which is usually pauci-immune on IF. According to the study by Said et al., 5 patients with primary myelofibrosis have a higher risk of developing myeloproliferative disorder-related glomerulopathy. In this case, there was myelofibrosis of long duration and renal dysfunction with nephrotic range proteinuria and normal serum complement level. ...
Proliferative glomerulonephritis in myelofibrosis is a very rare. Mesangial proliferation and sclerosis with changes of chronic thrombotic microangiopathy have been reported, but pauci-immune focal crescentic glomerulonephritis has not been described so far. Herein, we present a 68-year-old male who was a known case of myelofibrosis and presented with rapidly progressive glomerulonephritis and nephrotic range proteinuria. He was diagnosed as anti-neutrophil cytoplasmic antibody (ANCA)-negative focal crescentic glomerulonephritis, and he responded well to a course of intravenous methylprednisolone and cyclophosphamide. Pauci-immune focal crescentic glomerulonephritis may occur in myelofibrosis without ANCA and may be related to unknown pathogenetic mechanisms in myeloproliferative disorders or suggest any superimposed pathology that might respond well to immunosuppressants.
... In brief, patients who ultimately sufered from CKD had a signifcantly poorer prognosis than those without groups ( Figure 2) (P � 0.002). Since the entity "MPN-related glomerulopathy" was reported in 2011 [24], the association between MPNs and renal hypofunction has attracted attention. Te incidence of CKD at the time of ET diagnosis is reportedly higher than in the general population [25,26], being 12.9 to 28.9% [13, 15-17, 27, 28]. ...
Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease, thrombosis, and all-cause death. However, few studies have examined the association between CKD and the prognosis of patients with essential thrombocythemia (ET). We collected ET patients who met the WHO classification 2017 and performed a retrospective clinical study to clarify the association between the presence and onset of CKD and prognosis. Of 73 patients who met the diagnostic criteria, 21 (28.8%) had CKD at the time of ET diagnosis. The age of patients with CKD was significantly higher, and a high proportion of these patients had the JAK2V617F gene mutation. The presence of CKD was a risk factor for the prognosis (hazard ratio (HR): 3.750, 95% confidence interval (CI): 1.196–11.760, P=0.023), and the survival curve was significantly poorer. Furthermore, we analyzed patients without CKD at the time of ET diagnosis using the onset of CKD as a time-dependent variable and identified the onset of CKD as a risk factor for the prognosis (HR: 9.155, 95% CI: 1.542–54.370, P=0.005). In patients with renal hypofunction at the time of ET diagnosis or those with a reduction in the kidney function during follow-up, strict renal function monitoring at regular intervals is necessary.
... This pattern of glomerular injury was described in multiple reports, including a large series that examined kidney postmortem findings in 57 patients with MPNs. [17][18][19][20][21] The pathophysiology behind the accelerated glomerulosclerosis remains uncertain, but it has been postulated that growth factors, such as fibroblast growth factor, platelet-derived growth factor, and transforming growth factor-β (TGF-β), which play a central role in MPN-related myelofibrosis, may be implicated. 22 These growth factors are potent triggers of mesangial cell proliferation, mesangial and subendothelial matrix production, and subsequent endothelial and podocyte damage that eventually lead to glomerular scarring. ...
... This phenomenon could potentially explain the features of chronic thrombotic microangiopathy (TMA) observed in many cases. 18,19 Other glomerulopathies associated with CMML include amyloid light chain amyloidosis, membranous nephropathy, infection-related-like glomerulopathy, crescentic glomerulonephritis, and even extramedullary (intracapillary) hematopoiesis. 14,19,[27][28][29] In a recent case series by Gipe et al, 20 out of 14 patients with CMML and kidney involvement, 2 patients presented with nephrotic syndrome and had minimal change disease (MCD), 1 patient had incidental IgA nephropathy, 1 patient had resolving postinfectious glomerulonephritis, and 1 patient had unspecified MPN-related glomerulopathy. ...
... Steroids have been tried without success, but mycophenolate mofetil at a dose of 1.5 g/d successfully lowered proteinuria from 27 g/d to 1 g/d in a case of membranous nephropathy. 18,28 Cyclophosphamide and azathioprine were useful in controlling the disease in 1 report. 14 Unfortunately, the prognosis of patients with glomerular involvement is guarded, and they often experience a progressive deterioration in kidney function despite therapy, eventually reaching kidney failure. ...
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy affecting the bone marrow and resulting in peripheral blood monocytosis. Kidney and urinary tract involvement is common and can present dramatically with life-threatening consequences. Kidney involvement can be the result of direct or indirect mechanisms, including prerenal azotemia, glomerular disease, tubulointerstitial involvement, and renovascular disorders. Urinary tract involvement, electrolyte and acid-base disorders, as well as nephrotoxicity from treatment of the disorder can also occur. Given this multifactorial pathogenesis involving several mechanisms concomitantly, nephrologists must exercise heightened awareness and maintain a low threshold for kidney biopsy. There is a pressing need for future research endeavors to elucidate and target the manifestations of CMML that involve the kidneys with the ultimate goal of augmenting overall prognosis and therapeutic outcomes.
... The observed discordance between normal serum biomarkers such as creatinine and eGFR, and the presence of renal impairment as detected by MRI underscores the potential utility of this imaging technique in revealing subclinical pathology that is often missed by conventional testing. The clinical implications at this stage are uncertain, but as renal function is a prognostic factor in MPN, examination of larger patient groups is warranted (14,15). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ...
Assessment of organ impairment in patients with chronic myeloid neoplasms is pivotal in selecting treatments and for accurate prognostication of patient outcomes. In order to determine the multi-organ health of patients with chronic myeloid neoplasms, we conducted a prospective, observational study utilising a novel MRI technology which quantitatively assesses the health of multiple organs in one scan. Organ impairment was significantly higher in the patient cohort compared to healthy controls, most notably with increased rates of kidney fibroinflammation 28% vs 0% (p-value = 0.002). MRI-defined kidney impairment was prevalent in patients with normal serum biomarkers of kidney disease, demonstrating the added value of MRI as a tool to identify occult organ impairment. This has wider implications for enhancing the assessment of organ health in patients with a variety of blood cancers at diagnosis and throughout treatment, guiding more personalised strategies and improving patient outcomes.
... A number of case reports and case series from MPN patients who underwent kidney biopsy or autopsy revealed the existence of MPN-related glomerulopathy (MPNrG); this is a typical pathohistological finding in MPN at the level of glomeruli [48]. Typical pathohistological features include glomerular hypercellularity and sclerosis, mesangial sclerosis, thrombotic microangiopathy, and extramedullary hematopoiesis [49][50][51][52]. Kidneys of MPN patients show significantly higher degree of glomerular scarring exceeding age-related alterations and higher frequency of intracapillary platelet aggregates compared to control patients [51]. ...
The exact prognostic role of cardiovascular (CV) risk factors in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms (MPNs) remains unknown as it is often masked by other MPN-related features that bear strong prognostic impact on thrombotic risk. Therefore, current MPN treatment is not primarily guided by presence of CV risk factors. Treatment of CV risk factors in MPN patients usually mirrors that from the general population, despite the fact that CV risk factors in MPNs have their own specificities. Moreover, the optimal target levels for different metabolic deflections in MPNs (i.e., low-density lipoprotein, serum uric acid, or glycated hemoglobin levels) have not been defined. In the current review, we separately discuss the most important aspects of every individual CV risk factor (arterial hypertension, hyperlipidemia, chronic kidney disease, smoking, diabetes mellitus, hyperuricemia, and obesity and cachexia) in MPNs, summarize recent advances in the field, and propose future directions and research areas which may be needed to appropriately manage CV risk factors in MPNs.
... The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms. Chronic myeloid leukemia (16) Polycythemia vera (14) Essential thrombocythemia (10) Primary myelofibrosis (7) Controls N = 188 matched adult native kidney biopsies ...
... 9 The glomerular histological pattern of MPN-related kidney injury, termed MPN-related glomerulopathy (MPN-RG), was described in a clinicopathological study of 11 patients with MPN and glomerular disease. 10 All patients had high levels of proteinuria (>3 g/day), and four had nephrotic syndrome. The kidney biopsies were remarkable for mesangial sclerosis and hypercellularity, as well as features of chronic glomerular thrombotic microangiopathy and intracapillary hematopoietic cells. ...
... In this study, we described the largest clinicopathological series of kidney biopsies in patients with MPN. We observed glomerular lesions attributable to MPN-RG, as previously described [10][11][12][13] and we demonstrated the association between MPN-RG and myelofibrosis, as well as the guarded renal prognosis in such patients. As previously observed, we acknowledge that the finding of intracapillary hematopoietic cells in a kidney biopsy should raise the hypothesis of an underlying MPN. ...
... The importance of immune deregulation [35,36] with increasing T-cell exhaustion and tumor immune evasion consequent to defective tumor immune surveillance has been repeatedly underscored as one of the major mechanisms, contributing not only to MPN development and disease progression but also to the development of second cancers and their poorer survival as compared to the same cancers in the background population [30,31,34]. Highly intriguing, other inflammation-mediated comorbidities are also prevalent in MPNs, including much earlier development of drusen and age-related macular degeneration [37][38][39][40][41][42], increased risk of fractures, likely mediated by the chronic inflammatory state [43][44][45][46][47][48][49][50], chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) [51][52][53][54], and chronic kidney disease [55][56][57][58][59][60][61][62][63][64][65]. Accordingly, patients with MPNs are not only at a constantly increased risk of major thrombosis in, e.g., the brain, heart, lungs, legs and abdominal arteries and veins [11][12][13][14][15] but also at an increased risk of being burdened by inflammation-mediated multimorbidities , including an increased risk of second cancers [20-23,29-34]. ...
... Sixth, MPNs are associated with an increased risk of chronic kidney failure [55][56][57][58][59][60][61][62][63][64][65], which is considered to develop as a consequence of a chronic inflammatory state with ensuing renal impairment. It is intriguing to consider if "MPN-glomerulopathy" actually develops due to fibrogenesis in the kidneys as a consequence of the intramedullary release of growth factors-mitogenic for fibroblasts and endothelial proliferation (e.g., PDGF, TGGbeta, and VEGF). ...
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10–30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation—“a wound that never heals”—we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.
... Patients with ET are known to be at increased risk of thrombotic disorders, such as cerebrovascular disease, myocardial infarction, and pulmonary embolism, and pregnancy complications, but the association between ET and kidney complications is less well known. Only a few reports have described such complications, i.e., FSGS, IgA nephropathy, and fibrillary glomerulonephritis (4)(5)(6)(7)(8)(9). ...
... Said et al. evaluated glomerular disease in 11 patients with myeloproliferative neoplasms, including 1 patient with ET and FSGS whose kidney biopsy showed segmental sclerosis with prominent luminal hyalinosis and adhesion to Bowman's capsule (7). CD61 immunohistology showed infiltration of intracapillary megakaryocytes. ...
... In our case, CD61 staining confirmed that the ET-related infiltrations of megakaryocytes in glomeruli were related to FSGS, which is in agreement with the report by Said et al. (7). ...
A 72-year-old man was admitted for examination of proteinuria (9.14 g/day) and leg edema. Essential thrombocythemia (ET) was diagnosed because of thrombocytosis (platelet count, 57.9×10⁴/μL), elevated megakaryocytes in bone marrow biopsy, and JAK2 V617 mutation. Kidney biopsy led to a diagnosis of focal segmental glomerulosclerosis (FSGS) cellular variant (characterized by glomerular capillaries filled with swollen endothelial cells containing foam cells) in 6 glomeruli, FSGS tip variant in 5 glomeruli, and additional FSGS variants in other glomeruli. Affected glomeruli had anti-CD61 antibody staining-positive megakaryocyte infiltrations. ET mayinduce FSGS because megakaryocyte infiltration increases intraglomerular pressure, resulting in hypertension and proteinuria.
... Aside from nonspecific chronic changes attributable to arterionephrosclerosis, 13 (35%) biopsies demonstrated coexisting pathology including 4 with direct involvement of the kidney by underlying neoplasm (2 AML, 1 CMML, and 1 with intraglomerular neuroendocrine carcinoma), 3 with extramedullary hematopoiesis, 2 with myeloproliferative neoplasm associated glomerulopathy, 27 2 with immune complex mediated glomerulonephritis (1 mild IgA nephropathy and 1 endocapillary proliferative glomerulonephritis with "full-house" staining in a patient with an uncharacterized autoimmune disease), 1 idiopathic nodular glomerulosclerosis (without history of smoking or diabetes), and 1 with diffuse diabetic glomerulosclerosis. In 2 cases, given its severity, arterionephrosclerosis was felt to be the finding that best correlated with the clinical presentation. ...
Introduction:
Lysozyme-associated nephropathy (LyN), a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML), has not been well described to date. We report the clinicopathologic spectrum of LyN from a multi-institutional series.
Method:
We identified 37 native kidney biopsies with LyN and retrospectively obtained clinicopathologic data.
Results:
Thirty-seven patients had a median age of 74 years and included 78% males. Their most common presentation was acute kidney injury (AKI) or AKI on chronic kidney disease (CKD) (66%) with median estimated glomerular filtration rate (eGFR) of 21.7 ml/min per 1.73 m2, and proteinuria of 1.7 g. A minority (15%) had partial Fanconi syndrome. Serum lysozyme levels were elevated in all tested. Hematologic disorder (n = 28, 76%) was the most common etiology, including CMML (n = 15), acute myeloid leukemia (n = 5), and myelodysplastic syndrome (MDS) (n = 5). Nonhematologic causes (n = 5, 14%), included metastatic neuroendocrine carcinoma (n = 3), sarcoidosis, and leprosy. Etiology was unknown in 4 (11%). Pathology showed proximal tubulopathy with abundant hypereosinophilic intracytoplasmic inclusions, with characteristic staining pattern by lysozyme immunostain. Mortality was high (8/30). However, among the 22 alive, including 85% treated, 7 had improved kidney function, including 1 who discontinued dialysis and 6 with increase in eGFR >15 ml/min per 1.73 m2 compared with eGFR at the time of biopsy.
Conclusion:
Increased awareness of the full clinicopathologic spectrum of LyN may lead to prompt diagnosis, earlier treatment, and potentially improved outcome of this rare entity.
