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- Hindawi Publishing Corporation
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- Copyright © 2019 Shoja Rahimian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 2090-6706
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- 2090-6714
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- 10.1155/2019/5086963
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Abstract
Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 5086963, 5 pages https://doi.org/10.1155/2019/5086963 Case Report A Case of Essential Thrombocythemia and IgA Nephropathy with Literature Review of the Concurrence Shoja Rahimian , Timothy Johnson , and Ronald Herb Department of Internal Medicine, Reading Hospital-Tower Health, USA Correspondence should be addressed to Shoja Rahimian; shorahimian@gmail.com Received 19 February 2019; Revised 23 July 2019; Accepted 4 August 2019; Published 2 September 2019 Academic Editor: Josep M. Ribera Copyright © 2019 Shoja Rahimian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Myeloproliferative neoplasms such as essential thrombocythemia (ET) have been associated with glomerular disease on rare instances. A case of ET associated with immunoglobulin A nephropathy (IgAN) is described in a 57-year-old man with a history of hypertension. Progressively worsening renal function was noted in the patient along with unexplained mild thrombocytosis. Pathological review of renal biopsy identified IgAN concurrently with newly diagnosed JAK2-mutated ET. The patient was started on aspirin therapy and closely monitored for his renal function. A literature review of the association of ET and renal disease revealed nine cases of ET associated with IgAN, focal segmental glomerulosclerosis, and fibrillary glomerulonephritis. Comparison of the pathological features of the renal biopsies within the cases noted mesangial proliferation as a common finding, which has been described to be potentiated by platelet-derived growth factor (PDGF). This commonality may represent a link between ET and glomerular disease which deserves further attention in future cases. Improved management of such cases depends on the recognition of the combined occurrence of ET and glomerular diseases and uncovering the shared pathogenesis between platelets and glomeruli. 1. Introduction to an increased concentration of hemoglobin and hematocrit, is associated with a JAK2V615F mutation that has been seen Essential thrombocythemia (ET) is a type of myeloprolifera- in approximately 95% of cases. In contrast, JAK2 mutations tive neoplasm (MPN) that results in an increased number of are typically seen in 50-60% of ET cases [3]. In ET cases that platelets in circulation. The current 2016 WHO classification lack JAK2 mutation, CALR and MPL genes have been shown for diagnosis of ET requires major criteria of a platelet count to possess mutation. Past cohorts studying ET patients found equal to or over 450 × 10 /L, demonstration of JAK2, MPL, that these mutations (JAK2, CALR, and MPL) are seen in or CALR mutation, bone marrow biopsy with mature mega- 62-64%, 22-24%, and 4%, respectively [4, 5]. While patients with ET are at a known increased risk for karyocyte proliferation but without significant production of neutrophils, erythrocytes, or reticulin fibers, and lack of thrombotic conditions such as cerebral vascular accidents, meeting criteria for other myeloproliferative diseases. ET myocardial infarction, pulmonary embolism, and pregnancy can alternatively be diagnosed by meeting three of the major complications, there is a lesser known association between criteria in addition to lone minor criteria of a clonal marker ET and glomerulonephropathy. Various forms of glomerulo- or absence of evidence for reactive thrombocytosis [1, 2]. nephropathy have been reported in patients with ET including The presence of distinct genotypes is central to both the IgA nephropathy (IgAN), focal segmental glomerulosclerosis diagnosis and, at times, treatment of MPNs. Where some (FSGS), diffuse mesangial sclerosis, and fibrillary glomerulo- nephritis [6–8]. Described here is a case of a 57-year-old MPNs are the result of an individually distinct mutation, others may stem from various genetic aberrations. For man diagnosed with ET that was subsequently diagnosed instance, polycythemia vera (PV), a form of MPN that leads with IgAN. 2 Case Reports in Oncological Medicine 2. Case Description given that his SCr remained 1.6-1.7 mg/dL with proteinuria less than 300 mg per day, it was decided to continue the A 57-year-old Caucasian man with a history of chronic kid- ACE-I without immunosuppressive therapy unless further ney disease (CKD), essential hypertension, migraines, and progression became evident. obstructive sleep apnea presented to the clinic for establish- ment as a new patient. Besides occasional migraines, he did 3. Discussion not have any other immediate complaints. His blood pres- sure was mildly elevated at 148/92 mmHg while on lisinopril The development of glomerulonephropathy in patients with 10 mg and propranolol 160 mg daily, and physical examina- MPNs is not well understood and is infrequently encoun- tion was benign, including lack of lymphadenopathy, rashes, tered. While cases have been described within many of the or edema. Review of his laboratory results was notable for myeloproliferative neoplasm subtypes, this association seems worsened renal function in the past year from a serum creat- to be more commonly documented within PV and primary inine (SCr) of 1.10 mg/dL and globular filtration rate (GFR) myelofibrosis (PMF). Cases of PV describing the develop- of 69.25 mL/min to a SCr of 1.66 mg/dL and GFR of ment of nephrotic range proteinuria often report FSGS fol- 42.91 mL/min. Initially, this was attributed to his angiotensin- lowing renal biopsy [7–9]. While FSGS is described in most converting enzyme inhibitor (ACE-I); however, its discontinu- PV cases, some cases of PV-related nephropathies have also ation did not result in recovery of renal function. Additional described IgA nephropathy [10]. Furthermore, there is a review of records dating 6 years ago revealed thrombocytosis reported case for which Said et al. proposed the term of around 600 × 10 /μL which was more recently in the “MPN-related glomerulonephropathy” to distinguish MPN- 418‐440 × 10 /μL range. The patient had never experienced related glomerular disease from other common glomerular arterial or venous thrombotic events, and etiology of his diseases based on histopathologic findings. MPN-related glo- thrombocytosis had not been investigated in the past. Sev- merulonephropathy was characterized by (1) mesangial scle- eral laboratory studies were ordered with focus on his CKD rosis and more pronounced mesangial proliferation, (2) a and thrombocytosis. lack of nodular mesangial sclerosis, (3) absence of immune Thrombocytosis was pursued with genetic mutation test- deposits, (4) presence of intracapillary hematopoietic cell(s), ing, which returned with positive JAK2 mutation and nega- and (5) segmental duplication of the glomerular basement tive BCR-ABL1. The patient was diagnosed with ET and membrane with findings that mimic chronic thrombotic was started on aspirin. Hydroxyurea therapy was not indi- microangiopathy (TMA) but without intracapillary fibrin cated given a platelet count of 419 × 10 /μL. thrombi, arteriolar thrombotic lesions, or features of micro- Two months later, investigation of his progressive chronic angiopathic hemolytic anemia [11]. kidney disease had revealed proteinuria with 560 mg/24 hours Similar to PV, cases that describe ET-related glomerulo- urine protein content, and he was seen by a nephrologist. nephropathy often report findings of FSGS (Table 1). Nine The electrolytes, uric acid, glucose, serum lipid profile, hep- other cases were identified of glomerulonephropathy in atitis panel, liver function tests, prostate serum antigen, and patients with ET and seemingly no other etiologic explana- serum complement levels of C3 and C4 were normal. Serum tion in a PubMed database search of the English literature and urine protein electrophoresis did not identify significant [12–15]. Our case presented above marks the tenth ET- paraproteins. Further testing for autoimmune and systemic related nephropathy case and the second describing IgAN disease was negative, which included sedimentation rate, in a patient with ET. C-reactive protein, antinuclear antibody, and antiproteinase On comparison of the ET and glomerulonephropathy 3. Ultrasonography revealed normal renal parenchymal previously described cases with ours, only the ET case in echogenicity of both kidneys, which measured 10.9 cm in Said et al. had the histological appearance of the proposed length on the right and 9.9 cm on the left. There was mini- MPN-related glomerulonephropathy. Four of the ten were mal postvoid bladder residual volume of 21 mL, and no consistent with FSGS, two were not given an official diag- hydronephrosis or solid renal mass was seen. nosis, two IgAN (including our case), one fibrillary glomer- The patient agreed to undergo a renal biopsy. The speci- ulonephritis, and one MPN-related glomerulonephropathy. mens were prepared in periodic acid-Schiff, trichrome and Mesangial proliferation was a common finding as it is stated silver stains. Microscopic analysis resulted in a diagnosis of in 9 out of 10 of the cases. Another is immune complex depo- IgA predominant nephropathy (Figure 1). sition, being stated in 6 out of the 10. Our case shared the In the following months, the patient was monitored rou- mesangial proliferation and deposition of immune com- tinely for findings such as hematuria, increased proteinuria, plexes, which may be an affected process with the shared and swelling. He was continued on lisinopril for mild pro- pathophysiology of ET. teinuria. Repeat testing 3 months after his prior results found A possible pathogenic correlation between ET and glo- an elevated SCr of 1.91 mg/dL and GFR of 36.50 mL/min. merular disease could be with platelet-derived growth fac- Urine testing at that time however found improved protein- tor (PDGF) and its role in fibrotic processes such as uria with 23 mg/24 urine. On subsequent follow-up visits, glomerulosclerosis and myelofibrosis. In a study of fibro- the patient’s blood pressure remained in the range of 118- genic growth factors in IgAN and FSGS, Stein-Oakley 140/82-92 mmHg. His platelet count in the 6 months after et al. concluded that these glomeruli express higher levels his renal biopsy remained consistently between 797 and of PDGF receptors which were strongly associated with dis- ease severity, particularly with FSGS. Likewise, the amount 876 × 10 /μL without cytoreductive therapy. Subsequently, Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) (f) (g) Figure 1: Renal biopsy pathology. Up to fourteen glomeruli were identified under light microscopy, and analysis found glomeruli with diffuse thickening of capillary membranes (a, b). There was mild mesangial matrix expansion and hypercellularity (c, d). There was no evidence of glomerular sclerosis. Segmental duplication of capillary walls with accumulation of eosinophilic deposits was noted between the duplicated membranes. Silver stain reveals thickened capillary walls, duplication of basement membranes with eosinophilic deposits in between (e, f). Trichrome stain showed mild to moderate focal interstitial fibrosis associated with tubular atrophy and drop out with scattered lymphocytes within the fibrotic interstitium. No acute tubulitis was seen. Electron microscopy found diffuse effacement of podocyte foot processes and prominent thickening of capillary loops by a combination of subendothelial deposits, basement membrane duplication, and mesangial cell interposition. On immunofluorescence, there was a diffuse 2 to 3+ mesangial reaction and segmental capillary loop reaction for IgA, IgM, C3, kappa, and lambda (g). The reaction for IgG was only 1+, and there was no reaction for C1q or fibrin. Pronase-retrieval IgG stain on paraffin-embedded tissue was negative. The results indicated a diagnosis of IgA predominant nephropathy. of mesangial proliferation was associated with the higher in a process of podocyte injury that is described in the expression of PDGF in glomeruli of patients with IgAN early stages of FSGS. In the FSGS and ET case described by and FSGS [16]. In studies comparing ET and PDGF levels, Haraguchi et al., higher levels of TGF-β as well as PDGF were mutations of JAK2, CALR, and MPL have been linked to found [14]. increased concentrations of PDGF, with CALR mutations Similarly, PV-associated nephropathies have been leading to three times higher levels than with the other thought to involve fibrogenic cytokines such as PDGF. Addi- mutations. This has been used to offer an explanation as tionally, it has been proposed that with the resultant hyper- to the significantly higher incidence of primary myelofibro- viscosity of PV, chronic increases in blood volume and viscosity can lead to vascular damage to the intima of vessels, sis in patients of ET and CALR mutation [17]. Increased fibrogenicity as a result of ET mutations also with subsequent microthrombi causing renal capillary occlu- stems from transforming growth factor-β (TGF-β). TGF-β sion that ultimately decrease glomerular filtration. This is has also been proposed to have a role in glomerular diseases supported with findings of pronounced hypertension and 4 Case Reports in Oncological Medicine Table 1: Biopsy results of essential thrombocythemia and glomerulonephropathy cases. Time after ET Case Sex Age Renal biopsy findings Renal diagnosis Source diagnosis Mesangial PAS (+) fibrillary deposits without mesangial proliferation or crescent formation Asaba et al. 1 Male 68 Fibrillary glomerulonephritis 30 years (+) IgG on immunohistochemical staining [6] Weakly (+) IgA, IgM, and C3 Diffuse mesangial sclerosis with proliferation 2 Male 25 Segmental capillary thickening immunohistochemical FSGS Unknown Au et al. [7] staining (-) Global & segmental sclerosis 3 Female 39 FSGS Unknown Au et al. [7] Segmental mesangial IgM and C3 deposits Mesangial proliferation Foot process effacement on electron microscopy Usui et al. 4 Female 70 N/A 24 years Mesangial deposits (-) for immunoglobulin or [8] complement Glomerular sclerosis Diffuse mesangial proliferation Myeloproliferative neoplasm- Said et al. 5 Female 74 7 years Features of chronic thrombotic microangiopathy related glomerulopathy [11] Glomerular basement membrane thickening Mesangial proliferation IgM (+) on immunohistochemical staining Fujita and 6 Female 63 N/A 3 years Weakly IgA (+) on immunohistochemical staining Hatta [13] Without mesangial deposits on electron microscopy Mesangial proliferation with crescent formation IgG and IgA (+) on immunohistochemical staining Fujita and 7 Female 76 IgA nephropathy 3 years Dense deposits in the mesangium on electron Hatta [13] microscopy Segmental sclerosis and hyalinosis 0 (same time Haraguchi 8 Male 76 Segmental IgM (+) deposits FSGS diagnoses) et al. [14] Foot process effacement on electron microscopy Glomerular sclerosis Saigusa et al. 9 Male 75 Glomerular basement membrane thickening with FSGS 4 years [15] mesangial proliferation Mesangial hypercellularity Membrane thickening with mesangial proliferation Rahimian 10 Male 59 IgG and IgA (+) on immunohistochemical staining IgA nephropathy 2 months (2019) Foot podocyte effacement and subendothelial on electron microscopy hyperuricemia in patients with PV-related glomerulonephro- In the case described above, JAK2 mutation was present pathy (8 of 23 described cases being IgA nephropathy) [10]. and the glomerular injury had shown mesangial proliferation. In the present case, cytoreductive therapy was not found Glomerular sclerosis was not present, which may depend on the specific mutation of ET and the subsequently induced to be necessary given the lower risk and stable levels of thrombocytosis. Interestingly, the use of anagrelide in ET level of fibrogenesis. The other cases did not all specify which has been found to decrease the levels of PDGF which may ET gene mutation was found. This could be an area of carry an important implication in the treatment of glomeru- improvement as the role of ET and fibrogenesis in glomeru- lonephropathies in patients with ET [18]. In consideration of lonephropathy is further investigated. the importance of PDGF in the shared pathogenesis of these conditions, other cytoreductive therapies such as interferon 4. Conclusion and hydroxyurea would benefit from a study of their effects on plasma PDGF levels. Even so, potential renal impairment As it stands, the rare combination in the present case of ET directly from these agents should be considered if treatment and IgAN will likely proceed with separate management of is initiated. MPN patients who are on cytoreductive therapies the renal disease and the ET. Until a clear understanding of with profound renal impairment, which does not recover the combined pathogenesis is established, platelet numbers with dosage decrease, may benefit from renal biopsies to will dictate only the treatment of ET and not worsening of identify a concurrent glomerulonephropathy. the renal function. Practice-changing management strategies Case Reports in Oncological Medicine 5 [15] T. Saigusa, Y. Kikuchi, M. Yamada et al., “A case of essential can be obtained if clinicians can recognize the concurrence of thrombocytosis developing nephrotic syndrome and severe ET and glomerulonephropathy, and future studies are devel- endothelial damage,” Journal of Nephrology, vol. 19, no. 5, oped to better clarify associations of ET mutations and renal pp. 656–659, 2006. histopathological findings. [16] A. N. Stein-Oakley, J. A. Maguire, J. Dowling, G. Perry, and N. M. Thomson, “Altered expression of fibrogenic growth fac- Conflicts of Interest tors in IgA nephropathy and focal and segmental glomerulo- sclerosis,” Kidney International, vol. 51, no. 1, pp. 195–204, The authors declare that they have no conflicts of interest. [17] G. Gadomska, A. Bartoszewska-Kubiak, J. Boinska et al., References “Selected parameters of angiogenesis and the JAK2, CALR, and MPL mutations in patients with essential thrombocythe- [1] T. Barbui, J. Thiele, H. Gisslinger, G. Finazzi, A. M. Vannucchi, mia,” Clinical and Applied Thrombosis/Hemostasis, vol. 24, and A. Tefferi, “The 2016 revision of WHO classification no. 7, pp. 1056–1060, 2018. of myeloproliferative neoplasms: clinical and molecular [18] P. R. Lev, R. F. Marta, P. Vassallu, and F. C. Molinas, “Varia- advances,” Blood Reviews, vol. 30, no. 6, pp. 453–459, 2016. tion of PDGF, TGF, and bFGF levels in essential thrombo- [2] T. Barbui, J. Thiele, H. 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Published: Sep 2, 2019