Renal biopsy cases in myeloproliferative neoplasms (MPN)

We performed renal biopsy in three cases complicated by myeloproliferative neoplasms (MPN). Although several cases of glomerulonephritis associated with MPN have been reported, the etiologies of the renal disorders were not established (Plomley et al., Aust NZ J Med, 13:125–129, 1983; Sharma et al., Nephron, 69:361, 1995; Kanauchi et al., Intern Med, 33:36–40, 1994; Kasuno et al., Nephrol Dial Transplant, 12:212–215, 1997; Au et al., Am J Kid Dis, 34:889–893, 1999; Kosch et al., Nephrol Dial Transplant, 15:1710–1711, 2000; Oymak et al., Nephron, 86:346–347, 2000; Chun et al., Am J Nephrol, 20:344–346, 2000; Chung et al., Am J Nephrol, 22:397–401, 2002; Asaba et al., Clin Exp Nephrol, 7:296–300, 2003; Haraguchi et al., Clin Exp Nephrol, 10:74–77, 2006; Saigusa et al., J Nephrol, 19:656–658, 2006; Okuyama et al., Clin Nephrol, 6:412–415, 2007; Nishi et al., Clin Nephrol, 5:393–398, 2010; Ulusoy et al., Intern Med, 49:2477, 2010). A review of previous reports of renal biopsy cases with MPN in the English literature suggested that circulation control is important for the treatment of renal disorders that mimic glomerulonephritis in MPN.


Introduction
Although several cases of glomerulonephritis with myeloproliferative neoplams (MPN) such as polycythemia vera (PV) or essential thrombocythemia (ET) have been reported, the association between MPN and glomerulonephritis is still obscure. The purpose of this article was to evaluate whether MPN can cause glomerulonephritis.
We describe three MPN cases in which renal biopsies were performed. Paraffin sections from the biopsied specimens of the three cases were examined with hematoxylin and eosin, periodic acid-Schiff, methenamine silver, and Masson's trichrome stains. Immunoglobulins (IgG, IgA, and IgM), complement (C3 and C1q), and fibrinogen were assessed by a direct immunofluorescence staining method on frozen sections for two cases and by immunostaining on paraffin sections for the other case. Electron microscopy was performed for all three cases.
Here, we also review previously reported cases in the English literature of renal glomerular disorders associated with MPN, which were examined by renal biopsy. remarkable heart, lung, or abdominal abnormalities. Pitting edema was demonstrated in her lower extremity.
Renal biopsy was performed (Fig. 1); 13 glomeruli could be evaluated, 2 of which exhibited global sclerosis. Moderate mesangial proliferation with several crescents and arteriolosclerotic changes were observed. Immunohistological staining was positive for IgG and IgA with a granular pattern and negative for IgM, C1q, C3, and fibrinogen. Electron microscopy showed electron-dense deposits in the mesangium. The patient was diagnosed with IgA nephropathy with an active lesion, and treatment consisting of 30 mg prednisolone, 50 mg cyclophosphamide, and 80 mg telmisartan per day was started. Although treatment improved the proteinuria and hematuria, the patient's serum creatinine level remained unchanged. Telmisartan decreased her blood pressure, but her hematocrit level could not be normalized. The patient experienced a complicated acute myocardial infarction 3 years later. She died 5 years later from ischemic bowel disorder and heart failure.

Case 2
A 62-year-old woman was admitted to our hospital because of general fatigue and chest discomfort. She had experienced acute glomerulonephritis 6 years previously, but the details of the clinical course were not known. Proteinuria had been detected while she was pregnant, and she had been treated for hypertension for 15 years. She had been diagnosed with ET at another hospital 3 years earlier. No remarkable cardiac problems were found when she was examined at the Department of Cardiology after admission. She was referred to the Department of General Medicine for a renal biopsy to investigate the persistent proteinuria.
The patient's height, weight, and blood pressure were 148 cm, 55 kg, and 179/107 mmHg, respectively. Her consciousness level was alert and she looked well. A systolic murmur was detected at the 4 left sternal border. She did not have remarkable abnormalities in the lungs and abdomen and did not show pitting edema.

Case 3
A 51-year-old man was admitted to our hospital for renal biopsy. Proteinuria had been detected when the patient was approximately 30 years of age, and he had experienced tonsillitis several times. The patient had been diagnosed with PV with an abnormality of the JAK2 gene 3 years earlier. Renal biopsy was planned because his proteinuria had become more apparent over the past 2 years.
The patient's height, weight, and blood pressure were 165 cm, 66 kg, and 120/73 mmHg, respectively. His consciousness level was alert, and he appeared healthy. No remarkable abnormalities were found in the heart, lungs, or abdomen, and pitting edema was not observed.
Renal biopsy was performed (Fig. 3) and 22 glomeruli could be evaluated, 5 of which showed global sclerosis. Histological findings included mesangial proliferative glomerulonephritis with crescents and focal segmental necrosis. Arteriosclerotic changes were also observed. Immunofluorescence staining was positive and revealed strong immunoreactivity for IgA and C3. Electron microscopy showed electron-dense deposits in the mesangium. He was diagnosed with IgA nephropathy. Tonsillectomy plus steroid pulse therapy and an angiotensin II receptor blocker were selected as treatments for the patient. His proteinuria and hematuria disappeared after 6 months.
The average patient age of these 24 cases (16 men and 8 women) was 55.1 years. PV was found in 17 patients and ET in 7 patients. Of the 24 cases, 5 cases, including 2 of ours, were diagnosed with IgA nephropathy (IgAN) after renal biopsy: focal segmental glomerulosclerosis (FSGS) in 10 cases, membranous glomerulonephritis in 1 case, membranoproliferative glomerulonephritis in 1 case, purpura nephritis in 1 case, and fibrillary glomerulonephritis in 1 case. The other 5 cases were not specified. Hypertension was observed in 20 of 24 cases. Treatments consisted of antihypertensive drugs for 13 patients, phlebotomy for 12 patients, corticosteroid for 8 patients, hydroxycarbamide for 8 patients, and cyclophosphamide for 4 patients. Urinalysis improvement was seen in 13 cases, 9 of which were treated with antihypertensive agents, 7 with phlebotomy, and 6 with corticosteroid. Four cases worsened despite treatment.
Cases of glomerular disease associated with MPN have been reported occasionally. Although Au et al. [5] detected 5 cases of FSGS (3.6 %) among 138 patients with MPN, the frequency of glomerular disorders among MPN patients is unknown. Therefore, reports that various types of glomerular disease are associated with MPN indicate that the pathogenesis of this condition is complex. Au et al. suggested that high platelet counts and abnormal activation of megakaryocytes are predisposing factors for glomerulosclerosis and that aggressive treatment to lower the platelet count can prevent the development of renal abnormalities [5]. On the other hand, antihypertensive agents, such as an angiotensin II receptor blocker (ARB), were selected for treatment because of complication of hypertension. Ulusoy reported the successful treatment of 1 case with antihypertensive drug administration and phlebotomy [15]. A good response after phlebotomy was observed in 2 cases [3,6]. MPN, especially PV and ET, are susceptible to complication by thrombosis or hypertension [17]. Alternation of renal hemodynamics in patients with MPN might cause glomerular endothelial injury. Endothelial cell damage could induce activation of platelets and release of cytokines such as PDGF (platelet-derived growth factor). Floege et al. [18] suggested that PDGF might mediate glomerular injury and cause exacerbation of glomerulonephritis. They clarified that PDGF could induce mesangial and endothelial cell proliferation. Other candidate  cytokines such as insulin-like growth factor-1, plateletactivating factor, transforming growth factor-b, and plasmalemmal vesicle-associated protein-1 had been reported to play a role in the pathogenesis of glomerulonephritis in MPN patients, though a definite role for these factors has not been established [2,4,5,14]. Sharma et al. [2] and Kosch et al. [6] reported that improvement of hematocrit levels might be useful for reducing protein urea and recovering renal function. Controlling renal hemodynamics and blood cell proliferation might be important for improving renal disease in MPN patients. Unfortunately, with regard to our cases, the effectiveness of these treatments could not be clarified.
Regarding the clinical course, glomerulonephritis was thought to have preceded MPN in 2 of our cases (cases 2 and 3). In case 1, a case of IgA nephropathy, the onset of IgA nephropathy did not occur until 2 years after the PV diagnosis. Although the documented onset of MPN preceded renal disease in 9 of the 21 previously reported cases, a period of 10 years or more passed between the onset of MPN and that of renal disease in 3 cases, indicating that an association between MPN and the onset of renal disease is unlikely. In those cases, glomerular diseases were considered to simply overlap with MPN. However, MPN might exacerbate glomerular disease because of the alternation of renal hemodynamics at least in part. Time course from onset of MPD to renal biopsy. In 13 cases, renal biopsies were performed when MPDs were diagnosed almost simultaneously, so spaces are not occupied