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Clinical History

A 70-year-old man with a history of hypertension and primary myelofibrosis manifested as splenomegaly and thrombocythemia presented at routine follow-up with worsening proteinuria. Bone marrow biopsy performed in the past showed extensive marrow fibrosis with leukopenia and large, atypical megakaryocytes, and < 5% blasts. Because of his progressive symptoms, he was initiated on Ruxolitinib and had been on it for the past several years. Low grade proteinuria was noted for multiple years, but most recent spot urine protein to creatine ratio was increased at 8 g/g. Serum albumin was 4 g/dL. His renal function had been stable at 1.2 mg/dL. He had no history of diabetes mellitus. Serologies were negative for ANA, dsDNA ab, and complements were normal. 

 

Kidney Biopsy Findings: 

Sections stained with H&E, PAS, trichrome, and JMS showed 2 cores of renal cortex with a total of 15 glomeruli, 1 of which was globally sclerotic. The glomeruli appear enlarged and were notable for mild to moderate segmental increase in mesangial matrix and cellularity. Focal glomeruli showed segmental double contours and segmental occlusion of capillaries by marginating megakaryocytes. Immunohistochemistry for CD61, a marker of megakaryocytes, was performed, but non-contributory as additional deeper sections did not have megakaryocytes present on those levels to stain. One (1) glomerulus contained a segmental scar with accumulation of hyaline and adhesion of the tuft to Bowman’s capsule. Mild tubular atrophy and interstitial fibrosis affecting approximately 20% of the cortex sampled was seen. There was no significant interstitial inflammation. Vessels displayed mild arteriosclerosis.

Immunofluorescence showed no significant positivity for all immunoglobulins and complement.

Electron microscopy revealed segmental mesangial interposition and duplication of GBMs producing double contours associated with segmental inframembranous electron dense plasmatic insudation/hyaline. Podocytes show near complete foot process effacement with microvillous transformation of podocyte cytoplasm.

Figure 1 (PAS, original magnification x100): Enlarged glomeruli with a segmental sclerotic lesion identified in a glomerulus (orange arrow).

Figure 2 (H&E, original magnification x400): An intracapillary megakaryocyte is noted (orange arrow).

Figure 3 (PAS, original magnification x400): A glomerular capillary shows an infiltrating megakaryocyte (blue arrow). There is segmental mesangial hypercellarity (orange arrow).

Figure 4 (PAS, original magnification x400): Segmental features of chronic thrombotic microangiopathy (orange arrow).

Figure 5: Electron microscopy shows expansion of the mesangial matrix, duplication of the GBMs, and diffuse foot process effacement. 

FINAL DIAGNOSIS

Focal segmental glomerulosclerosis with mesangial sclerosing and mesangial proliferative features, focal GBM duplications and intracapillary megakaryocytes, consistent with myeloproliferative neoplasm-associated glomerulopathy (myelofibrosis-associated/clinical). 

DISCUSSION

Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders comprising of chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U) [1]. Renal involvement by MPN is uncommon and have been described in only a few case reports and small cohort studies [2-6]. PMF accounts for approximately 64% to 73% of cases of MPN-related kidney disease [2 3 6].

The most common renal manifestations are nephrotic-range proteinuria (with or without nephrotic syndrome) and renal insufficiency. On renal biopsy, most cases show extramedullary hematopoiesis predominantly in the form of interstitial infiltration by hematopoietic cells undergoing trilineage hematopoiesis and/or glomerular pathology such as focal segmental glomerulosclerosis (FSGS), mesangial sclerosis and hypercellularity, features of chronic thrombotic microangiopathy (TMA), and intracapillary hematopoietic cells. These constellation of glomerular pathology in the setting of MPN have been named by some authors as MPN-related glomerulopathy. There is usually no significant positivity by immunofluorescence in MPN-related glomerulopathy. Features of mild chronic TMA can be appreciated by electron microscopy as GBM double contours, widening of the subendothelial zone by electron lucent “fluff” and mesangiolysis. Foot process effacement (FPE) range from focal to diffuse (range of 30% to 95% with average of 63% [3]). In a study by Alexander et al [2], about 33% of MPN-associated glomerulopathy with FSGS showed diffuse FPE typical of a primary podocytopathy. Rare fibrillary-like glomerulonephritis (GN) have also been described; though these cases did not show immunostaining typical of fibrillary GN [2].

Possible pathogenesis of MPN-related glomerulopathy may be related to megakaryocyte-derived overproduction of growth factors PDGF and TGF-ß, which can stimulate mesangial cell proliferation and extracellular matrix production by mesangial cells[7 8]. Pro-apoptotic effects of TGF-ß on podocytes is also thought to lead to podocyte depletion and formation of FSGS [9]. The mild chronic TMA may be related to mild chronic endothelial injury secondary to intracapillary platelet aggregation and activation [3].

MPN-related renal involvement typically presents as a late complication of the disease [3]. Despite treatment of the underlying MPN and steroids, renal outcome appears guarded.

               

REFERENCES

1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues: International agency for research on cancer Lyon, 2008.
2. Alexander MP, Nasr SH, Kurtin PJ, et al. Renal extramedullary hematopoiesis: interstitial and glomerular pathology. Modern Pathology 2015;28(12):1574-83
3. Said SM, Leung N, Sethi S, et al. Myeloproliferative neoplasms cause glomerulopathy. Kidney international 2011;80(7):753-59
4. Haraguchi K, Shimura H, Ogata R, et al. Focal segmental glomerulosclerosis associated with essential thrombocythemia. Clinical and experimental nephrology 2006;10(1):74-77
5. Au WY, Chan KW, Lui SL, Lam CC, Kwong YL. Focal segmental glomerulosclerosis and mesangial sclerosis associated with myeloproliferative disorders. American journal of kidney diseases 1999;34(5):889-93
6. Strati P, Glass WF, Abdelrahim M, et al. Renal complications of primary myelofibrosis. Leuk Lymphoma 2019;60(2):507-10 doi: 10.1080/10428194.2018.1474525[published Online First: Epub Date]|.
7. Jiang T, Che Q, Lin Y, Li H, Zhang N. Aldose reductase regulates TGF-beta1-induced production of fibronectin and type IV collagen in cultured rat mesangial cells. Nephrology (Carlton) 2006;11(2):105-12 doi: 10.1111/j.1440-1797.2006.00553.x[published Online First: Epub Date]|.
8. Floege J, Burns MW, Alpers CE, et al. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 1992;41(2):297-309 doi: 10.1038/ki.1992.42[published Online First: Epub Date]|.
9. Schiffer M, Bitzer M, Roberts IS, et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 2001;108(6):807-16 doi: 10.1172/jci12367[published Online First: Epub Date]|.