Risk factors for progressive kidney impairment among patients with polycythemia vera (PV) are recapitulated and treatable in mouse models of PV

Abstract

Abstract Background: PV is characterized by clonal hematopoiesis, thrombotic events, and potential progression to myelofibrosis (MF). The prevalence of impaired kidney function is higher in European patients with PV vs the general population (Gecht J. Cancers (Basel). 2021), but this has not been explored in US patients. We report a post hoc analysis of real-world data on kidney impairment and potential associations with disease progression from the large Prospective Observational Study of patients with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159). We also evaluated kidney impairment and treatment response in JAK2V617F-driven mouse models. Methods: Data from patients enrolled in REVEAL with baseline measurements and ≥2 optional measurements at Years 1, 2, 3, or 4 for both serum creatinine and JAK2V617F status (by ddPCR) were analyzed. Patients were assessed in 2 subgroups, those with or without rapid loss of estimated glomerular filtration rate (eGFR, defined as >3 mL/min/1.7 m2/year) from baseline during the study period, calculated by the CKD-EPI equation. PV progression was defined as meeting any of the following on study: 1) death from MF/myelodysplastic syndrome/acute myeloid leukemia; 2) new/worsening splenomegaly plus 2 of the following: white blood cell count >11×109/L, platelets <100×109/L, hemoglobin <100 g/L; 3) evidence of progression to MF by bone marrow (BM) biopsy; 4) new/worsening splenomegaly plus >1% blasts. GFR was measured transcutaneously in 14-week-old vavCre-driven JAK2V617F+ transgenic mice and in wild-type littermate controls. In a second model, competitive hematopoietic stem cell transplantation was performed in 8-week-old C57BL/6 mice who received a 1:1 mix of SCL-Cre-driven JAK2V617F+ transgenic and wild-type cells. After engraftment, interferon (IFN) α or vehicle was administered for 8 weeks intraperitoneally, and kidneys of all mice were collected for histology. Mesangial expansion and tubular dilation were scored by a blinded nephropathologist. Results: Of 2510patients enrolled in REVEAL, 505 (20.1%) had abnormal eGFR (<90) and data from 624 were analyzed (eGFR decline: >3, 153 [24.5%]; ≤3, 471 [75.5%]). Characteristics at enrollment were similar between cohorts, eg, median duration from PV diagnosis to enrollment 4.8 vs 4.1 years; no prior PV treatment 92.2% vs 89.4%. Baseline blood cell counts were similar, as was median JAK2V617F variant allele frequency. Significantly more patients with rapid eGFR decline had history of thromboembolism (TE; 30.7% vs 20.0%, P=0.0057) and had high-risk PV (age ≥60 years and/or history of TE, 87.6% vs 79.8%, P=0.0311; age ≥60 years and history of TE, 22.9% vs 15.1%, P=0.0256), but incidence was similar among patients with single risk factors. Baseline median eGFR (84.7 vs 76.7, P=0.0012) and LDH (252.5 vs 209.0 U/L, P=0.0007) were significantly higher for the rapid eGFR decline subgroup. The percentage of patients with PV progression on study was significantly higher in the rapid eGFR decline subgroup (14.4% vs 5.9%, P=0.0008), primarily reflecting an increased rate of BM progression of MF (8.5% vs 2.8%, P=0.002). In PV mouse models, mean±SD GFR was mildly but significantly reduced in JAK2V617F transgenic mice (n=7) vs littermate controls (n=3) (235.8±12.8 vs 261.1±4.5 mL/min, P=0.0006). Mesangial expansion was prominent in glomeruli of 1-year-old JAK2V617Ftransgenic mice compared with controls (2.8±0.5 vs 1.5±0.8, P=0.0417) and also evident in younger (24 weeks) JAK2V617F BM chimeras (1.3±0.2 vs 2.0±0.2, P=0.0137). Tubular dilation was prominent in JAK2V617FBM chimeras compared with controls (1.6±0.3 vs 0.7±0.4, P=0.0306) and reduced following 8 weeks of IFNα therapy (0.5±0.2, P=0.0085).Conclusions: This real-world analysis of data from REVEAL is the largest prospective evaluation of kidney impairment in patients with PV, uncovering associations of rapid eGFR decline with novel early markers (history of TE, high-risk PV, and elevated LDH), as well as progression to MF. Further studies are warranted to determine the impact of rapid eGFR decline on PV outcomes and if PV-directed therapy may confer renal protection. Mouse models replicated effects of JAK2V617F-driven PV on renal dysfunction in humans and provided insights into the mechanism of kidney impairment, as observed by notable mesangial expansion and tubular dilation, with evidence of protection seen with IFNα treatment.