| BACKGROUNDHypertension is the second reason of chronic kidney disease(CKD).Malignant hypertension(MHT)is a clinical syndrome of severely elevated blood pressure(?120mmHg)and bilateral retinal hypertensive Keith-Wegner ?-? stage with a high proportion of renal involvement Malignant Hypertensive Nephrosclerosis(MHN).It has relatively poor prognosis.However,the mechanism and correlations between pathologic lesions and prognosis is studied insufficiently and the prognostic factors are controversial.We observed peritubular capillary(PTC)loss in essential MHT patients correlated with renal function,which need further study.The glomerular capillary was under high pressure,which injury was still unknown.The endothelial was under regulation of vascular microenvironment.Pericytes can be recruited to capillaries through platelet-derived growth factor receptor?(PDGFR?),which maintain the endothelial integrity and stability.PDGFR? positive cells compose of pericytes and perivascular fibroblasts,which are able to recognize danger signal and secrete chemokine to recruit monocyte and macrophage.Macrophages polarize to M1 activating inflammation,while to M2 exacerbating fibrosis.The polarization of macrophage in MHN is still unknown.Therefore,this study retrospectively analyzed the clinical and pathological characteristics and prognosis of 100 essential MHT patients confirmed by renal biopsy.The glomerular and peritubular capillary losses,the PDGFR? positive cell as well as macrophage polarization in vascular microenvironment were also evaluated,aiming to provide possible clues for the MHN mechanism and the predictive factors of prognosis.PURPOSE:1.Retrospectively analyze the clinical and pathological characteristics of essential MHT patients,and identify the factors correlated with prognosis preliminarily.2.Evaluate the glomerular capillary and PTC loss and its associations with clinical manifestations and prognosis in essential MHT patients.Analyze the association of capillary and PDGFR? positive cell.3.Observe the patterns and function of renal infiltrated macrophage and circulating monocyte in MHN.METHODS:The clinical records and follow-up data of 100 patients with essential MHN confirmed by renal biopsy in Peking Union Medical College Hospital from January 2003 to December 2016 were reviewed.The primary endpoint is defined as end stage renal disease or death.The pathological features including glomerular sclerosis,tubular atrophy and interstitial fibrosis are evaluated semi-quantitatively,and glomerular density and volume is evaluated through digital pathology.Immunohistochemistry staining of CD34,PDGFR? and TGF?,and co-immunofluorescence of PDGFR(3/CD34 and PDGFR?/CCL2 was performed to evaluated microvascular injury and its correlation to clinic,pathology and prognosis.The immunofluorescence double-staining of D68/CD86,CD68/TLR4,CD68/CD163,CD68/CD206,CD68/TGF was performed to assess polarization and function of macrophage.Flowcytometry was used to evaluate the circulating monocyte subtypes in MHN patients and health control.Continuous variables are displayed as mean ± standard deviation and compared using student's t-test,one-way analysis of variance or Pearson's correlation coefficients.Categorical variables are expressed as percentage and compared with chi-square test.Kaplan-Meier analysis and Cox proportional hazard model were also used.A P-value of<0.05 was considered significant.Statistical analysis was performed with the SPSS software(version 19.0 for Windows).RESULTS:1.The clinic-pathological characteristics and prognosis of essential MHN patientsThe enrolled 100 patients were mostly male(M:F 7.3:1)and relatively young(age 34.7±8.9),with the maximum blood pressure of 225.2±26.4mmHg over 152.0±25.0mmHg.The serum creatinine(Scr)was 465.3±333.9?mol/L,eGFR was 22.13±15.17 ml/min/1.73m2 and the 24h urine protein(24hUpro)was 1.64±1.22g/24h.They presented with anemia(48.5%),hyperuricemia(73.5%),hypertriglyceridemia(67%),and systemic inflammation activation including high ESR(65.2%)and CRP elevation(42.1%).They presented with severe glomerular sclerosis(1.56±0.50),tubular atrophy(62.8±19.1%)and interstitial fibrosis(62.8±19.1%)closely correlated with Scr and 24hUpro.Glomerular Density(GD)is positively correlates with renal function and nonsclerotic is negatively correlates with glomerular sclerosis index.Inflammation factors including ESR,lymphocyte,Complement C3 and IgM are correlated with renal function and tubular atrophy.Multifactor analysis revealed glomerular sclerosis,tubular atrophy,discharge DBP and lymphocyte were independently correlated withi GFR.,meanwhile tubular atrophy was independent correlated with 24hUpro?After adequate anti-hypertension therapy,the blood pressure,renal function and 24hUpro improved significantly(P<0.001).The mean follow-up time of 56.8±37.1 month,and the renal survival rate at 1,3 and 5 year was 93%?80%?66%and 27%respectively.COX regression revealed 24hUpro,eGFR and tubular atrophy as independent risk factor of prognosis.2.The microvascular loss and prognosis in essential MHN patientsThe glomerular capillary and PTC proportion in essential MHN patients was significantly less than that of GML patients and BHN patients,which correlated with Scr,hemoglobin,24hUpro,glomerular sclerosis index,tubular atrophy proportion and interstitial proportion.Cox proportional hazard model identified PTC loss(RR=0.236,95%CI(0.08,0.74),P=0.013)and glomerular capillary loss(RR=0.275,95%CI(0.08,0.91),P=0,034).as independent risk factor for renal outcomeGlomerular PDGFR? positive cell detachment with capillary was observed in essential MHN patients.Glomerular PDGFR? expression is lower than BHN and GML control,while tubular interstitial PDGFR? is elevated in MHN compared with BHN and GML control.3.Macrophage polarity and function in the vascular microenvironment MHN patientsThe PDGFR? and CCL2 co-positive cell was detected.M2a macrophage(CD206/CD68)was mainly macrophage subtype in renal and circulating monocyte.Flowcytometry revealed M2 proportion was higher in classic monocyte(75.14±3.66%,39.26±6.50%,P=0.002)and intermediate monocyte(80.84±5.72%,31.51±7.89%,P=0.003).The co-localization of CD68 and TGF?1 revealed that macrophage was able to secrete TGF?1.CONCLUSION:1.The essential MHN patients presented with severe renal involvement together with metabolic disorder and inflammation activating.Multifactor analysis revealed glomerular sclerosis,tubular atrophy,discharge DBP and lymphocyte were independently correlated withi GFR.24hUpro,eGFR and tubular atrophy as independent risk factor of prognosis.2.Glomerular capillary and PTC loss in essential MHN patients correlated with renal funtction well and might predict the long time renal outcome independently.Glomerular PDGFR? expression is lower,while tubular interstitial PDGFR? is elevated in MHN compared with BHN and GML control.PDGFR? positive cell detachment with capillary was observed in essential MHN patients.3.The PDGFR? positive cell could secrete CCL2 to recruit M2 macrophage,which proportion in MHN was higher than classic monocyte and intermediate monocyte compared with control.Macrophage was able to secrete TGF?1. |
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