[Protective effect of ginsenoside Rg_1 aganist diabetic retinopathy by inhibiting NLRP3 inflammasome in type 2 diabetic mice].

Ginsenoside Rg_1, one of the main active components of precious traditional Chinese medicine Ginseng Radix et Rhizoma, has the anti-oxidative stress, anti-inflammation, anti-aging, neuroprotection, and other pharmacological effects. Diabetic retinopathy(DR), the most common complication of diabetes, is also the main cause of impaired vision and blindness in the middle-aged and the elderly. The latest research shows that ginsenoside Rg_1 can protect patients against DR, but the protection and the mechanism are rarely studied. This study mainly explored the protective effect of ginsenoside Rg_1 against DR in type 2 diabetic mice and the mechanism. High fat diet(HFD) and streptozotocin(STZ) were used to induce type 2 diabetes in mice, and hematoxylin-eosin(HE) staining was employed to observe pathological changes in the retina of mice. The immunohistochemistry was applied to study the localization and expression of nucleotide-binding oligomerization domain-like receptors 3(NLRP3) and vascular endothelial growth factor(VEGF) in retina, and Western blot was used to detect the expression of nuclear factor-kappa B(NF-κB), p-NF-κB, NLRP3, caspase-1, interleukin-1ß(IL-1ß), transient receptor potential channel protein 6(TRPC6), nuclear factor of activated T-cell 2(NFAT2), and VEGF in retina. The results showed that ginsenoside Rg_1 significantly alleviated the pathological injury of retina in type 2 diabetic mice. Immunohistochemistry results demonstrated that ginsenoside Rg_1 significantly decreased the expression of NLRP3 and VEGF in retinal ganglion cells, middle plexiform layer, and outer plexiform layer in type 2 diabetic mice. According to the Western blot results, ginsenoside Rg_1 significantly lowered the expression of p-NF-κB, NLRP3, caspase-1, IL-1ß, TRPC6, NFAT2, and VEGF in retina of type 2 diabetic mice. These findings suggest that ginsenoside Rg_1 can significantly alleviate DR in type 2 diabetic mice, which may be related to inhibition of NLRP3 inflammasome and VEGF. This study provides experimental evidence for the clinical application of ginsenoside Rg_1 in the treatment of DR.

Clinicopathological study of mixed cryoglobulinemic glomerulonephritis secondary to hepatitis B virus infection.

BACKGROUND: Cryoglobulinemic glomerulonephritis (CryoGn) caused by hepatitis B virus (HBV) infection was rarely reported. Our study aimed to investigate the clinical features, renal pathology findings, and prognosis in patients with HBV related CryoGn. METHODS: This was a retrospective study including seven Chinese patients with HBV related CryoGn in a tertiary referral hospital from April 2016 to March 2019. The clinical and pathological data were collected and analyzed. RESULTS: Age at renal biopsy was 47 ± 12 years, with female/male ratio 3/4. Urine protein was 5.6 (3.0, 6.6) g/d and five cases presented with nephrotic syndrome. The baseline eGFR was 23.5 (20.2, 46.3) ml/min per 1.73m2. The extrarenal manifestations included purpura (n = 6), arthralgia (n = 1), peripheral neuropathy (n = 1), and cardiomyopathy (n = 1). Six cases had type II cryoglobulinemia with IgMκ, the other one had type III. The median cryocrit was 4.0 (1.0, 15.0) %. Renal pathologic findings on light microscopy: endocapillary proliferative glomerulonephritis (Gn) (n = 3), membranoproliferative Gn (n = 3), and mesangial proliferative Gn (n = 1). On immunofluorescence microscopy, the predominant type of immunoglobulin deposits was IgM (n = 5). HBsAg and HBcAg deposits were found in one case. Ultrastructural studies showed granular subendothelial and mesangial electron-dense deposits in all patients and microtubules in one case. All patients received antiviral medications. They were given corticosteroid alone (n = 2) or combined with cyclophosphamide (n = 4) or mycophenolate mofetil (n = 1). Two patients received plasmapheresis. The median follow-up time was 18 (6, 37) months. Four patients got remission, two patients died of pneumonia, and one progressed to end-stage renal disease (ESRD). At endpoint of follow-up, 24hUP was 2.1 (0.8-5.2) g/d, and eGFR was 55.3 (20.7, 111.8) ml/min per 1.73m2. The median cryocrit decreased to 1.0 (0, 5.75) %. CONCLUSIONS: The etiology of mixed CryoGn should be screened for HBV infection. Endocapillary proliferative Gn and membranoproliferative Gn were the common pathologic patterns. Diagnosis and treatment in early stage benefit patients' renal outcomes. Immunosuppressive therapy should be considered for severe renal disease, based on efficient antiviral therapy.

Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy.

OBJECTIVE: Renal thrombotic microangiopathy (TMA) is an uncommon pathological finding in lupus nephritis (LN), and its clinical significance remains to be defined. METHODS: Twenty-four patients with lupus nephritis (LN) and renal TMA were selected from a retrospective review of 677 biopsy-proven LN patients, and compared with 48 LN controls without TMA (1:2 ratio) matched according to demographics and treatments. RESULTS: Renal TMA was noted in 3.5% of kidney biopsies of LN. TMA was associated with a higher prevalence of anti-Ro (45.8% vs 18.8%; p = 0.016), higher Systemic Lupus Erythematosus Disease Activity Index scores (21.4 ± 8.5 vs 10.8 ± 2.3; p < 0.001), lower estimated glomerular filtration rate (eGFR; 16.8 ± 11.7 ml/min vs 77.8 ± 28.6 ml/min; p < 0.001), and a higher percentage of patients who required dialysis (37.5% vs 2.1%; p < 0.001) at the time of kidney biopsy. Activity and chronicity indices [median (range)] were higher in the TMA group [11 (2-19) and 3 (1-8), respectively, compared with 7 (0-15) and 1 (0-3) in controls; p = 0.004 and p < 0.001; respectively]. Patients with TMA showed inferior 5-year renal survival and higher incidence of chronic kidney disease at last followup (70% and 66.6%, respectively, compared with 95% and 29.2% in controls; p = 0.023 and 0.002, respectively). The TMA group also showed lower median eGFR compared with controls [50.1 (IQR 7-132) ml/min vs 85.0 (IQR 12-147) ml/min; p = 0.003]. Five-year patient survival rate was similar between the 2 groups (87% and 98% in TMA and control group, respectively; p = 0.127). CONCLUSION: TMA in kidney biopsy was associated with more severe clinical and histological activity, and significantly inferior longterm renal outcome in LN.

A Cohort Study of Incidences and Risk Factors for Thromboembolic Events in Patients with Idiopathic Membranous Nephropathy.

Objective The aims of this study were to assess incidences and characteristics of arterial thromboembolic events (ATEs) and venous thromboembolic events (VTEs) in Chinese patients with idiopathic membranous nephropathy (IMN), and to identify the predisposing risk factors of them.Methods A total of 766 consecutive Chinese patients with IMN were enrolled in this retrospective cohort study. The cumulative incidences of newly diagnosed ATEs and VTEs were calculated using Kaplan-Meier methods. Univariable risk prediction model analysis followed by multivariable survival analysis was used to evaluate the potential risk factors of ATE and VTE.Results At 0.5, 1, 2, 3, and 5 years after biopsy diagnosis of IMN, the cumulative incidence of newly diagnosed ATEs were 4.3%, 5.7%, 6.3%, 7.1%, and 8.0%, and of newly diagnosed VTEs were 5.9%, 6.8%, 6.9%, 7.0%, and 7.2%, respectively. In 78 ATEs events (71 patients), cardiovascular diseases, thrombotic ischemic stroke (IS) and peripheral artery disease accounted for 50%, 45% and 5% respectively; in 60 VTEs events(53 patients), the deep vein thrombosis, renal vein thrombosis and pulmonary embolism accounted for 60%, 13% and 27% respectively. At the time of event, 42.1% patients with ATEs and 81.5% patients with VTEs were at nephrotic syndrome(NS) status (χ 2=18.1, P<0.001). Severe proteinuria, aging, smoking, hypertension and prior ATE history were associated with ATEs. Aging was demonstrated as the independent risk factor for ATEs (P=0.001), and hypoalbuminemia was the dominant independent risk factor for VTEs (P=0.03). Conclusions Patients with IMN have increased incidences of ATEs and VTEs, and most of events occurred within the first 6 months of the disease. IS was very common in ATEs in our cohort. Severe proteinuria and classic risk factors for atherosclerosis were associated with onset of ATEs. Hypoalbuminemia independently predicted VTEs. Risks of both ATEs and VTEs were particularly high in the status of NS, particularly VTEs.

Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis.

Objective To investigate the efficacy and safety of rituximab (RTX) in the treatment of idiopathic membranous nephropathy (IMN) with nephrotic syndrome with a systematic review and meta-analysis. Methods PubMed, Embase, Cochrane Library and Clinical Trials (December 2016) were searched to identify researches investigating the treatment of RTX in adult patients with biopsy-proven IMN. Complete remission (CR) or partial remission was regarded as effective therapy, and the cumulated remission rate was calculated. Result Seven studies involved 120 patients (73% were men) were included in our systematic review and meta-analysis. All were prospective observation cohort studies or matched-cohort studies, mainly came from two medical centers, and one study was multi-centric (four nephrology units in northern Italy). The creatinine clearance was more than 20 ml/(min·1.73 m2) and persistent proteinuria higher than 3.5 g/d for at least 6 months. All patients received treatment previously [44 (36.7%) had immunosuppressive treatment]. In 12- and 24-month, 56% (95%CI, 0.47-0.65) and 68% (95%CI, 0.41-0.87) patients could reach remission, while 15% (95%CI, 0.09-0.23) and 20% (95%CI, 0.12-0.32) patients could reach CR. The reduction in proteinuria was gradual and obvious, paralleled with upward trend of serum albumin level and decreasing serum cholesterol level. Renal functions were stable. Relapses happened in 24 months were around 8%. RTX related adverse events were mild and were mostly infusion-related reactions. Conclusions RTX treatment in IMN was efficient, well tolerated and safe. More than 60% patients can reach partial remission or CR in 24 months, and relapse is rare. Adverse events of RTX are mostly infusion-related reactions and generally mild.

Renal involvement in primary Sjögren's syndrome: A retrospective study of 103 biopsy-proven cases from a single center in China.

AIM: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results. METHODS: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed. RESULTS: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05). CONCLUSION: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis.

Clinicopathological Features of Idiopathic Membranous Nephropathy in 33 Adolescents.

Objective To investigate the clinicopathological features and prognosis of idiopathic membranous nephropathy(IMN)in adolescents. Methods This was a retrospective study on IMN patients hospitalized between June 2012 and December 2014,and a total of 33 IMN patients aged between 13 and 24 years old were enrolled in the study.Meanwhile,33 IMN patients aged more than 24 years old were selected randomly as control group during the same period.Diagnosis was confirmed by renal biopsy,and the secondary causes of membranous nephropathy were ruled out.Data collected from medical record and biopsy were analyzed. Results In the adolescent IMN group,the mean age at renal biopsy was(20±3)years old,and the male/female ratio was 22/11.Twenty-three cases presented as nephrotic syndrome.Systolic and diastolic pressures were(127±13)mmHg and(77±9)mmHg,respectively.The median 24-hour urine protein was 5.14(3.39,9.31)g/d,and the median serum creatinine was 62(52,73)µmol/L.The positive rate of serum anti-phospholipase A2 receptor in adolescent group was 54%.Compared with control group,the adolescent patients had lower incidence of hypertension and higher baseline estimated glomerular filtration rate level [15.2% vs.39.3%,χ2=4.889,P=0.03;125 ml/(min·1.73m2)vs.100 ml/(min·1.73m2),U=137.5,P<0.001].According to IMN staging criteria in electron microscopy,adolescent patients were classified as one case in stage I,21 in stage Ⅱ,and 11 in stage Ⅲ or higher.The positive rates of IgG1,IgG2,IgG3 and IgG4 subclass staining in glomeruli were 46.9%,3.1%,56.3%,and 87.5%,respectively.Compared with control group,the adolescent patients had lower incidence of renal interstitial fibrosis and arteriolar lesions(6.1% vs.66.7%,χ2=26.19,P<0.001;15.2% vs.66.7%,χ2=18.11,P<0.001).Three patients lost to follow-up while others started steroid combined with cyclosporine A(n=20),cyclophosphamide(n=7),or mycophenolate(n=1)or solely(n=2).After a median follow-up of 18(12,24)months,the median proteinuria decreased to 0.20(0.10,0.42)g/d,whereas serum creatinine level remained stable [69(56.8,81.3)µmol/L].Seventeen patients(56.7%)achieved complete remission(CR),and the remaining 13 patients(43.4%)achieved partial remission(PR).The median time of CR and PR were three and six months,respectively.Only one patient relapsed during the follow-up.Also,21 cases received maintenance therapy including cyclosporine A(n=18),azathioprine(n=2)and mycophenolate(n=1).Conclusions The immunofluorescence IgG subclass in glomeruli and distribution of serum anti-phospholipase A2 receptor in adolescent IMN patients are similar to those in older IMN patients.IMN patients in adolescents responded well to immunosuppressive therapy.Cyclosporine A in low dose as maintenance therapy is effective after achieving remission,and will not increase risk of nephrotoxicity.

The Neglected Significance of Glomerular Density as a 5-year Progression Indicator for IgA Nephropathy△.

Objective To investigate whether glomerular density (GD) could be an independent prognostic factor for patients of IgA nephropathy with estimated glomerular filtration rate (eGFR) of 30 to 60 ml/min per 1.73 m2, or for patients with time-average proteinuria < 0.5 g/d. Methods A total of 173 patients with biopsy-confirmed IgA nephropathy diagnosed from January 2000 to December 2010 were included. All of these patients were followed up for more than 5 years. The endpoint was a > 30% of decline in eGFR from baseline after 5-year follow-up. The optimal cut-off value of GD was calculated by ROC curve. Kaplan-Meier method and Cox regression analysis was used for survival analysis. Results A 30% of decline in eGFR occurred in 14.5% of all patients. The optimal diagnostic cut-off value of GD was 1.99/mm2 (AUC = 0.90, sensitivity = 84.0%, specificity = 81.8%) determined by ROC curve. The low GD group (GD < 1.99 per mm2) experienced a significant increase in renal endpoint for patients with eGFR of 30 to 60 ml/min per 1.73 m2 (six patients in lower GD group, while one patient in the other group). For patients with time-average proteinuria < 0.5 g/d, the lower GD group showed a higher eGFR decline from baseline (4.5±16.7 ml/min per 1.73 m2 vs. -8.1±21.4 ml/min per 1.73 m2, P = 0.038); two patients in this group reached the endpoint, while no patients in the higher GD group did. Conclusion GD could be an independent prognostic factor for patients of IgA nephropathy with eGFR at 30 to 60 ml/min per 1.73 m2 of body surface, particularly for those with time-averaged amount of urine protein less than 0.5 g per day.

Clinical features of 30 patients with cryoglobulinemia.

OBJECTIVE: To summarize the clinical features of cryoglobulinemia. METHOD: We retrospectively analyzed the clinical data of 30 patients admitted to Peking Union Medical College Hospital from January 2003 to March 2013 due to cryoglobulinemia. RESULTS: The average age was(53.8±11.9)years in these 30 patients(12 men and 18 women),among whom 22 patient(73.3%)developed infectious diseases including hepatitis B(n=11)and hepatitis C(n=11);in addition,3 hepatitis B patients and 1 hepatitis C patient also had malignancies. Four patients(13.3%)were accompanied with malignant lymphocytic proliferation diseases,and three(10.0%)with connective tissue diseases. The cause of disease was unclear in 5 patients(16.7%). The clinical manifestations varied due to the primary diseases;notably,20 patients(66.7%)had an onset of purpura rash,22(73.3%)and 19(63.3%)were accompanied with hypertension and chronic renal insufficiency,respectively. The severity of renal involvement was relevant with the increase of C reactive protein,erythrocytes,sedimentation rate,and IgM and the decrease of complements. Treatment should be directed at the primary diseases. Glucocorticoid and immunosuppressants were good choices for relieving renal involvement. Elderly, type 1 cryoglobulinemia,and poor renal function were associated with the poor prognosis. CONCLUSIONS: Cryoglobulinemia is mainly seen in middle and elderly patients. It can often affect multiple systems,in particular the kidney. Inflammatory markers,IgM,and complements is related with the disease severity. Age,primary disease,and renal function are related with prognosis.

Correlations of podocyte injury with glucose regulated protein 78 expression and proteinuria in patients with diabetic nephropathy.

OBJECTIVE: To explore the podocyte injury in patients with diabetic nephropathy (DN) and analyze its relationship with glucose regulated protein 78 (GRP78) and proteinuria. METHODS: The clinical data of 48 patients diagnosed as DN by renal biopsy were reviewed. All patients were divided into two groups according to proteinuria (>3.5 g/d, n=31 and 3.5 g/d, n=17). The density of podocytes was illustrated by immunohistochemistry staining of Wilms tumor-1 (WT-1), and the immunofluorescence double-staining results of synaptopodin and GRP78 in podocytes were detected. RESULTS: The podocyte dentistry of urine protein > 3.5 g/d group was significantly lower than that of urine protein>3.5 g/d group urine protein<3.5 g/d group(P=0.003), and it was negatively correlated with proteinuria (P=0.005). The expressions of synaptopodin and GRP78 in podocytes were also negatively correlated with proteinuria (P=0.004 and P=0.001). CONCLUSION: The podocyte injury is aggravated with increased proteinuria in DN patients, along with the decrease of the adaptive ability of endoplasmic reticulum to stress.

Pilot 24 month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome.

AIM: This pilot study compared mycophenolate mofetil (MMF) and tacrolimus (Tac) in the treatment of severe membranous lupus nephritis (MLN). METHOD: This was a 24 month prospective, randomized, open-label multi-centre exploratory study on Chinese patients with biopsy-proven pure Class V MLN with nephrotic syndrome. Patients were randomized to treatment with either MMF or Tac, both in combination with prednisolone and the efficacy and tolerability outcomes were examined. RESULTS: Sixteen patients were included, seven in the MMF and nine in the Tac treatment arm. At 24 months the complete response, partial response and overall response rates were 57.1% vs. 11.1% (P = 0.049), 14.3% vs. 44.4% (P = 0.197) and 71.4% vs. 55.6% (P = 0.515) in the MMF and Tac groups, respectively. The two groups had similar reduction of proteinuria and longitudinal profiles of serum albumin and creatinine levels. Serum creatinine remained stable in both groups, except in two patients who had a transient increase associated with high Tac blood levels. Adverse events in the MMF group included herpes zoster in one patient and reversible leucopenia in another, while in the Tac group four patients had severe infections and one developed new onset diabetes. No relapse occurred during the study period. CONCLUSION: Both MMF and Tac when combined with corticosteroids are effective treatment options for severe MLN.

Th17/Treg imbalance in adult patients with minimal change nephrotic syndrome.

To determine whether Th17/Treg balance was abnormal in adult patients with minimal change nephrotic syndrome (MCNS), we studied 25 patients with new-onset MCNS and 20 normal persons. The results showed that MCNS patients exhibited a significant increase in Th17 number, Th17-related cytokines (IL-17 and IL-23), and transcription factor (RORγt) levels, as well as an obvious decrease in Treg number, Treg-related cytokines (TGF-ß1 and IL-10), and transcription factor (Foxp3) levels. The Th17/Treg ratios increased along with increased proteinuria and decreased albumin levels in patients with MCNS. IL-17 protein expression was also detected in the renal biopsy tissue of MCNS patients, particularly in patients with acute renal failure. Further, Th17/Treg balance returned to normal after effective corticosteroids therapy in 16 MCNS patients. These results indicated that Th17/Treg imbalance existed in MCNS patients, suggesting a potential role of Th17/Treg imbalance in the pathogenesis of MCNS.

Cyclosporine treatment in idiopathic membranous nephropathy nephrotic syndrome in adults: a retrospective study spanning 15 years.

BACKGROUND: Cyclosporine is effective in treating nephrotic syndrome (NS) with idiopathic membranous nephropathy (IMN) in adults. But high relapse rate remains a major concern. The way to manipulate cyclosporine is inconclusive. The aim of this study was to introduce the way how to titrate the cyclosporine to maintain complete remission without relapse. METHODS: Patients with biopsy-proven IMN with NS treated with cyclosporine for at least 1 month from 1996 to 2011 at Peking Union Medical College Hospital were reviewed. RESULTS: Mean age of the 51 eligible patients was 52 years, with 39 men. Mean proteinuria was (7.47 ± 3.14) g/d, serum albumin (24.50 ± 6.29) g/L, and serum creatinine (82.62 ± 21.18) mmol/L. Cyclosporine was commenced at a mean dose of (3.46 ± 0.63) mg×kg(-1)×d(-1). Oral prednisone (0.40 ± 0.29) mg×kg(-1)×d(-1) was given concomitantly in 38 patients. Cyclosporine was administered for a median of 16 months (range 1 - 93 months) and stopped in non-responders by month six. By month 3 (n = 47), the number in complete remission (CR) and partial remission (PR) was 3 and 24, which shifted to 12 and 17 by month 6 (n = 41). Male gender, heavy proteinuria, low serum albumin level, and high serum creatinine level were significant determinants in poor response by month six (P < 0.05 in all variables compared with responders). There was a significant reversible serum creatinine increase within 25% during month 3 to 12 (P < 0.05 in all variables compared with baseline value). Eleven patients maintained cyclosporine for more than 24 months with a cyclosporine dose of (1.04 ± 1.06) mg×kg(-1)×d(-1). Nine patients were in CR. Renal function, systolic and diastolic blood pressure remained stable. Renal impairment (> 30% rise of serum creatinine), secondary infection, hypertension, gingival hyperplasia and liver impairment occurred in 6, 4, 10, 4, and 1 patients, respectively. CONCLUSIONS: The observation time for cyclosporine to effectively induce CR of NS in IMN adults should be at least six months. Long-term and low-dose of cyclosporine therapy is safe and effective to maintain CR in those responders.

Diagnosis and treatment of infective endocarditis in chronic hemodialysis patients.

OBJECTIVE: To analyze the clinical features of hemodialysis patients complicated by infective endo carditis. METHODS: The clinical features of six such patients admitted to Peking Union Medical College Hospital during the year 1990 to 2009 were analyzed. All of them were diagnosed based on Chinese Children Diagnostic Criteria for Infective Endocarditis. RESULTS: The average age of the six patients was 52.3 +/- 19.3 years old. Four were males. Vascular accesses at the onset of infective endocarditis were as follows: permanent catheters in three, temporary catheters in two, and arteriovenous fistula in one. Three were found with mitral valve involvement, two with aortic valve involvement, and one with both. Five vegetations were found by transthoracic echocardiography, and one by transesophageal echocardiography. Four had positive blood culture results. The catheters were all removed. Four of the patients were improved by antibiotics treatment, in which two were still on hemodialysis in the following 14-24 months and the other two were lost to follow-up. One patient received surgery, but died of heart failure after further hemodialysis for three months. One was well on maintenance hemodialysis for three months after surgery. CONCLUSIONS: Infective endocarditis should be suspected when hemodialysis patients suffer from long-term fever, for which prompt blood culture and transthoracic echocardiography confirmation could be performed. Transesophageal echocardiography could be considered even when transthoracic echocardiography produces negative findings. With catheters removed, full course of appropriate sensitive antibiotics and surgery if indicated could improve the outcome of chronic hemodialysis patients complicated by infective endocarditis.

Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: a multicenter randomized controlled trial.

BACKGROUND: Idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults, is usually treated with corticosteroids in combination with cyclophosphamide or cyclosporine. A recent placebo-controlled study suggested that tacrolimus monotherapy was effective in IMN. However, the effectiveness of tacrolimus versus classic regimen and its potential nephrotoxicity remain inconclusive. This study evaluated the efficacy and safety of tacrolimus plus prednisone in patients with nephrotic IMN. METHODS: Seventy-three patients with nephrotic IMN were recruited in this multicenter randomized controlled trial, 39 receiving tacrolimus and prednisone, while 34 receiving cyclophosphamide and prednisone. Tacrolimus was given at 0.1 mg/kg/d initially and adjusted to a blood trough level at 5 to 10 ng/mL for 6 months and then reduced to 2 to 5 ng/mL in the subsequent 3 months. RESULTS: Intention-to-treat analysis suggested that the remission rate at the end of the sixth month was significantly higher in tacrolimus group than that in cyclophosphamide group (85% versus 65%, P < 0.05). The decrease of proteinuria was significantly greater in tacrolimus group. At the end of the 12th month, the remission rates were comparable between these 2 groups. Patients treated with tacrolimus were more likely to develop glucose intolerance (or diabetes mellitus), infection, and hypertension. No obvious nephrotoxicity of calcineurin inhibitor was found in repeat renal biopsy. CONCLUSIONS: Tacrolimus plus corticosteroids is an alternative therapeutic regimen for nephrotic IMN. The short-term efficacy might be better than cyclophosphamide plus prednisone.

Differential effect of three mitogen-activated protein kinases on lipoprotein (a)-induced human mesangial cell proliferation.

BACKGROUND: Mesangial hypercellularity is a critical early histopathological finding in human and experimental glomerular diseases. Hyperlipidemia and the glomerular deposition of lipoproteins are commonly associated with mesangial hypercellularity and play an important pathobiological role in the development of glomerular diseases. The activated cytoplasmic mitogen-activated protein kinase (MAPK), including mainly extracellular-signal regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38, has been thought to translocate into the nucleus and activate various transcription factors and protooncogenes associated with cell growth and proliferation. Lipoprotein (a) (Lp(a)) has been shown to stimulate proliferation of mesangial cells, but the events of Lp(a) signaling have not yet been characterized. The purpose of this study was to investigate the signal transduction pathways involved in Lp(a)-induced cell proliferation and provide an evidence for the participation of Lp(a) in intracellular signaling pathways for mesangial cell proliferation. METHODS: Lp(a) was isolated from a patient who was being treated with low density lipoprotein (LDL)-apheresis by density gradient ultracentrifugation and then chromatography. Human mesangial cells (HMCs) were isolated by the sequential sieving technique and stimulated with Lp(a) in different concentration and time course. The DNA synthesis of the cells was measured by [3H] thymidine incorporation for detecting the proliferation. The expression of all the three members of MAPK family, including ERK1/ERK2, JNK, and p38, and their phosphorylation were detected by Western blotting. RESULTS: Lp(a) could induce a significant dose-dependent proliferation of HMCs. The 3H-TdR incorporation was 1.64+/-0.31, 1.69+/-0.48, 3.59+/-0.68 (P<0.01), 4.14+/-0.78 (P<0.01), and 4.05+/-0.55 (P<0.01) (10(3) cpm) at the Lp(a) concentration of 0, 5, 10, 25, and 50 microg/ml, respectively. Lp(a) induced an increase in ERK1/ERK2 phosphorylation between 5 and 60 minutes, and in JNK phosphorylation between 15 and 30 minutes after incubating with HMCs, whereas the level of p38 and its phosphorylation was not changed. CONCLUSIONS: Lp(a) could stimulate the proliferation of HMCs by activiating the phosphorylation of ERK1/ERK2 and JNK MAPK signaling pathway, whereas p38 pathway had no effect on the Lp(a)-induced HMC proliferation, which indicated that three MAPKs seem to be distinctly involved in the effect. In particular, it also provides the evidence that Lp(a) may act as one of the major endogenous modulators for mitogenic signaling response and cell proliferation within the glomerulus.

Endoplasmic reticulum stress is involved in acetylated low-density lipoprotein induced apoptosis in THP-1 differentiated macrophages.

BACKGROUND: Cardiovascular disease is a major cause of mortality and morbidity in patients with chronic kidney disease. Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. In vitro data from peritoneal macrophages show apoptosis triggered through endoplasmic reticulum (ER) stress caused by free cholesterol accumulation plays an important role. Here we used THP-1 cells differentiated by 100 ng/ml of phorbol 12-myristate 13-acetate (PMA) for five days as an in vitro model, to investigate if acetylated low-density lipoprotein (AcLDL) loading could also induce apoptosis and its underlying mechanisms. METHODS: Oil red O staining was used to examine the lipid droplets. Confocal microscopy was used to visualize the uptake of AcLDL. Hoechst 33258 stain and the caspase 3,7 assay were used to detect apoptosis. High performance liquid chromatography was used in the intracellular free cholesterol (FC) and cholesterol ester (CE) assay. Western blotting was used to demonstrate the protein level. Real-time PCR was used to detect the changes of mRNAs. ER free cholesterol was also assayed. RESULTS: Confocal microscopy showed THP-1 cells differentiated by 100 ng/ml of PMA for five days uptake more AcLDL than differentiated for two days. Hoechst 33258 stain showed AcLDL could induce apoptosis in THP-1 macrophages in a time and dose dependent manner. Exposure of THP-1 macrophages to 100 microg/ml of AcLDL for 24 hours resulted in a significant increase in caspase 3,7 activity, a significant increase in FC and CE mass of 1.5 and 2.4-fold, meanwhile, a significant increase in transcription factor C/EBP homologous protein and a decrease in Bcl-2 both in protein and mRNA levels were observed with an 8-fold rise of free cholesterol in the ER. CONCLUSION: ER stress is involved in AcLDL induced apoptosis in THP-1 macrophages with free cholesterol accumulation in the ER.

Glomerular disease associated with Takayasu arteritis: 6 cases analysis and review of the literature.

OBJECTIVE: To evaluate the clinical features, renal histopathology and therapeutic response to glucocorticoid and immunosuppressive agents in patients with glomerular disease associated with Takayasu arteritis (TA). METHODS: Patients with TA and renal biopsy-confirmed glomerular disease were investigated retrospectively. None of them had renal artery stenosis or occlusive changes. RESULTS: Six patients with glomerulopathy, accounting for 3.75% of the 160 TA patients admitted to our hospital at the same period, were analyzed. All of them were females with a mean age of 35.5 +/- 10.0 years. Four cases presented with lower extremity edema. Laboratory tests showed that one was nephrotic syndrome, three were nephrotic range proteinuria, and two of them had mild renal dysfunction. The other two patients were asymptomatic microscopic hematuria and proteinuria. Renal pathology revealed mild immunoglobulin A nephropathy in two cases, mild mesangial proliferative glomerulonephritis (GN), membranoproliferative GN, minimal change disease, and fibrillary GN in one case respectively. Five cases received glucocorticoids and cyclophosphamide therapy. Proteinuria and microscopic hematuria disappeared in 2 to 4 weeks after the initiation of therapy in three cases. The patient with membranoproliferative GN also reached complete remission of proteinuria and recovered renal function 6 months after the treatment. CONCLUSIONS: TA may induce glomerular disease as a part of its histological spectrum. Apart from ischemic glomerular disease, glomerular disease should be suspected when TA patients have microscopic hematuria or proteinuria, that may be therapeutically responsive to glucocorticoids and immunosuppressive agent in relative early phase.

[Effect of low-flux polysulphone membranes on the serum levels of inflammatory cytokines, C-reactive protein, lipoprotein (a), and beta2 microglobulin in hemodialysis patients].

OBJECTIVE: To explore the effect of low-flux polysulphone membranes on the serum levels of inflammatory cytokines, hyper-sensitivity C reactive protein (hsCRP), lipoprotein (a) [Lp (a)], and beta2 microglobulin (beta 2MG) in hemodialysis patients. METHODS: The blood samples and dialysate samples were collected at pre-dialysis, 120 minutes later during the session, and post-dialysis in 27 stable hemodialysis patients. Variables determined included serum Lp (a), hsCRP, interleukin (IL)-1 beta, IL-6, and beta 2MG. The endotoxin levels were also detected. RESULTS: There were no significant changes either in endotoxin level of dialysate or in all variables tested during one session (P > 0.05). CONCLUSION: Low-flux polysulphone membrane has no effects on serum Lp (a), hsCRP, IL-1 beta, IL-6, and beta 2MG during one session in hemodialysis patients.

[A clinicopathological analysis of non-haematological malignancy in nephrotic syndrome].

OBJECTIVE: To analysis the clinical and pathological features, results of laboratory tests and prognosis of nephrotic syndrome (NS) in patients with non-haematological malignancy. METHODS: The data were collected from 25 patients who presented with NS around the diagnosis of non-haematological malignancy. RESULTS: Twenty-five cases were investigated (age: (56.6 +/- 17.7) years; male/female ratio: 20/5). Malignancy and NS occurred within one year in 92% patients. There was a wide distribution of malignancy with involvement of 36% in digestive system and 20% in respiratory system. Ten patients (40%) presented with NS as their initial manifestation. Haematuria appeared in 67% patients and acute renal insufficiency was complicated in 12% cases before treatments. Some other non-specific laboratory tests were found including elevated serum gamma-globulin in 50% and anemia not related with renal failure in 28% cases. Membranous nephropathy was the most common pathological changes in 67% cases. Although NS still continued for several weeks in 8 of 9 cases after surgery and/or chemical therapy, glucocorticoids was helpful to achieve the remission in these patients. However, no remission was achieved in patients without the treatment for malignancy. CONCLUSION: Malignancy may present with NS as its initial manifestation. It should be inspected routinely and regularly in elder patients with NS, especially in those with membranous nephropathy, as well as gamma-globulinemia and anemia.