Hao Bao

Successful Treatment of Class V+IV Lupus Nephritis with Multitarget Therapy

Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.

Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population

BACKGROUND We sought to identify the long-term renal survival rate and related risk factors of progression to renal failure in Chinese adult patients with IgA nephropathy (IgAN) and to quantify the effects of proteinuria during the follow-up on outcome in patients with IgAN. METHODS Patients with biopsy-proven primary IgAN in the Nanjing Glomerulonephritis Registry were studied. Renal survival and the relationships between clinical parameters and renal outcomes were assessed. RESULTS One thousand one hundred and fifty-five patients were enrolled in this study. The 10-, 15- and 20-year cumulative renal survival rates, calculated by Kaplan-Meier method, were 83, 74 and 64%, respectively. At the time of biopsy, proteinuria>1.0 g/day [hazard ratio (HR) 3.2, P<0.001], estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 (HR 2.6, P<0.001), hypertension (HR 1.9, P<0.001), hypoproteinemia (HR 2.0, P<0.001) and hyperuricemia (HR 2.1, P<0.001) were the independent risk factors. Multivariate Cox analysis showed the time-average proteinuria (TA-P) during follow-up was the most important risk factor of renal failure. Patients with TA-P>1.0 g/day were associated with a 9.4-fold risk than patients with TA-P<1.0 g/day (P<0.001) and 46.5-fold risk than those with TA-P<0.5 g/day (P<0.001). Moreover, patients who achieved TA-P<0.5 g/day benefit much more than those with TA-P between 0.5 and 1.0 g/day (HR 13.1, P<0.001). CONCLUSIONS Thirty-six percent of Chinese adult patients with IgAN progress to end stage renal disease within 20 years. Five clinical features-higher proteinuria, hypertension, impaired renal function, hypoproteinemia and hyperuricemia-are independent predictors of an unfavorable renal outcome. The basic goal of anti-proteinuric therapy for Chinese patients is to lower proteinuria<1.0 g/day and the optimal goal is to lower proteinuria to <0.5 g/day.

MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy

Glomerular endothelial cells (GEnCs) contribute to renal injuries in IgA nephropathy (IgAN). Here we profiled microRNAs (miRNAs) in GEnCs treated with conditioned medium from human mesangial cells in vitro. Levels of miR-223 in GEnCs decreased after incubation with the medium prepared with pIgA from patients with glomerular endothelial proliferation and were also decreased in the glomerular tissues of patients with glomerular endothelial proliferation. Mesangial-derived IL-6 caused miR-223 levels to decrease. The addition of exogenous miR-223 inhibited cell proliferation, ICAM-1 expression, and monocyte adhesion. The NF-κB and STAT3 signaling pathways collaborate during the activation process. MiR-223 mimics inhibited the nuclear localization and DNA binding of p65 and STAT3 but had no effect on the expression of upstream molecules. Instead, importin α4 and α5 (multipurpose nuclear transport receptors), validated as targets of miR-223, were responsible for the nuclear transport of p65 and STAT3. Importin α4 and α5 siRNA inhibited the nuclear localization of p65 and STAT3 and prevented cell proliferation and monocyte adhesion. The level of miR-223 in circulating endothelial cells was decreased and related to the clinical and pathological parameters. Thus, miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgAN. Monitoring the level of miR-223 in circulating endothelial cells may provide a noninvasive method for evaluating the severity of IgAN.

Inhibition of miRNA-21 prevents fibrogenic activation in podocytes and tubular cells in IgA nephropathy.

Podocytopathy and tubular interstitial fibrosis impact on renal outcomes of IgA nephropathy (IgAN). We found that level of miR-21 was up regulated in both glomerular and tubular-interstitial tissues of patients with IgAN. Enhanced expression of miR-21 mainly located in podocytes and tubular cells. Mesangial cell derived cytokines contributed to the increase of miR-21 in podocytes and HK2 cells. IgA-HMC medium prepared with pIgA from IgAN, lead to obvious fibrogenic activation, evidenced by the loss of Podocin and CD2AP in podocytes, loss of E-cadherin and Megalin in HK2 cells and increase of FN and Col I in both cells. miR-21 targeted PTEN in these cells. Expression of PTEN was decreased and phosphorylation of Akt was increased in podocytes and HK2 cells exposed to the medium prepared with pIgA from IgAN. Inhibition of miR-21 preserved the expression of PTEN, prevented the activation of Akt and inhibited the fibrogenic activation in podocytes and HK2 cells exposed to the IgA-HMC medium prepared with pIgA from IgAN. In conclusion, our study suggests that inhibition of miR-21 prevents fibrogenic activation in podocytes and tubular cells by preventing PTEN/Akt pathway activation in IgAN.

Increased miR-374b promotes cell proliferation and the production of aberrant glycosylated IgA1 in B cells of IgA nephropathy

The number of B cells is increased and the O‐glycans of IgA1 are incompletely galactosylated in IgA nephropathy (IgAN). Here we report that expression of phosphatase and tensin homolog (PTEN) and Cosmc is decreased in B cells, and correlates with B cell number and the aberrant glycosylation of IgA1 in IgAN. Patients with IgAN exhibit higher miR‐374b in B cells compared to controls. We show that miR‐374b targets PTEN and Cosmc by luciferase assays and western blot analysis. Inhibition of miR‐374b increased PTEN and Cosmc expression, and prevented cell proliferation and aberrant glycosylation of IgA1, thus representing a new therapeutic approach for IgAN.

Glucocorticoid with or without additional immunosuppressant therapy for patients with lupus podocytopathy: a retrospective single-center study.

Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0–6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7–12.0 weeks) in combination therapy (p = 0.076). Twenty-seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6–125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen.

Clinical and morphological features of fibronectin glomerulopathy: a report of ten patients from a single institution.

AIMS Fibronectin glomerulopathy is a rare glomerular disease caused by the progressive deposition of fibronectin. We report 10 Chinese patients with fibronectin glomerulopathy. METHODS Renal biopsies were performed on all patients, and the clinical and pathological parameters for all patients were analyzed. RESULTS There were 6 males and 4 females, with an average age of 29±8 years. One patient had a family history of renal disease, all patients presented with proteinuria, and 80% of them suffered nephrotic range proteinuria. No patient demonstrated gross hematuria. The levels of serum creatinine were elevated, and the eGFR was decreased in 5 patients. Renal biopsy revealed a lobulated glomerular tuft. Patients showed numerous periodic acid-Schiff-positive and fuchsinophilic deposits in the mesangial area and along the capillary loops. Immense levels of fibronectin were detected in the glomerulus after immunofluorescence analysis. An electron microscopy scan found numerous electron-dense deposits in the mesangial and subendothelial areas. Immune-electron microscopy confirmed that the deposits consisted of fibronectin. CONCLUSION Nephrotic proteinuria and massive intraglomerular fibronectin deposits are the most significant features of fibronectin glomerulopathy.

Risk Factors for Renal Survival in Chinese Patients with Myeloperoxidase-ANCA–Associated GN

BACKGROUND AND OBJECTIVES Our study explored the association of histopathologic classification of ANCA-associated GN with renal survival in Chinese patients with myeloperoxidase-ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Two hundred fifteen patients with biopsy-proven myeloperoxidase-ANCA-associated GN were included from January of 1996 to December of 2014. The biopsies included focal (n=27), mixed (n=82), crescentic (n=47), and sclerotic (n=59) classes. The long-term renal outcome and risk factors of myeloperoxidase-ANCA-associated GN for different histopathologic classes were retrospectively analyzed. RESULTS During a median follow-up time of 22 (9-51) months, 88 (40.9%) patients reached ESRD. The 5-year renal survival (overall 58.7%) was highest in the focal class (100.0%) and lowest in the sclerotic class (20.7%), with no difference between the mixed (58.9%) and crescentic (67.4%) classes. Patients in the mixed (hazard ratio, 0.34; 95% confidence interval, 0.20 to 0.57; P<0.001) and crescentic (hazard ratio, 0.31; 95% confidence interval, 0.16 to 0.59; P<0.001) classes were at lower risk for ESRD compared with patients in the sclerotic class, as were patients who received glucocorticoids plus mycophenolate mofetil (hazard ratio, 0.32; 95% confidence interval, 0.18 to 0.60; P<0.001) compared with those receiving glucocorticoids alone. In addition, patients with a serum creatinine level ≥4 mg/dl (hazard ratio, 2.93; 95% confidence interval, 1.77 to 4.85; P<0.001) or hypoalbuminemia (hazard ratio, 2.11; 95% confidence interval, 1.32 to 3.34; P=0.002) were at higher risk for ESRD. A serum creatinine level ≥4 mg/dl and a percentage of global sclerotic glomeruli ≥60% were the two independent risk factors for ESRD in the sclerotic class. CONCLUSIONS The histopathologic classification of ANCA-associated GN in combination with serum creatinine and serum albumin levels and treatment regimen is associated with renal outcome in myeloperoxidase-ANCA-associated GN. The evaluation of serum creatinine level and percentage of global sclerotic glomeruli provides additional information on the risk of renal survival in the sclerotic class of myeloperoxidase-ANCA-associated GN.

Clinical and morphological features of collagen type III glomerulopathy: a report of nine cases from a single institution

We report nine Chinese patients with collagen type III glomerulopathy.