Preparation, characteristics and cytotoxicity of green synthesized selenium nanoparticles using Paenibacillus motobuensis LY5201 isolated from the local specialty food of longevity area.

Selenium is an essential micronutrient element. For the extremely biotoxic of selenite, Selenium nanoparticles (SeNPs) is gaining increasing interest. In this work, a selenium-enriched strain with highly selenite-resistant (up to 173 mmol/L) was isolated from the local specialty food of longevity area and identified as Paenibacillus motobuensis (P. motobuensis) LY5201. Most of the SeNPs were accumulated extracellular. SeNPs were around spherical with a diameter of approximately 100 nm. The X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy showed that the purified SeNPs consisted of selenium and proteins. Our results suggested that P. motobuensis LY5201could be a suitable and robust biocatalyst for SeNPs synthesis. In addition, the cytotoxicity effect and the anti-invasive activity of SeNPs on the HepG2 showed an inhibitory effect on HepG2, indicating that SeNPs could be used as a potential anticancer drug.

Comparison of comfort and complications of Implantable Venous Access Port (IVAP) with ultrasound guided Internal Jugular Vein (IJV) and Axillary Vein/Subclavian Vein (AxV/SCV) puncture in breast cancer patients: a randomized controlled study.

BACKGROUND: Axillary vein/subclavian vein (AxV/SCV) and Internal jugular vein (IJV) are commonly used for implantable venous access port (IVAP) implantation in breast cancer patients for chemotherapy. Previous research focused on comparison of complications while patient comfort was ignored. This study aims to compare patient comfort, surgery duration and complications of IVAP implantation between IJV and AxV/SCV approaches. METHODS: Two hundred forty-eight breast cancer patients were enrolled in this randomized controlled study from August 2020 to June 2021. Patients scheduled to undergo IVAP implantation were randomly and equally assigned to receive central venous catheters with either AxV /SCV or IJV approaches. All patients received comfort assessment using a comfort scale table at day 1, day 2 and day 7 after implantation. Patient comfort, procedure time of operation as well as early complications were compared. RESULTS: Patient comfort was significantly better in the AxV/SCV group than that of IJV group in day 1 (P < 0.001), day 2 (P < 0.001) and day 7(P = 0.023). Procedure duration in AxV/SCV group was slightly but significantly shorter than IJV group (27.14 ± 3.29 mins vs 28.92 ± 2.54 mins, P < 0.001). More early complications occurred in AxV/SCV group than IJV group (11/124 vs 2/124, P = 0.019). No difference of complications of artery puncture, pneumothorax or subcutaneous hematoma between these two groups but significantly more catheter misplacement in AxV/SCV group than IJV group (6/124 vs 0/124, P = 0.029). Absolutely total risk of complications was rather low in both groups (8.87% in AxV/SCV group and 1.61% in IJV group). CONCLUSIONS: Our study indicates that patients with AxV/SCV puncture have higher comfort levels than IJV puncture. AxV/SCV puncture has shorter procedure duration but higher risk of early complications, especially catheter misplacement. Both these two approaches have rather low risk of complications. Consequently, our study provides an alternative choice for breast cancer patients to reach better comfort.

Comparative Efficacy and Safety of TKIs Alone or in Combination With Antiangiogenic Agents in Advanced EGFR-Mutated NSCLC as the First-Line Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: Several studies have suggested that patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) might benefit from the use of tyrosine kinase inhibitors (TKIs) in combination with antiangiogenic agents. This study aimed to comprehensively review the available evidence regarding the efficacy and safety of first-line TKI plus antiangiogenic agents versus TKIs alone in EGFR-mutated advanced NSCLC. MATERIALS AND METHODS: A literature search was performed using PubMed to identify studies published up to Feb. 2020. Abstracts from major international conferences reported over the last 5 years were searched. The primary outcome was progression-free survival (PFS), and the secondary outcomes included overall survival (OS), the objective response rate (ORR), and toxicity. RESULTS: In total, 7 relevant trials comprising 1612 patients were identified. TKIs plus antiangiogenic agents led to significant improvements in PFS regardless of the EGFR mutation subtype and presence of brain metastasis. In particular, in the subgroup with the L858R mutation, the hazard ratio (HR) of PFS was 0.58 (95% confidence interval [CI], 0.48-0.71, P < .001). The OS following combined treatment was similar to that following TKI monotherapy. The ORR was increased with the use of TKIs plus antiangiogenic agents (HR 1.10, 95% CI, 1.01-1.20, P = .029). In the safety analyses, TKIs plus antiangiogenic agents exhibited a significantly increased incidence of adverse events of grade 3 or higher. CONCLUSION: The use of TKIs plus antiangiogenic agents is associated with significantly improved PFS and ORR compared with TKIs alone in untreated EGFR-mutated NSCLC. The toxicities of combination therapy should be considered when making treatment choices.

Comparison of comfort and complications in breast cancer patients of implantable venous access port (IVAP) with ultrasound guided internal jugular vein (IJV) and axillary vein/subclavian vein (AxV/SCV) puncture: a randomized controlled study protocol.

BACKGROUND: Internal jugular vein (IJV) and axillary vein/subclavian vein (AxV/SCV) are commonly used for implantable venous access port (IVAP) implantation in breast cancer (BC) patients with chemotherapy. Previous studies focused on complications between these different approaches and ignored patient comfort. In this study, we aim to compare patient comfort between IJV and AxV/SCV approaches, as well as surgery duration and complications. METHODS: This is a single-center prospective randomized controlled clinical trial. A total of 200 patients diagnosed with invasive BC will be enrolled in this study. After signing written informed consent, patients schedule to undergo IVAP implantation will be randomized at a 1:1 ratio to receive central venous catheters (CVC) with either IJV or AxV/SCV approaches. Baseline as well as demographic data and procedure time of port implantation will be recorded. All patients will receive assessment of comfort with a comfort scale table at days 1, 2 and 7 after implantation surgery. Patients will be followed up and complications will be recorded until devices are removed at the end of the treatment period, or in case of complications. Patient comfort, procedure time of implantation and complications will be compared and analyzed between these two arms. DISCUSSION: To the best of our knowledge, this is the first study to compare patient comfort as primary outcome measure between IJV and AxV/SCV puncture. This study will further confirm the benefits of ultrasound guidance and may provide a better choice of IVAP implantation for BC patients. TRIAL REGISTRATION: This study has been registered at Chinese Clinical Trial Registry (ChiCTR, www. chictr.org.cn) and Chinese Ethics Committee of Registering Clinical Trials (No. ChiCTR2000034986).

[Highlights of PAPR Inhibitors in Small Cell Lung Cancer].

Small cell lung cancer (SCLC), characterized by early metastasis, relapse, relapse and resistance and poor prognosis, still faces difficulties in treatment. Recently, Immunotherapy is a novel treatment for SCLC, researchers are also eager to achieve a breakthrough in targeted treatment of SCLC. Genomic instability of SCLC and sensitivity to cytotoxic chemotherapy, therefore, poly ADP-ribose polymerase (PARP) inhibitors targeting DNA repair related pathways have become a hotspot in the research of SCLC targeted therapy. Studies on PARP inhibitors in SCLC have been conducted in combination with other therapeutic strategies, including the treatment of recurrent SCLC and first-line treatment,as well as maintenance treatment after induction. These studies also explored the predictive markers of PARP inhibitors in SCLC. Although the current results of PARP inhibitors in SCLC are limited, and the predictive markers are also inconsistent, we also see that PARP inhibitors could be a breakthroughfor precision medicine of SCLC.
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C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis.

Chronic tubulointerstitial injury impacts the prognosis of focal segmental glomerulosclerosis (FSGS). We found that the level of versican V1 was increased in tubular cells of FSGS patients. Tubular cell-derived versican V1 induced proliferation and collagen synthesis by activating the CD44/Smad3 pathway in fibroblasts. Both urine C3a and suPAR were increased and bound to the tubular cells in FSGS patients. C3a promoted the transcription of versican by activating the AKT/ß-catenin pathway. C3aR knockout decreased the expression of versican in Adriamycin-treated (ADR-treated) mice. On the other hand, suPAR bound to integrin ß6 and activated Rac1, which bound to SRp40 at the 5' end of exon 7 in versican pre-mRNA. This binding inhibited the 3'-end splicing of intron 6 and the base-pair interactions between intron 6 and intron 8, leading to the formation of versican V1. Cotreatment with ADR and suPAR specifically increased the level of versican V1 in tubulointerstitial tissues and caused more obvious interstitial fibrosis in mice than treatment with only ADR. Altogether, our results show that C3a and suPAR drive versican V1 expression in tubular cells by promoting transcription and splicing, respectively, and the increases in tubular cell-derived versican V1 induce interstitial fibrosis by activating fibroblasts in FSGS.

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.

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.

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

AIMS: We report nine Chinese patients with collagen type III glomerulopathy. METHODS AND RESULTS: Two males and seven females were studied, ranging in age from 21 to 67 years. Proteinuria and hypertension were the most common symptoms, with incidences of 88.9 and 77.8%, respectively. Two patients had abnormal renal function. Their histological appearances varied. Massive eosinophilic and weakly periodic acid-Schiff (PAS)-positive substances were deposited along the capillary loops and in the mesangial area in three cases, while others had thickened capillary walls with a chain-like structure or double-contour appearance of the PAS- and silver-stained sections. Immunofluorescence analysis showed the abundant deposition of collagen type III. Electron microscopy revealed massive scattered or bundle-shaped fibre-like materials in the subendothelial and mesangial areas. During follow-up, 44.4% of the patients suffered a doubling of serum creatinine. The level of serum creatinine at biopsy was an independent predictor of this doubled serum creatinine value. CONCLUSIONS: Collagen type III deposits in the subendothelial and mesangial areas. Some patients show global nodular lesions, while others show subtle changes only via PAS/silver staining. Proteinuria and hypertension are the most common symptoms, and the serum creatinine level at biopsy is an independent predictor of the doubling of serum creatinine during follow-up.

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.

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.

BACKGROUND: Treatment of lupus nephritis (LN) remains challenging. OBJECTIVE: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN. DESIGN: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616). SETTING: 26 renal centers in China. PATIENTS: Adults (aged 18 to 65 years) with biopsy-proven LN. INTERVENTION: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy. MEASUREMENTS: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events. RESULTS: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]). LIMITATION: The study was limited to 24 weeks of follow-up. CONCLUSION: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN. PRIMARY FUNDING SOURCE: National Basic Research Program of China, National Key Technology R&D Program.

Clinico-pathological features and outcomes of patients with propylthiouracil-associated ANCA vasculitis with renal involvement.

OBJECTIVE: To retrospectively investigate clinico-pathological features and outcomes of patients with renal involvement in propylthiouracil (PTU)-associated antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (PTU-AAV). METHODS: Clinico-pathological features and outcomes of 12 patients (female 11, average age 32.4 ± 13.8 years) who developed AAV after treatment with PTU were collected and analyzed. ANCA was detected by both immunofluorescence (IF) and enzyme linked immunosorbent assay (ELISA). All patients had renal biopsy. RESULTS: Twelve patients received PTU for 2-264 months (median 42 months) when PTUAAV was diagnosed. All patients had positive serum P-ANCA, 11 of them were MPO-ANCA, 1 was MPO and PR3-ANCA double positive. All patients presented with hematuria and proteinuria, 5 of them had gross hematuria, urine protein was 1.9 ± 1.6 g/24 h, 7 of 12 (58.3%) patients had renal dysfunction, among them 3 needed initial renal replacement therapy. Renal biopsy showed pauci-immune segmental necrotizing crescentic glomerulonephritis in ten patients, segmental necrotizing glomerulonephritis superimposed on membranous nephropathy in two patients. All patients withdrew PTU and received steroid and immunosuppressive therapy. After a median follow-up of 42 months (range 21-86), 3 patients developed to ESRD, 7 patients entered complete renal remission. Serum ANCA turned negative only in 2 patients, 10 patients had persistent positive serum ANCA. Three patients relapsed with the elevation of serum ANCA level. CONCLUSION: Renal damage of PTU-AAV could be pauci-immune necrotizing crescentic glomerulonephritis, and necrotizing glomerulonephritis coexisted with membranous nephropathy. Most patients had persistent positive serum ANCA and had a risk of relapse and progression to ESRD even after PTU withdrawal and immunosuppressive therapy.

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.

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 glycogen synthase kinase-3ß prevents NSAID-induced acute kidney injury.

Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3ß inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3ß targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3ß inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3ß, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3ß activity and prevented GSK3ß-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3ß abolished the effects of TDZD-8. Hence, inhibition of GSK3ß ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.

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.