Nicorandil protects podocytes via modulation of antioxidative capacity in acute puromycin aminonucleoside-induced nephrosis in rats.

Nephrotic syndrome, characterized by proteinuria and hypoalbuminemia, results from the dysregulation of glomerular podocytes and is a significant cause of end-stage kidney disease. Patients with idiopathic nephrotic syndrome are generally treated with immunosuppressive agents; however, these agents produce various adverse effects. Previously, we reported the renoprotective effects of a stimulator of the mitochondrial ATP-dependent K+ channel (MitKATP), nicorandil, in a remnant kidney model. Nonetheless, the cellular targets of these effects remain unknown. Here, we examined the effect of nicorandil on puromycin aminonucleoside-induced nephrosis (PAN) rats, a well-established model of podocyte injury and human nephrotic syndrome. PAN was induced using a single intraperitoneal injection. Nicorandil was administered orally at 30 mg/kg/day. We found that proteinuria and hypoalbuminemia in PAN rats were significantly ameliorated following nicorandil treatment. Immunostaining and ultrastructural analysis under electron microscopy demonstrated that podocyte injury in PAN rats showed a significant partial attenuation following nicorandil treatment. Nicorandil ameliorated the increase in the oxidative stress markers nitrotyrosine and 8-hydroxy-2-deoxyguanosine in glomeruli. Conversely, nicorandil prevented the decrease in levels of the antioxidant enzyme manganese superoxide dismutase in PAN rats. We found that mitochondrial Ca2+ uniporter levels in glomeruli were higher in PAN rats than in control rats, and this increase was significantly attenuated by nicorandil. We conclude that stimulation of MitKATP by nicorandil reduces proteinuria by attenuating podocyte injury in PAN nephrosis, which restores mitochondrial antioxidative capacity, possibly through mitochondrial Ca2+ uniporter modulation. These data indicate that MitKATP may represent a novel target for podocyte injury and nephrotic syndrome.NEW & NOTEWORTHY Our findings suggest that the mitochondrial Ca2+ uniporter may be an upstream regulator of manganese superoxide dismutase and indicate a biochemical basis for the interaction between the ATP-sensitive K+ channel and Ca2+ signaling. We believe that our study makes a significant contribution to the literature because our results indicate that the ATP-sensitive K+ channel may be a potential therapeutic target for podocyte injury and nephrotic syndrome.

HSPB5 suppresses renal inflammation and protects lupus-prone NZB/W F1 mice from severe renal damage.

BACKGROUND: Lupus nephritis (LN) is an inflammatory disease of the kidneys affecting patients with systemic lupus erythematosus. Current immunosuppressive and cytotoxic therapies are associated with serious side effects and fail to protect 20-40% of LN patients from end-stage renal disease. In this study, we investigated whether a small heat shock protein, HSPB5, can reduce kidney inflammation and the clinical manifestations of the disease in NZB/W F1 mice. Furthermore, we investigated whether HSPB5 can enhance the effects of methylprednisolone, a standard-of-care drug in LN, in an endotoxemia mouse model. METHODS: NZB/W F1 mice were treated with HSPB5, methylprednisolone, or vehicle from 23 to 38 weeks of age. Disease progression was evaluated by weekly proteinuria scores. At the end of the study, the blood, urine, spleens, and kidneys were collected for the assessment of proteinuria, blood urea nitrogen, kidney histology, serum IL-6 and anti-dsDNA levels, immune cell populations, and their phenotypes, as well as the transcript levels of proinflammatory chemokine/cytokines in the kidneys. HSPB5 was also evaluated in combination with methylprednisolone in a lipopolysaccharide-induced endotoxemia mouse model; serum IL-6 levels were measured at 24 h post-endotoxemia induction. RESULTS: HSPB5 significantly reduced terminal proteinuria and BUN and substantially improved kidney pathology. Similar trends, although to a lower extent, were observed with methylprednisolone treatment. Serum IL-6 levels and kidney expression of BAFF, IL-6, IFNγ, MCP-1 (CCL2), and KIM-1 were reduced, whereas nephrin expression was significantly preserved compared to vehicle-treated mice. Lastly, splenic Tregs and Bregs were significantly induced with HSPB5 treatment. HSPB5 in combination with methylprednisolone also significantly reduced serum IL-6 levels in endotoxemia mice. CONCLUSIONS: HSPB5 treatment reduces kidney inflammation and injury, providing therapeutic benefits in NZB/W F1 mice. Given that HSPB5 enhances the anti-inflammatory effects of methylprednisolone, there is a strong interest to develop HSBP5 as a therapeutic for the treatment of LN.

Relationship between Ideal Cardiovascular Health and Incident Proteinuria: A 5 Year Retrospective Cohort Study.

The objective of this study was to examine whether a higher number of ideal cardiovascular health (CVH) metrics are beneficial for lowering the risk of proteinuria. This is a retrospective cohort study with an average follow-up of 5 years. Participants between 21 and 75 years old and without a history of cardiovascular disease and proteinuria were enrolled. CVH metrics, including smoking, diet, physical activity, blood pressure, body mass index (BMI), cholesterol, and fasting glucose, were assessed by questionnaires, physical examination, and blood analysis. Proteinuria was assessed by dipstick measurement. During the follow-up period, 169,366 participants were enrolled, and 1481 subjects developed proteinuria. A higher number of ideal CVH metrics was related to a lower risk of proteinuria after adjustment. Among the components of CVH metrics, ideal blood pressure (HR = 0.33, 95% CI = 0.25-0.43), fasting glucose (HR = 0.17, 95% CI = 0.12-0.22), and BMI (HR = 0.20, 95% CI = 0.15-0.27) had beneficial effects on proteinuria. Despite no significant benefit of diet score, the corresponding lower sodium intake showed a lower risk of proteinuria (HR = 0.58, 95% CI = 0.43-0.79). Incident proteinuria was inversely related to the number of ideal CVH metrics. CVH metrics may be a predictor of proteinuria, and achieving a higher number of ideal scores should be recommended as a proteinuria prevention strategy.

Non-canonical Wnt/calcium signaling is protective against podocyte injury and glomerulosclerosis.

Activation of canonical Wnt signaling has been implicated in podocyte injury and proteinuria. As Wnts are secreted proteins, whether Wnts derived from podocytes are obligatory for promoting proteinuria remains unknown. To address this, we generated conditional knockout mice where Wntless, a cargo receptor protein required for Wnt secretion, was specifically deleted in glomerular podocytes. Mice with podocyte-specific ablation of Wntless (Podo-Wntless-/-) were phenotypically normal. However, after inducing kidney damage with Adriamycin for six days, Podo-Wntless-/- mice developed more severe podocyte injury and albuminuria than their control littermates. Surprisingly, ablation of Wntless resulted in upregulation of ß-catenin, accompanied by reduction of nephrin, podocin, podocalyxin, and Wilms tumor 1 proteins. In chronic injury induced by Adriamycin, increased albuminuria, aggravated podocyte lesions and extracellular matrix deposition were evident in Podo-Wntlessl-/- mice, compared to wild type mice. Mechanistically, specific ablation of Wntless in podocytes caused down-regulation of the nuclear factor of activated T cell 1 (NFAT1) and Nemo-like kinase (NLK), key downstream mediators of non-canonical Wnt/calcium signaling. In vitro, knockdown of either NFAT1 or NLK induced ß-catenin activation while overexpression of NLK significantly repressed ß-catenin induction and largely preserved nephrin in glomerular podocytes. Thus, our results indicate that podocyte-derived Wnts play an important role in protecting podocytes from injury by repressing ß-catenin via activating non-canonical Wnt/calcium signaling.

IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage.

Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.

CMIP interacts with WT1 and targets it on the proteasome degradation pathway.

BACKGROUND: The Wilms tumor 1 suppressor gene, WT1, is expressed throughout life in podocytes and is essential for their function. Downregulation of WT1 has been reported in podocyte diseases but the underlying mechanisms remain unclear. Podocyte injury is the hallmark of idiopathic nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults. An increase in the abundance of Cmaf-inducing protein (CMIP) has been found to alter podocyte function, but it is not known whether CMIP affects WT1 expression. METHODS: Transcriptional and post-transcriptional regulation of WT1in the presence of CMIP was studied using transient transfection, mouse models, and siRNA handling. RESULTS: We showed that overproduction of CMIP in the podocyte was consistently associated with a downregulation of WT1 according to two mechanisms. We found that CMIP prevented the NF-kB-mediated transcriptional activation of WT1. We demonstrated that CMIP interacts directly with WT1 through its leucine-rich repeat domain. Overexpression of CMIP in the M15 cell line induced a downregulation of WT1, which was prevented by lactacystin, a potent proteasome inhibitor. We showed that CMIP exhibits an E3 ligase activity and targets WT1 to proteasome degradation. Intravenous injection of Cmip-siRNA specifically prevented the repression of Wt1 in lipopolysaccharides-induced proteinuria in mice. CONCLUSIONS: These data suggest that CMIP is a repressor of WT1 and might be a critical player in the pathophysiology of some podocyte diseases. Because WT1 is required for podocyte integrity, CMIP could be considered a therapeutic target in podocyte diseases.

Angiotensin-converting enzyme inhibitors have adverse effects in anti-angiogenesis therapy for hepatocellular carcinoma.

At present, anti-angiogenic drugs (AADs) are widely used in the systemic treatment of hepatocellular carcinoma (HCC) or other types of cancer, and have achieved good anti-cancer effect, whereas treatment-related proteinuria can affect the routine use of AADs, which in turn abates the overall efficacy. Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria according to diabetic nephropathy guidelines or expert recommendations. However, the efficacy of ACEIs in reducing AAD-related proteinuria and its effect on the anticancer effect of AADs is unknown. Our clinical data showed that some HCC patients experienced tumor progression by ACEIs administration for the treatment of proteinuria caused by AADs. Here, we confirmed that in different tumor-bearing mouse models, ACEIs did not delay the appearance of proteinuria or alleviate proteinuria caused by AADs but compromised the anticancer efficacy of AADs. This effect is unrelated to the change in the VEGF signaling pathway. Our data showed that the combination of ACEIs and AADs flared the production of kidney-derived erythropoietin (EPO). In turn, EPO compromises the anti-angiogenic effects of AADs and decreases antitumor activity. In conclusion, for the treatment of proteinuria caused by AADs, ACEIs have no efficacy while also promoting AADs resistance. This finding is of great significance to guide clinical standardized management of side effects of anti-angiogenic therapy for cancer patients.

Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab.

PURPOSE: Proteinuria monitoring is required for patients receiving bevacizumab. Nonetheless, the frequency of monitoring is not specified in the package insert. A 2014 quality improvement study performed at Yale New Haven Health System (YNHHS) found that proteinuria occurred in 15% (all grade) of the 162 patients evaluated. These results led to decreasing the frequency of proteinuria monitoring from every treatment to every other treatment. The objective of this study is to assess the safety of the extended interval for urine protein (UP) monitoring. METHODS: Patients receiving at least four bevacizumab treatments at YNHHS from January to June 2017 were randomly selected and retrospectively reviewed. The following data were collected: baseline patient characteristics, comorbidities, medication history, and proteinuria monitoring. The grade, prevalence and management of proteinuria were evaluated. The minimum necessary sample size was determined to be 384 treatments to achieve a 95% confidence interval. RESULTS: Fifty-five patients and 388 bevacizumab treatments were evaluated. Urine protein was assessed in 52.5% of treatments. The incidence of proteinuria among patients was 7.2% (grade 2) and 0% (grade 3). Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria. Two patients with UP ≥ 2+ were further monitored using a 24-h urine collection test with negative results. No treatments were held due to proteinuria. CONCLUSION: Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is now monitored prior to every third bevacizumab treatment, reducing unnecessary labs and chair time.

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

Urinary DPP4 correlates with renal dysfunction, and DPP4 inhibition protects against the reduction in megalin and podocin expression in experimental CKD.

This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.

Metformin reduces proteinuria in spontaneously hypertensive rats by activating the HIF-2α-VEGF-A pathway.

Metformin has protective effects on diabetic nephropathy. However, the mechanism underlying the renoprotective action of metformin in spontaneously hypertensive rats (SHR) is not completely understood. We determined the role of metformin in proteinuria and investigated the mechanism. We measured the urinary protein concentration (mg/day) in 48-week-old SHR. Matched control animals were of the same genetic strain, Wistar-Kyoto (WKY). The rats received metformin (100 mg/kg/day) or vehicle for 10 months. Metformin improved renal function and reduced the proteinuria (urine protein: 48.4 ± 3.7 vs. 25.4 ± 1.8 mg, P < 0.01) induced by long-term high blood pressure. Metformin increased the production of vascular endothelial growth factor (VEGF)-A in rat kidneys and cultured rat podocytes. Metformin activated hypoxia-inducible factor-2α (Hif-2α) in response to VEGF but did not affect Hif-1α in rat kidneys and cultured rat podocytes. Metformin reduced the proteinuria induced by long-term high blood pressure in vivo and increased the VEGF-A production in rat kidneys and cultured rat podocytes, probably by activating the Hif-2α-VEGF signaling pathway. These findings provide a new mechanism for the renoprotective effects of metformin.

Melatonin attenuates hypertension and oxidative stress in a rat model of L-NAME-induced gestational hypertension.

Preeclampsia is a life-threatening multiorgan systemic disease with manifestations including gestational hypertension, oxidative stress, and vascular dysfunction. We aimed to evaluate the therapeutic effects of melatonin on an L-NAME (NLG-nitro-l-arginine methyl ester)-induced rat preeclampsia model. During gestation, L-NAME was added to drinking water at 50 mg/kg/day from gestation day (GD) 8. Rats received the combination of L-NAME with melatonin (10 mg/kg/day), or aspirin (1.5 mg/kg/day), and rats that received only L-NAME or no treatments were used as controls. Aspirin was mixed with rodent chow and melatonin was administered intraperitoneally. Blood pressure and urine protein content were monitored every 3 days. On GD19, blood samples were collected for biochemical analysis. Compared to untreated L-NAME rats, melatonin led to markedly lowered blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight, and the fetal weight/placental weight ratio. Compared to untreated L-NAME rats, plasma antioxidant capacity and plasma malondialdehyde were increased and decreased by melatonin, respectively, in L-NAME rats. Melatonin treatment also reduced sFlt-1, increased PlGF, and decreased the sFlt-1/PlGF ratio. In the placenta, melatonin also reduced sFlt-1 levels and increased Nrf2, PlGF, and HO-1 levels. We have demonstrated in a rat model of preeclampsia that melatonin exerts significant protective effects through lowering blood pressure and reducing oxidative stress.

Cys-peptide mediates the protective role in preeclampsia-like rat and cell models.

OBJECTIVE: The present study was designed to investigate whether the novel peptide cysteine-based peptide (Cys-peptide) had protective effects on preeclamptic animal and cell models. METHODS: We investigated effects of Cys-peptide on (1) preeclamptic symptoms (e.g. hypertension, proteinuria, fetal growth restriction (FGR)) in preeclampia-like rat models induced by lipopolysaccharides (LPS), (2) TNFα-induced cytotoxicity of human umbilical vascular endothelial cells (HUVECs) and HTR-8 cells (an immortalised human trophoblast cell line), (3) endothelial dysfunction and injured angiogenesis, (4) migration and invasion of trophoblast cells induced by TNFα. RESULTS: Cys-peptide ameliorated LPS-induced hypertension, proteinuria and FGR and other PE symptoms in preeclampia-like rat models. In addition, Cys-peptide attenuated TNFα-induced cytotoxicity by decreasing soluble fms-like tyrosine kinase-1 (sFlt-1), endothelin-1 (ET-1) and tissue plasminogen activator (tPA) mRNA expression in both cells. Furthermore, Cys-peptide restored endothelial dysfunction and rescued angiogenesis caused by TNFα in vitro. Importantly, Cys-peptide could reverse insufficient ability to invade and migrate of trophoblast cells. CONCLUSIONS: These results suggest Cys-peptide can play beneficial roles in preeclampsia-like rat and cell models. Therefore, we propose that Cys-peptide is probably a novel therapeutic candidate for PE.

Vitamin D in kidney transplant recipients
.

Kidney transplant recipients (KTRs) are susceptible to low levels of vitamin D, which may be responsible for mineral and bone metabolism disorders and play some role in the occurrence of cardiovascular, metabolic, immunologic, neoplastic, and infectious complications after kidney transplant. Kidney Disease Improving Global Outcomes (KDIGO) guidelines of the year 2017 recommended vitamin D supplementation in the first 12 months after transplant using the same treatment strategies for the general population. However, no recommendations are provided after the first 12 months due to a lack of sufficient data. This review analyses some studies that assessed the vitamin D status of KTRs and the effects of nutritional and active vitamin D supplementation on bone mineral density, cardiovascular disease, proteinuria, and graft function in KTRs.

Forsythiaside A alleviates renal damage in adriamycin-induced nephropathy.

Nephrotic syndrome (NS) is a common urinary system disease that carries a poor progrnosis due to nonresponsivess to current treatments. The purpose of this study was to investigate the therapeutic effects of Forsythiaside (FA) in a rat model of adriamycin-induced nephropathy (AN). Compared with control group, FA treatment significantly reduced proteinuria, serum creatinine and urea nitrogen levels and reduced the number of apoptotic cells in the kidneys. FA alleviated Adr induced renal injury, and increased the sactivity of superoxide dismutase (SOD), while decreasing malondialdehyde (MDA) and lactate dehydrogenase (LDH) in the serum. In addition, FA, in a dose-dependent manner, decreased the levels of NF-kappaBp65/MIP-2 in the kidenys, reduced the serum level of pro-inflammatory cytokines (IL-6, IL-1 ß and TNF-alpha), and increased the survival rate of Adr treated rats. Taken together, the results show that FA alleviates renal dysfunction in adriamycin-induced nephropathy rats.

Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do?

Immune checkpoint inhibitors have dramatically improved cancer therapy for many patients. These humanized monoclonal antibodies against various immune checkpoints (receptors and ligands) effectively treat a number of malignancies by unleashing the immune system to destroy cancer cells. These drugs are not excreted by the kidneys or liver, have a long half-life, and undergo receptor-mediated clearance. Although these agents have greatly improved the prognosis of many cancers, immune-related end organ injury is a complication that has come to light in clinical practice. Although less common than other organ involvement, kidney lesions resulting in acute kidney injury and/or proteinuria are being described. Acute tubulointerstitial nephritis is the most common lesion seen on kidney biopsy, while acute tubular injury and glomerular lesions occur less commonly. Clinical findings and laboratory tests are suboptimal in predicting the underlying renal lesion, making kidney biopsy necessary in the majority of cases to definitely diagnose the lesion and potentially guide therapy. Immune checkpoint inhibitor discontinuation and corticosteroid therapy are recommended for acute tubulointerstitial nephritis. Based on a handful of cases, re-exposure to these drugs in patients who previously developed acute tubulointerstitial nephritis has been mixed. Although it is unclear whether re-exposure is appropriate, it should perhaps be considered in patients with limited options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury. Treatment of cancer in patients with a kidney transplant with immune checkpoint inhibitors risks the development of acute rejection in some patients and requires close surveillance.

Effects of BSF on Podocyte Apoptosis via Regulating the ROS-Mediated PI3K/AKT Pathway in DN.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The ROS-mediated PI3K/AKT pathway plays a key role in podocyte apoptosis and DN progression. Our previous study demonstrated that Baoshenfang (BSF) can decrease proteinuria and attenuate podocyte injury. However, the effects of BSF on podocyte apoptosis induced by the ROS-mediated PI3K/AKT pathway remain unclear. Herein, in vivo and in vitro studies have been performed. In our in vivo study, BSF significantly decreased 24-h urinary protein, serum creatinine, and blood urea nitrogen levels in DN mice. Meanwhile, BSF significantly inhibited oxidative stress and podocyte apoptosis in our in vivo and in vitro studies. Moreover, BSF significantly decreased the inhibition of the PI3K/AKT pathway induced by HG in DN. More importantly, the effects of BSF on podocyte apoptosis were reversed by PI3K siRNA transfection. In conclusion, BSF can decrease proteinuria and podocyte apoptosis in DN, in part through regulating the ROS-mediated PI3K/AKT pathway.

Combination therapy of low-dose cyclosporine and steroid in adults with IgA nephropathy
.

BACKGROUND: A few clinical trials in IgA nephropathy (IgAN) have shown that cyclosporine A (CyA) had therapeutic efficacy in reducing proteinuria. MATERIALS AND METHODS: This is a retrospective study, and all cases were selected based on kidney biopsy-proven IgAN. We reviewed the data of IgAN patients in the glomerulonephritis registry at Kyung Hee University Medical center and collected data on 86 patients with urinary protein/Cr ratio (PCR; g/g) > 0.5 and estimated GFR (eGFR) of > 50 mL/min/1.73m2 who were treated with combination therapy of low-dose CyA plus low-dose steroid (C+P; n = 37) and high-dose steroid single therapy (P; n = 49). RESULTS: In the C+P group, the mean duration of therapy was 14.5 ± 13.1 months, and the mean duration of follow-up 66.2 ± 36.3 months. In the C+P group, the urine PCR levels significantly declined after treatment (< 0.05). After 6 months of treatment, 12 (32%) patients were in complete remission and 7 (19%) in partial remission in the C+P group, compared with 21 (42%) and 11 (22%) in the P group, respectively. Urine PCR levels were also significantly reduced in 12 patients in the C+P group who had initial urine PCR between 0.5 and 1.0. The degree of hematuria was significantly reduced after treatment in the C+P group. These effects of C+P therapy on proteinuria and hematuria were very comparable to high-dose P therapy. After 2 years, a decline in renal function, > 25% decrease in eGFR from baseline levels, developed in 3 (8.1%) in the C+P group, compared with 4 (8.2%) in the P group. The rate of decline in renal function during follow-up was -0.14 ± 0.40 mL/min/1.73m2/month in the C+P group compared with -0.12 ± 0.22 mL/min/1.73m2/month in the P group. There were no changes of mean eGFR during the first 24 months, but the eGFR significantly decreased at last follow-up in both groups. When patients in the C+P group were divided into progressive (n = 9) and nonprogressive (n = 28) groups, a significant reduction in the amount of proteinuria after treatment was observed in the nonprogressive group, in contrast to the progressive group. In the C+P group, there were no severe adverse effects, especially no acute renal impairment, requiring discontinuation of CyA in this study. The incidence of infection was much lower in the C+P group than that in the P group. The limitation is that CyA acts to nonspecifically reduce proteinuria, so it requires long-term follow-up off CyA therapy for more than 2 years to determine. CONCLUSION: Our retrospective uncontrolled study provides only weak evidence that combination therapy of low-dose C+P could be an alternative to high-dose P therapy and be safe in adult IgAN patients with relatively normal renal function and proteinuria of > 0.5 g/g. Development of safe and effective therapy is still a major challenge requiring well-controlled prospective studies with this or other combination therapies.

Renin-angiotensin system inhibitors for countering proteinuria induced by angiogenesis inhibitors: a retrospective observational analysis.

PURPOSE: Occurrence of proteinuria could result in cessation of bevacizumab and ramucirumab treatments. Renin-angiotensin system (RAS) inhibitors exert a renoprotective effect by countering proteinuria. However, the association between renoprotective effect of RAS inhibitors and blood pressure control is unclear. This study assessed the risk factors for proteinuria induced by bevacizumab or ramucirumab and the relationship between renoprotective effect of RAS inhibitors and blood pressure control. METHODS: A retrospective observational analysis was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to May 2018. Multivariate logistic regression analysis was used to identify risk factors for proteinuria induced by treatment with bevacizumab and ramucirumab. Renoprotective effect was assessed by analyzing blood pressure data in association with the use of RAS inhibitors. RESULTS: Out of 208 patients included in this study, proteinuria was observed in 50 (24%) patients. Body mass index ≥ 24 kg/m2 (OR = 2.45, 95% CI 1.21-4.96, p = 0.01), colorectal cancer (OR = 1.95, 95% CI 1.00-3.80, p < 0.05), and use of RAS inhibitors (OR = 0.25 95% CI 0.07-0.92, p = 0.04) were associated with proteinuria induced by treatment with bevacizumab and ramucirumab. A change in systolic blood pressure at second visit was higher in patients with RAS inhibitors compared with those in patients without RAS inhibitors (25 mmHg vs - 5 mmHg, p = 0.04). CONCLUSION: Although RAS inhibitors protected patients from proteinuria induced by bevacizumab or ramucirumab, RAS inhibitors could not adequately control their blood pressures in patients with proteinuria.

Salidroside ameliorates Adriamycin nephropathy in mice by inhibiting ß-catenin activity.

Salidroside is a major phenylethanoid glycoside in Rhodiola rosea L., a traditional Chinese medicine, with multiple biological activities. It has been shown that salidroside possesses protective effects for alleviating diabetic renal dysfunction, contrast-induced-nephropathy and other kidney diseases. However, the involved molecular mechanism was still not understood well. Herein, we examined the protective effects of salidroside in mice with Adriamycin (ADR)-induced nephropathy and the underlying molecular mechanism. The results showed that salidroside treatment ameliorates proteinuria; improves expressions of nephrin and podocin; and reduces kidney fibrosis and glomerulosclerosis induced by ADR. Mechanistically, ADR induces a robust accumulation of ß-catenin in the nucleus and stimulates its downstream target gene expression. The application of salidroside largely abolishes the nuclear translocation of ß-catenin and thus inhibits its activity. Furthermore, the activation of ß-catenin almost completely counteracts the protective roles of salidroside in ADR-injured podocytes. Taken together, our data indicate that salidroside ameliorates proteinuria, renal fibrosis and podocyte injury in ADR nephropathy, which may rely on inhibition of ß-catenin signalling pathway.