Multitarget therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy: a prospective randomized controlled trial.

BACKGROUND: The effectiveness of multitarget combination therapy with a corticosteroid, cyclosporine and mycophenolate mofetil for idiopathic membranous nephropathy (IMN) is unclear. In the present study, we aimed to compare the efficacy and safety of multitarget therapy with a cyclical corticosteroid-cyclophosphamide regimen in patients with IMN. METHODS: This was a single-centre, prospective, randomized, controlled trial. We randomly assigned patients with IMN to receive multitarget therapy (a combination of prednisone, cyclosporine and mycophenolate mofetil) or 6-month cyclical treatment with a corticosteroid and cyclophosphamide. The study patients were followed up for 12 months. The primary outcome was a composite of complete or partial remissions at 12 months. Adverse events were also assessed. RESULTS: The study cohort comprised 78 patients, 39 of whom received multitarget therapy and the other 39 cyclical alternating treatment with a corticosteroid and cyclophosphamide. At 12 months, 31 of 39 patients (79%) in the multitarget therapy group and 34 of 39 (87%) in the corticosteroid-cyclophosphamide group had achieved complete or partial remissions (relative risk 0.93; 95% confidence interval 0.72-1.21; P = .85; log-rank test). The prevalence of adverse events was significantly lower in the multitarget therapy group than in the corticosteroid-cyclophosphamide group [46% (18 of 39) vs 74% (29 of 39); P < .05]. CONCLUSIONS: Multitarget therapy for IMN patients is noninferior to cyclical alternating treatment with corticosteroid and cyclophosphamide in inducing proteinuria remission and has a better safety profile than the corticosteroid-cyclophosphamide combination.

Immunosuppressive therapy for progressive idiopathic membranous nephropathy: a cost-effectiveness analysis in China.

BACKGROUND: This study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective. METHODS: To estimate the cost-effectiveness of four regimens namely cyclophosphamide, cyclosporine, rituximab and tacrolimus-rituximab in treatment of IMN recommended by the updated Kidney Disease: Improving Global Outcomes (KDIGO) guideline 2021, a Markov model with five discrete states (active disease, remission, dialysis, kidney transplant and death) based on IMN patients aged 50 or above over a 30-years time horizon was constructed. Total costs were imputed from the Chinese healthcare system perspective, and health outcomes were converted into quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was used to describe the results. The willingness-to-pay (WTP) threshold was set at $12,044 (China's 2021 Gross Domestic Product per capita). Sensitivity analyses were performed to test the uncertainties of the results. RESULT: Compared with cyclophosphamide, both cyclosporine (incremental cost $28,337.09, incremental QALY-1.63) and tacrolimus-rituximab (incremental cost $28,324.13, incremental QALY -0.46) were considered at strictly dominated for their negative values in QALYs, and the ICER value of rituximab was positive (incremental cost $9,162.19, incremental QALY 0.44). Since the ICER of rituximab exceeds the pre-determined threshold, cyclophosphamide was likely to be the best choice for the treatment of IMN within the acceptable threshold range. The results of the sensitivity analysis revealed that the model outcome was mostly affected by the probability of remission in rituximab. In a probabilistic sensitivity analysis, cyclophosphamide had 62.4% probability of being cost-effective compared with other regimens when the WTP was $12,044 per QALY. When WTP exceeded $18,300, rituximab was more cost-effective than cyclophosphamide. CONCLUSION: Compared with cyclosporine, rituximab and tacrolimus-rituximab, our model results indicated that cyclophosphamide represented the most cost-effective regimen for patients with progressive IMN in China.

Pioglitazone downregulates Twist-1 expression in the kidney and protects renal function of Zucker diabetic fatty rats.

AIMS: Renal interstitial fibrosis and glomerulosclerosis are the characteristic presentation of diabetic nephropathy progression. Twist-1 overexpression contributes to renal fibrosis. Previous studies have demonstrated that pioglitazone (PIO), a PPAR-γ agonists, can ameliorate renal fibrosis and protect renal function. However, whether PIO attenuates renal fibrosis and delays diabetic nephropathy progression by regulating Twist-1 expression remains unclear. METHODS: Male Zucker diabetic fatty (ZDF) rats were randomly divided into 3 groups: (1) ZDF group, (2) ZDF + PIO group treated with PIO for 10 weeks, (3) ZDF + PIO + GW9662 group treated with GW9662 (a PPAR-γ antagonist) and PIO for 10 weeks. Age-matched Zucker lean rats (ZL group) were used as a control group. Urinary albumin/creatinine ratio (UACR) and renal blood flow were measured. Renal histopathology and Twist-1 expression were determined by immunohistochemistry. The protein and mRNA levels of Twist-1 and PPAR-γ were analyzed by Western blot and qRT-PCR. RESULTS: PIO considerably reduced UACR and improved renal blood flow. This was associated with amelioration of glomerulosclerosis and tubulointerstitial fibrosis evidenced by the expression decrease of collagen I, aquaporin 1, α-SMA, transforming growth factor ß1 and nephrin, although glycaemia remained high. Moreover, Twist-1 protein and mRNA expression in kidney of ZDF rats were significantly increased compared with ZL rats and PIO significantly decreased Twist-1 levels. CONCLUSIONS: This study shows that PIO can downregulate Twist-1 expression in the kidney, inhibit renal fibrosis and protect renal function in ZDF rats. These PIO-mediated effects are independent of glycemic control.

Role of UBIAD1 in Intracellular Cholesterol Metabolism and Vascular Cell Calcification.

Vascular calcification is an important risk factor associated with mortality among patients with chronic kidney disease. Intracellular cholesterol metabolism is involved in the process of vascular cell calcification. In this study, we investigated the role of UbiA prenyltransferase domain containing 1 (UBIAD1) in intracellular cholesterol metabolism and vascular cell calcification, and identified its subcellular location. Primary human umbilical vein smooth muscle cells (HUVSMCs) were incubated with either growth medium (1.4 mmol/L Pi) or calcification medium (CM) (3.0 mmol/L Pi). Under treatment with CM, HUVSMCs were further incubated with exogenous cholesterol, or menaquinone-4, a product of UBIAD1. The plasmid and small interfering RNA were transfected in HUVSMCs to alter the expression of UBIAD1. Matrix calcium quantitation, alkaline phosphatase activity, intracellular cholesterol level and menaquinone-4 level were measured. The expression of several genes involved in cholesterol metabolism were analyzed. Using an anti-UBIAD1 antibody, an endoplasmic reticulum marker and a Golgi marker, the subcellular location of UBIAD1 in HUVSMCs was analyzed. CM increased matrix calcium, alkaline phosphatase activity and intracellular cholesterol level, and reduced UBIAD1 expression and menaquinone-4 level. Addition of cholesterol contributed to increased matrix calcification and alkaline phosphatase activity in a dose-dependent manner. Elevated expression of UBIAD1 or menaquinone-4 in HUVSMCs treated with CM significantly reduced intracellular cholesterol level, matrix calcification and alkaline phosphatase activity, but increased menaquinone-4 level. Elevated expression of UBIAD1 or menaquinone-4 reduced the gene expression of sterol regulatory element-binding protein-2, and increased gene expression of ATP binding cassette transporters A1, which are in charge of cholesterol synthesis and efflux. UBIAD1 co-localized with the endoplasmic reticulum marker and the Golgi marker in HUVSMCs. In conclusion, high intracellular cholesterol content contributes to phosphate-induced vascular cell differentiation and calcification. UBIAD1 or menaquinone-4 could decrease vascular cell differentiation and calcification, probably via its potent role of inversely modulating cellular cholesterol.

[Retrospective analysis of influence of differential protein intake on renal prognosis for progressive chronic kidney disease].

OBJECTIVE: To explore retrospectively the influence of differential protein intake on renal prognosis for progressive chronic kidney disease (CKD). METHODS: A total of 159 chronic kidney disease patients at stages 2, 3 and 4 were enrolled and a questionnaire survey was conducted from January 2009 to July 2012. They were followed monthly and their clinical data collected, including primary disease, blood pressure, body mass index and adverse events. Laboratory tests were performed every 3 months, including biochemical parameters, protein-energy malnutrition (PEM), diet reviews and daily protein intake (DPI). A simplified MDRD formula was employed to evaluate the level of estimated glomerular filtration rate (eGFR). According to the level of DPI, they were divided into 3 groups of very low protein diet (VLPD): DPI ≤ 0.6 g · kg(-1) · d(-1), low-protein diet (LPD): DPI >0.6-<0.8 g · kg(-1) · d(-1) and normal-protein diet (NPD): DPI ≥ 0.8 · g · kg(-1) · d(-1). RESULTS: Among them, 4 cases (2.50%) progressed to uremia stage and received renal replacement therapy, 2(1.25%) experienced rapid decline in renal function, 9(5.66%) were hospitalized from cardio-cerebral diseases and the 2-year kidney survival rate was 97.5%. At the end of study, among 9 patients of PEM, 2 subjects had a serum level of albumin under 32 g/L and another 7 with a BMI<20 kg/m(2). No significant difference existed in PEM among different stages of CKD. There was no significant correlation between DPI and Δ GFR (all P > 0.05). CONCLUSION: Within a certain range, differential protein intake may not significantly affect the prognosis of kidney for progressive CKD patients.

The inhibitory effect of quercetin on asymmetric dimethylarginine-induced apoptosis is mediated by the endoplasmic reticulum stress pathway in glomerular endothelial cells.

Asymmetric dimethylarginine (ADMA) is considered an independent mortality and cardiovascular risk factor in chronic kidney disease (CKD) patients, and contributes to the development of renal fibrosis. Quercetin (QC), a natural component of foods, protects against renal injury. Here, we explored the possible mechanisms that are responsible for ADMA-induced renal fibrosis and the protective effect of QC. We found that ADMA treatment activated the endoplasmic reticulum (ER) stress sensor proteins phosphorylated protein kinase RNA-activated-like ER kinase (PERK) and inositol requiring-1α (IRE1), which correspondingly induced C/EBP homologous protein (CHOP) expression and phosphorylated c-Jun N-terminal kinase (JNK) phosphorylation in glomerular endothelial cells (GEnCs). Following this, ADMA promoted ER stress-induced apoptosis and resulted in transforming growth factor ß (TGF-ß) expression in GEnCs. SP600125, an inhibitor of JNK, and CHOP siRNA protected against ADMA-induced cell apoptosis and TGF-ß expression. QC prevented ADMA-induced PERK and IRE1 apoptotic ER stress pathway activation. Also, ADMA-induced GEnCs apoptosis and TGF-ß expression was reduced by QC. Overexpression of CHOP blocked QC-mediated protection from apoptosis in ER stressed cells. Overall, these observations indicate that ADMA may induce GEnCs apoptosis and TGF-ß expression by targeting the PERK-CHOP and IRE1-JNK pathway. In addition, drugs such as QC targeting ER stress may hold great promise for the development of novel therapies against ADMA-induced renal fibrosis.

Effect of long intermittent hemodialysis on improving dialysis adequacy of maintenance hemodialysis patients.

BACKGROUND: With the increase in hemodialysis (HD) patients, the blood dialysis patient's quality of life (QoL) and long-term survival are still a challenge for clinicians. Recent studies have found that most of the HD patients have sleep disorders, which have a certain correlation with long-term survival and QoL. But there are few studies of Chinese in this field. This study aimed to investigate whether increasing the dialysis dose can improve sleep quality, so we treated HD patients on long intermittent hemodialysis (LIHD). METHODS: Forty patients who were treated by conventional HD at the Beijing Friendship Hospital Blood Purification Center were offered the option of LIHD. The patients' laboratory data, medication use, and questionnaire answers were analyzed. Conventional HD was delivered thrice weekly with 4 hours per treatment, and LIHD was delivered thrice weekly with 8 hours per treatment. The study lasted 6 months. Questionnaires included sleep quality survey and QoL SF-36; the former includes the Athens Insomnia Scale, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). RESULTS: After conversion to LIHD the dialysis efficiency (Kt/V) significantly increased than before (P < 0.05) and clearance rate of urea nitrogen also increased from 67 to 78% (P < 0.01). After conversion, median values for Hb increased from 108.95 to 126.55 g/L (P < 0.01); albumin increased from 38.85 to 40.05 g/L (P < 0.01). Phosphorus decreased from 2.69 to 1.54 mmol/L (P < 0.01), but there was no alteration in blood calcium; phosphorus and calcium-phosphate product levels were under more control, but parathyroid hormone (iPTH) level did not change after conversion to LIHD. After conversion, blood pressure (BP) was better controlled than before and the mean number of antihypertensive drugs prescribed declined from 2.9 to 0.5 (P < 0.01). There was a significant reduction in the use of erythropoietin-stimulating agent of 5250 U/w (P < 0.01). Sleep quality significantly improved in the 2 months after conversion to LIHD, and the PSQI score decreased from 10.80 to 5.45 and the ESS score decreased from 12.05 to 5.30 (P < 0.01). However, sleep quality started to decline after 2 months on LIHD. QoL SF-36 score increased from 410.92 to 592.53 (P < 0.01). CONCLUSION: LIHD offers an effective improvement in dialysis adequacy for Chinese maintenance HD patients, but it improves sleep quality only briefly which may be related to loss of serum calcium and parathyroid dysfunction.

One hemodialysis patient with headache, blurred vision, and hypotension induced by pituitary prolactinoma.

We reported a rare case of a dialysis patient coincident pituitary prolactinoma with calcification. A 55-year-old woman who had undergone hemodialysis for 8 years was admitted to the nephrology unit because of headache, blurred vision, and hypotension. Physical examination was normal; endocrinological examination demonstrated elevated serum levels of prolactin (> 4240 mIU/L), but other hormonal profiles, such as growth hormon, adrenocorticotropic hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, follicle-stimulating hormone and luteinizing hormone, were absolutely or relatively lower. A cranial computed tomography (CT) suggested saddle area a high-density screenage with an anteroposterior diameter of 1.0 cm. A cerebral magnetic resonance scan confirmed the pituitary adenoma accompanied with calcification. Contrast-enhanced T1-weighted images revealed a less enhancing tumor, 14 mm wide round lesion with a high intensity signal. It enlarges the sella turcica, but the optic chiasma is not displaced. We suggest that in the differential diagnosis of any hemodialysis patient with severe headache, hypotension, and visual disturbances, this syndrome should be considered as prompt pituitary adenoma.

Preservation of residual renal function with limited water removal in hemodialysis patients.

Residual renal function (RRF) is of paramount importance for hemodialysis (HD) adequacy, morbidity, and mortality. Some studies have shown that overhydration is beneficial for preservation of RRF, but it can also increase the probability of adverse events such as hypertension and heart failure in HD patients. To determine the optimal amount of dehydration, we performed HD with limited water removal in HD patients. Eighteen HD patients included in this self-controlled study underwent HD with limited water removal. Water removal volume was determined by a previous volume as follows. Total water removal volume was divided into levels: ≤3.0, 3.0-9.0, and >9.0 L per week. Water removal was performed to obtain dry weight in the last dialysis, and was performed three times with a ratio of 1:1:2 and 2:2:3, respectively. Urine volume, endogenous creatinine clearance rate, Kt/V, hemoglobin, and serum albumin were recorded before and after the study at 3, 6, 9, and 12 months. The follow-up period was 12 months. Ten patients withdrew from the study because of adverse events including hypertension (n = 3), heart failure (n = 3), angina (n = 1), polycystic kidney rupture (n = 1), obvious edema (n = 1), and one patient had too much interdialytic weight gain to continue. As a result, we stopped this study after 1 month. Our data suggest that the preservation of RRF with limited water removal in HD patients must be interpreted with caution.