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Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [-0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4. ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.

In this trial, patients with autosomal dominant polycystic kidney disease were randomly assigned to tolvaptan, a vasopressin V 2 -receptor antagonist, or placebo. Over 3 years, the increase in total kidney volume in the tolvaptan group was half that in the placebo group. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and the fourth leading cause of end-stage kidney disease in adults worldwide. 1 , 2 It results in the progressive development of kidney cysts, kidney pain, hypertension, and, ultimately, kidney failure. Effective treatment for ADPKD has been lacking. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its second messenger adenosine-3′,5′-cyclic monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V 2 -receptor blockade all reduce the . . .

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8 + T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8 + T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration. Cancer immunotherapy can be used in combination with other therapies for a better response. Here, the authors conduct a phase Ib clinical study and report the clinical activity and the immune response of the anti-PDL1 agent, atezolizumab, in combination with bevacizumab in ten patients with metastatic renal cell carcinoma.

In patients with autosomal dominant polycystic kidney disease, the rate of increase in total kidney volume was not slowed by lisinopril and telmisartan, as compared with lisinopril and placebo, but was slowed with rigorous blood-pressure control. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by gradual cyst enlargement over a period of decades before the loss of kidney function. 1 – 3 Total kidney volume in ADPKD is accurately measured with the use of magnetic resonance imaging (MRI). 4 – 6 Hypertension occurs early 6 , 7 and is associated with progression to end-stage renal disease (ESRD) and death from cardiovascular causes in patients with ADPKD. 8 , 9 Immunohistologic studies 10 , 11 and clinical studies 12 , 13 support a central role of the renin–angiotensin–aldosterone system (RAAS) in the pathogenesis of hypertension in patients with ADPKD. Activation of the RAAS may promote renal-cyst growth by means . . .

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60ml/min per 1.73m2. Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25–60ml/min per 1.73m2. We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log–transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log–transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Endothelial progenitor cells are known to reverse acute kidney injury by paracrine mechanisms. We previously found that microvesicles released from these progenitor cells activate an angiogenic program in endothelial cells by horizontal mRNA transfer. Here, we tested whether these microvesicles prevent acute kidney injury in a rat model of ischemia–reperfusion injury. The RNA content of microvesicles was enriched in microRNAs (miRNAs) that modulate proliferation, angiogenesis, and apoptosis. After intravenous injection following ischemia–reperfusion, the microvesicles were localized within peritubular capillaries and tubular cells. This conferred functional and morphologic protection from acute kidney injury by enhanced tubular cell proliferation, reduced apoptosis, and leukocyte infiltration. Microvesicles also protected against progression of chronic kidney damage by inhibiting capillary rarefaction, glomerulosclerosis, and tubulointerstitial fibrosis. The renoprotective effect of microvesicles was lost after treatment with RNase, nonspecific miRNA depletion of microvesicles by Dicer knock-down in the progenitor cells, or depletion of pro-angiogenic miR-126 and miR-296 by transfection with specific miR-antagomirs. Thus, microvesicles derived from endothelial progenitor cells protect the kidney from ischemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative program.

The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.

Developmental programming in the kidney has been recognised for more than two decades, but its contribution to the global burden of kidney diseases remains underappreciated by policy makers.3 In view of the many factors known to affect fetal kidney development, including maternal health and nutrition, exposure to stress, poverty, pollutants, drugs, and infections during gestation,3 a holistic strategy to prevent such programming effects is consistent with the life-course approach and aligns with the United Nations (UN) Sustainable Development Goals to foster health.2 Chronic kidney disease is an important contributor to the NCD burden that has been relatively neglected in WHO's Global Action Plan for the Prevention and Control of NCDs, despite chronic kidney disease being a major cause of hypertension and a major risk multiplier of cardiovascular disease.1,4 Although the prevalence of chronic kidney disease in many low-income countries remains unknown, the disease is most prevalent among disadvantaged populations within industrialised nations-eg, African-Americans and Aboriginal Australians.5 The number of people receiving dialysis or transplantation is projected to double, from 2·6 million in 2010 to 5·4 million in 2030.6 In 2010, 2·3-7·1 million adults died from lack of access to dialysis and transplantation in low-income countries.6 In view of the clinical outcomes and often prohibitively high costs of treatment, prevention and early detection are the only sustainable solutions to address this growing global burden. 16

In this 2-year, double-blind trial, patients with ADPKD were randomly assigned to receive either placebo or the mTOR inhibitor everolimus, since the mTOR pathway is important in cyst growth. Although everolimus slowed the increase in kidney volume, as assessed by means of magnetic resonance imaging, it did not slow the progression of renal impairment. Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1 of every 1000 persons in the general population 1 and develops, by means of slowly progressive renal-cyst growth, to end-stage renal disease in over 50% of patients. Hepatic and pancreatic cysts, as well as cerebral and abdominal aneurysms, contribute to ADPKD-associated morbidity and mortality. Arterial hypertension, recurrent urinary tract infection, nephrolithiasis, and abdominal pain are frequently the presenting symptoms. 2 Approximately 85% of patients with ADPKD have mutations in the polycystic kidney disease 1 gene ( PKD1 ), whereas most of the remaining 15% have polycystic kidney disease 2 gene ( PKD2 ) . . .

In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. Sirolimus (rapamycin) suppresses mTOR signaling and was studied in this 18-month open-label, randomized, controlled trial involving adults with ADPKD and early chronic kidney disease. Sirolimus at a daily target dose of 2 mg did not halt polycystic kidney growth. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary kidney disease and the cause of end-stage renal disease in 7 to 10% of all patients undergoing dialysis. 1 – 3 The disease is characterized by the growth of numerous kidney cysts, which leads to progressive destruction of the adjacent renal parenchyma and massive enlargement of the kidneys. 4 Renal function is often preserved until the age of 40 years because functioning nephrons undergo compensatory hypertrophy. 5 Subsequently, the glomerular filtration rate (GFR) decreases, and end-stage renal disease ensues in many patients by the fifth decade. As yet, no treatment is available to . . .