Emerging non-pharmacological interventions in ADPKD:an update on dietary advices for clinical practice

Purpose of review Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) reach kidney failure at a median age of 58 years. There has been a strong interest in medical interventions to improve prognosis. With increasing understanding of the underlying pathophysiology, there is also a rationale for non-pharmaceutical interventions. However, these have received little attention. This review, therefore, focuses on dietary interventions in ADPKD. Recent findings Recent studies regarding salt, protein and water intake, caloric restriction, BMI, caffeine and alcohol are discussed in this review. In general, these studies suggest that advices do not need to be different from those in chronic kidney disease (CKD). On the basis of research in the general population and CKD, these advices will likely decrease cardiovascular morbidity and mortality. With respect to delaying ADPKD progression, evidence for salt restriction is growing. For increasing water intake and targeting glucose metabolism by intermittent fasting, preclinical studies are promising. Long-term randomized human intervention studies are, however, lacking. In ADPKD, advices regarding dietary interventions can, in general, be the same as in CKD to decrease cardiovascular morbidity and mortality. Whether these interventions also delay disease progression needs further study

Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD

Somatostatin in renal physiology and autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD

Thiazide diuretics and the rate of disease progression in autosomal dominant polycystic kidney disease:an observational study

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin-angiotensin-aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. METHODS: We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. RESULTS: A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference -0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) -0.83 to -0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5-4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI -0.46 to -0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05-2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50-1.29), P = 0.4]. CONCLUSIONS: These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives

Control of Electrons' Spin Eliminates Hydrogen Peroxide Formation during Water Splitting

The production of hydrogen through water splitting in a photoelectrochemical cell suffers from an overpotential that limits the efficiencies. In addition, hydrogen-peroxide formation is identified as a competing process affecting the oxidative stability of photoelectrodes. We impose spin-selectivity by coating the anode with chiral organic semiconductors from helically aggregated dyes as sensitizers; Zn-porphyrins and triarylamines. Hydrogen peroxide formation is dramatically suppressed, while the overall current through the cell, correlating with the water splitting process, is enhanced. Evidence for a strong spin-selection in the chiral semiconductors is presented by magnetic conducting (mc-)AFM measurements, in which chiral and achiral Zn-porphyrins are compared. These findings contribute to our understanding of the underlying mechanism of spin selectivity in multiple electron-transfer reactions and pave the way toward better chiral dye-sensitized photoelectrochemical cells

Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial

BACKGROUND AND PURPOSE: Body temperature is a strong predictor of outcome in acute stroke. However, it is unknown whether antipyretic treatment leads to early and clinically worthwhile reduction of body temperature in patients with acute stroke, especially when they have no fever. The main purpose of this trial was to study whether early treatment of acute ischemic stroke patients with acetaminophen (paracetamol) reduces body temperature. METHODS: Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 500 mg (low dose) or 1000 mg (high dose) acetaminophen or with placebo, administered as suppositories 6 times daily during 5 days. Body temperatures were measured with a rectal electronic thermometer at the start of treatment and after 24 hours and with an infrared tympanic thermometer at 2-hour intervals during the first 24 hours and at 6-hour intervals thereafter. The primary outcome measure was rectal temperature at 24 hours after the start of treatment. RESULTS: Treatment with high-dose acetaminophen resulte

High Circular Polarization of Electroluminescence Achieved via Self-Assembly of a Light-Emitting Chiral Conjugated Polymer into Multidomain Cholesteric Films.

We demonstrate a facile route to obtain high and broad-band circular polarization of electroluminescence in single-layer polymer OLEDs. As a light-emitting material we use a donor-acceptor polyfluorene with enantiomerically pure chiral side-chains. We show that upon thermal annealing the polymer self-assembles into a multidomain cholesteric film. By varying the thickness of the polymer emitting layer, we achieve high levels of circular polarization of electroluminescence (up to 40% excess of right-handed polarization), which are the highest reported for polymer OLEDs not using chiral dopants or alignment layers. Mueller matrix ellipsometry shows strong optical anisotropies in the film, indicating that the circular polarization of luminescence arises mainly after the photon has been generated, through selective scattering and birefringence correlated in the direction of the initial linear polarization of the photon. Our work demonstrates that chirally substituted conjugated polymers can combine photonic and semiconducting properties in advanced optoelectronic devices