Heparanase: another renal player controlled by vitamin D

Vitamin D deficiency is inevitable in chronic kidney diseases. Clinical and experimental therapies with vitamin D supplements or analogues have demonstrated nephroprotective effects, which vitamin D exerts partly by controlling the renin–angiotensin–aldosterone system, but also by modulating other signalling pathways. In recent work published in the Journal of Pathology, Garsen and colleagues identified heparanase as a novel target of vitamin D and its antiproteinuric activity. Heparanase is an endoglycosidase with a role in remodelling the extracellular matrix through its ability to degrade heparan sulphate, and is involved in the pathogenesis of several proteinuric and fibrotic renal diseases. The new evidence that vitamin D inhibits heparanase expression sets the stage for a better understanding of the vitamin's kidney‐protecting effects and its possible application to proteinuric and non‐proteinuric chronic kidney diseases. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Does exercise echocardiography have an added value over exercise testing alone in asymptomatic patients with severe aortic stenosis?

BACKGROUND AND AIM OF THE STUDY: The study aim was to assess the clinical utility and added value of exercise stress echocardiography (ESE) over exercise testing alone in asymptomatic patients with severe aortic stenosis (AS). METHODS: The results of treadmill ESE in 101 consecutive patients (59 males, 42 females; mean age 69 +/- 10 years; range: 35-85 years) with asymptomatic severe AS (aortic valve area (AVA) <1 cm2 and/or mean transvalvular pressure gradient > or =50 mmHg) and normal left ventricular function, were analyzed. The test was considered abnormal if stopped prematurely because of limiting symptoms, a fall or small rise in systolic blood pressure, or complex ventricular arrhythmia. RESULTS: The mean resting AVA was 0.74 +/- 0.13 cm2, and peak and mean transvalvular gradients were 91 +/- 19 and 57 +/- 13 mmHg, respectively. In total, 69 patients (68%) developed an abnormal response, including symptoms (n = 48) and abnormal blood pressure response (n = 44). There were no cases of syncope or other major complications. Exercise transaortic pressure gradients could not be used to discriminate patients with otherwise normal and abnormal ESE or cardiac events. An abnormal contractile response was observed in 12 patients, in seven of whom it was the only ESE abnormal parameter. A total of 96 patients (95%) was followed up for a mean of 35 +/- 14 months. Aortic valve replacement-free survival was significantly lower in patients with an abnormal ESE result compared to those with a normal result. CONCLUSION: ESE has a limited added value to exercise testing alone in asymptomatic patients with severe AS. In a small percentage of these cases an abnormal contractile response, despite otherwise normal exercise parameters, constitutes a new finding that deserves further investigation.     

Hypomethylation of NLRP3 gene promoter discriminates glucocorticoid‐resistant from glucocorticoid‐sensitive idiopathic nephrotic syndrome patients

AbstractTo assess whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid (GC)‐resistant from GC‐sensitive idiopathic nephrotic syndrome (INS), patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), we measured the methylation level of NLRP3 promoter in DNA from peripheral blood cells of 10 adult patients with GC‐resistant FSGS already in hemodialysis and 18 patients with GC‐sensitive INS (13 MCD/5 FSGS) and in 21 pediatric patients with INS with MCD/FSGS before starting any treatment. Association of NLRP3 inflammasome with GC resistance was recapitulated in vitro in monocytic cell lines (THP‐1 and U937). In both adults and pediatric patients, NLRP3 promoter methylation was significantly reduced in GC‐resistant compared with GC‐sensitive patients. Indeed, NLRP3 methylation distinguished GC‐resistant and GC‐sensitive patients (area under the receiver operating characteristic curve [AUROC] 86.7% in adults, p = 0.00019, and 73.5% in children, p = 0.00097). NLRP3 knock‐down augmented sensitivity to GCs in THP‐1 cells, whereas NLRP3 inflammasome activation lowered GC receptor concentration, increasing GC resistance in U937 cells. Our results uncovered a new biological mechanism by which patients with INS may acquire GC resistance, that could be used in future as a novel noninvasive diagnostic tool. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Approximately 80% of patients with idiopathic nephrotic syndrome (INS) respond to glucocorticoids, with the remaining 20% being steroid‐resistant.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid‐resistant from glucocorticoid (GC)‐sensitive INS.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ In both adults and children, NLRP3 promoter methylation was significantly reduced in leukocytes of patients with GC‐resistant compared with GC‐sensitive INS. NLRP3 inflammasome activation lowered GC receptor concentration and augmented GC resistance, whereas NLRP3 knockdown increased sensitivity to GCs in cell lines representative of monocytes (U937 and THP1).

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Our findings uncovered a new biological mechanism whereby patients with INS may develop resistance to GCs that could be used in the future as a novel noninvasive diagnostic tool.     

Validation of a Georgian language headache questionnaire in a population-based sample

In a pilot phase of a survey of the prevalence of primary headache disorders in the Republic of Georgia, we validated a Georgian language questionnaire for migraine (MIG), tension-type headache (TTH), MIG+TTH and trigeminal autonomic cephalalgias (TAC). A population-based sample of 186 people with headache completed the questionnaire and were blindly examined by one of two headache experts. The questionnaire diagnoses were: MIG 49, TTH 76, MIG+TTH 45 and TAC 16. The physicians’ diagnoses were: MIG 59, TTH 77, MIG+TTH 34, TAC 2 and “symptomatic headache” in 14 subjects. Sensitivity and specificity for MIG were 0.75 and 0.96, for TTH 0.79 and 0.86, and for MIG+TTH 0.61 and 0.84 respectively. Of 16 TAC diagnoses, the physicians confirmed cluster headache in two patients only. The questionnaire can be utilised to investigate the prevalence of MIG and of TTH. It offers preliminary screening only for TAC, which should be confirmed during a face to face examination. This is a “Springer Open Choice” article. Unrestricted non-commercial use, distribution, and reproduction in any medium is permitted, provided the original author and source are credited. An erratum to this article can be found at     

Refractory chronic migraine: a Consensus Statement on clinical definition from the European Headache Federation

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).     

Role and mechanism of subcellular Ca2+ distribution in the action of two inotropic agents with different toxicity

Pro-arrhythmic risk strongly limits the therapeutic value of current inotropic interventions. Istaroxime (previously PST2744) is a novel inotropic agent, significantly less pro-arrhythmic than digoxin that, in addition to block Na⁺/K⁺ pump, stimulates sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA2). Here we compare istaroxime and digoxin effects to further address the role of SR modulation in reducing the toxicity associated with Na⁺/K⁺ pump blockade. In murine ventricular myocytes both compounds increased cell twitch (inotropy) in a concentration-dependent fashion. At high concentrations digoxin, but not istaroxime, induced unstimulated contractions, a sign of pro-arrhythmic toxicity. To evaluate the mechanism of this difference, we compared the two drugs at concentrations exerting equal inotropy but different toxicity. At these concentrations: (1) the two drugs equally inhibited the Na⁺/K⁺ pump; (2) digoxin induced larger increases in resting Ca²⁺ and in diastolic Ca²⁺ during pacing; (3) neither drug affected the relationship between RyR-mediated SR Ca²⁺ leak and Ca²⁺ content; (4) istaroxime, but not digoxin, enhanced SR Ca²⁺ reuptake rate. In conclusion, digoxin toxicity was associated to larger accumulation of cytosolic Ca²⁺, which did not result from RyR facilitation, but which might ultimately induce it to promote unstimulated Ca²⁺ release. The lower toxicity of Na⁺/K⁺ pump blockade by istaroxime may thus reflect improved Ca²⁺ confinement within the SR, likely to result from concomitant SERCA2 stimulation.