Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

BackgroundThe transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1.Methodology/Principal FindingsBy using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL) fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves.ConclusionsOur results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests that non-neuronal TRPA1 in the airways is functional and potentially capable of contributing to inflammatory airway diseases.

Background. The utility of renal biopsy in patients with diabetes is highly debated. Diabetics with rapidly worsening renal disease are often 'clinically' labelled as having diabetic nephropathy (DN), whereas, in many cases, they are rather developing a nondiabetic renal disease (NDRD) or mixed forms (DN þ NDRD). Methods. We performed a systematic search for studies on patients with diabetes with data on the frequency of DN, NDRD and mixed forms, and assessed the positive predictive values (PPVs) and odds ratios (ORs) for such diagnoses by metaanalysing single-study prevalence. Possible factors explaining heterogeneity among the different diagnoses were explored by meta-regression. Results. In the 48 included studies (n ¼ 4876), the prevalence of DN, NDRD and mixed forms ranged from 6.5 to 94%, 3 to 82.9% and 4 to 45.5% of the overall diagnoses, respectively. IgA nephropathy was the most common NDRD (3-59%). PPVs for DN, NDRD and mixed forms were 50.1% [95% confidence interval (CI): 44.7-55.2], 36.9% (95% CI: 32.3-41.8) and 19.7% (95% CI: 16.3-23.6), respectively. The PPV when combining NDRD and mixed forms was 49.2% (95% CI: 43.8-54.5). Metaregression identified systolic pressure, HbA1c, diabetes duration and retinopathy as factors explaining heterogeneity for NDRD, creatinine and glomerular filtration rate for mixed forms and only serum creatinine for DN. ORs of DN versus NDRD and mixed forms were 1.71 (95% CI: 1.54-1.91) and 4.1 (95% CI: 3.43-4.80), respectively. Conclusions. NDRD are highly prevalent in patients with diabetes. Clinical judgment alone can lead to wrong diagnoses and delay the establishment of adequate therapies. Risk stratification according to individual factors is needed for selecting patients who might benefit from biopsy.

Background: Although the number of patients reaching end-stage kidney disease without a biopsy-proven diagnosis is increasing, the utility of renal biopsy is still an object of debate. We analyzed epidemiological data and the main indications for renal biopsy with a systematic, evidence-based review at current literature. Summary: There is a high discrepancy observed in biopsy rates and in the epidemiology of glomerular diseases worldwide, related to the different time frame of the analyzed reports, lack of data collection, the different reference source population and the heterogeneity of indications. The evidence-based analysis of indications showed that renal biopsy should be crucial in adults with nephrotic syndrome or urinary abnormalities as coexistent hematuria and proteinuria and in corticosteroid resistant-children with severe proteinuria. The knowledge of renal histology can change the clinical management in patients with acute kidney injury significantly, after the exclusion of pre-renal or obstructive causes of kidney damage. Scarce evidence indicates that renal biopsy can be useful in patients with advanced chronic kidney disease and its use should always be considered after weighing the benefits and potential risks. Renal biopsy should be crucial in patients with renal involvement due to systemic disease. In patients with diabetes with atypical features, renal biopsy may be fundamental to diagnose an unexpected parenchymal disease mislabeled as diabetic nephropathy. Finally, in elderly patients, the indications and the risks are not different from those in the general population. Key Message: Renal biopsy still remains a concrete approach for managing a substantial percentage of renal diseases.

Muscle sympathetic nerve activity (MSNA) has shown that sympathetic activation may occur in essential hypertension (EHT). However, the small sample size of the studies, the heterogeneity of the patients examined, and the presence of confounders represented major weaknesses not allowing to draw definite conclusions. Among the 432 studies identified providing information in EHT on MSNA, 63 were eligible (1216 patients) and meta-analyzed grouping them on the basis of clinically relevant questions: (1) Is MSNA increased in hypertension of mild/moderate-to-severe degree? (2) Does sympathetic activation occur in borderline, white-coat, and masked EHT? (3) Is MSNA related to clinic and ambulatory blood pressure and target organ damage? (4) Are heart rate and venous plasma norepinephrine valuable surrogate markers of MSNA in clinical practice? The results show that MSNA was significantly greater (1.5×; <0.001) in mild-to-moderate and severe EHT as compared with normotensive controls and that this was the case also in borderline, white-coat, and masked hypertension as well. Interestingly, MSNA was significantly greater in both untreated and treated hypertension (<0.001 for both), related to clinic and ambulatory blood pressure (=0.67 and =0.83;<0.001 for both), inversely related to heart rate (=-0.38; <0.001) and directly to venous plasma norepinephrine (=0.28; <0.001) and left ventricular mass index (=0.27; <0.001). Thus, EHT is a condition characterized by a sustained sympathetic overdrive, whose magnitude is proportional to its clinical severity. This is more clearly manifest when MSNA rather than indirect markers of adrenergic drive, such as heart rate and plasma norepinephrine, are used.