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Chronic inflammation is associated with cachexia and increased mortality risk in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Inflammation suppresses appetite and causes the loss of protein stores. In CKD patients, increased serum levels of pro-inflammatory cytokines may be caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions. Cachexia is brought about by the synergistic combination of a dramatic decrease in appetite and an increase in the catabolism of fat and lean body mass. Pro-inflammatory cytokines act on the central nervous system to alter appetite and energy metabolism and to provide a signal—through the nuclear factor-κB and ATP-ubiquitin-dependent proteolytic pathways—that causes muscle wasting. Further research into the molecular pathways leading to inflammation and cachexia may lead to novel therapeutic therapies for this devastating and potentially fatal complication of chronic disease. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation in patients with predialysis chronic kidney disease (CKD) is quite common. We aimed to investigate the relationship of the percentage of immature granulocytes (IG%) and immature granulocyte count (IGC) with inflammation in children with predialysis CKD. Methods: The data from children with stage 2–4 CKD and a control group of healthy children were evaluated retrospectively. A highly-sensitive C-reactive protein (hs-CRP) level above 5 mg/dL was considered the presence of inflammation. The IGCs were calculated in the white cell differential channel of the Sysmex XN-9000 using the fluorescent flow cytometry method. The IG% was expressed as percentage of total leucocyte concentration. Results: The data from 57 patients (30 stage 2 CKD, 15 stage 3 CKD, 12 stage 4 CKD) and 46 controls were analyzed. hs-CRP levels, IG%, IGC, white blood cell (WBC) and neutrophil counts, and neutrophil-to-lymphocyte ratio (NLR) were higher in patients than the control group (p < 0.000, p < 0.000, p < 0.000, p = 0.001, p = 0.002, p < 0.000, respectively). Both IG% and IGC were positively correlated with hs-CRP, WBC and neutrophil counts, and NLR (r = 0.485, p < 0.000; r = 0.379, p = 0.004; r = 0.543, p < 0.000; r = 0.628, p < 0.000 for IG%; r = 0.379, p = 0.004; r = 0.351, p = 0.007; r = 0.525, p < 0.000; r = 0.601, p < 0.000 for IGC, respectively). A ROC analysis of the relationship between IGC, IG%, and inflammation showed IGC and IG% had predictive value for the presence of inflammation (cut-off value: 0.035 × 106/mL, AUC: 0.799 ± 0.061, sensitivity: 74.2%, specifity: 63%, p < 0.001 for IGC; cut-off value: 0.45%, AUC: 0.838 ± 0.056, sensitivity: 70.8%, specifity: 67.3%, p = 0.001 for IG%). Conclusions: Immature granulocytes may be used as a biomarker of inflammation in children with predialysis CKD. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Background: Skin autofluorescence (sAF) was examined as a marker of the accumulation of advanced glycation end products (AGEs) in tissues of children with chronic kidney disease (CKD) in relation to renal function, dialysis modality and markers of endothelial inflammation and dysfunction. Methods: A total of 76 children with CKD were enrolled in the study, of whom 20 children were on hemodialysis (HD), 20 were on peritoneal dialysis (PD) and 36 were treated conservatively. A control group of 26 healthy subjects was also included in the study. In all children, sAF intensity, carotid intima-media (cIMT) thickness and plasma concentrations of sE-selectin, matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and plasminogen activator inhibitor type 1 (PAI-1) were measured. Results: Compared to the controls, children with CKD had significantly elevated sAF levels. sAF in the children with CKD was positively correlated with sE-selectin, MMP-9, TIMP-1, ADMA, SDMA and PAI-1 levels. In the predialysis group (conservative treatment) sAF levels were positively correlated with sE-selectin and ADMA levels and negatively correlated with glomerular filtration rate. Multiple regression analysis showed a significant association of sAF with sE-selectin and MMP-9 in CKD children. Conclusions: The results reveal that AGEs were accumulated in the children with CKD. This accumulation was related to early vascular changes and a number of biochemical vascular risk markers. sAF measurement, as a noninvasive method, may be useful for identification of clinical risk factors of vascular disease in CKD children. [ABSTRACT FROM AUTHOR]

Protein-energy wasting (PEW), a condition of decreased body protein and fat mass, is highly prevalent in patients with chronic kidney disease (CKD) and a potent predictor of mortality in this population. In adults with CKD, PEW has typically been defined on the basis of (1) deranged biochemical parameters, (2) reduced body mass, (3) reduced muscle mass, and (4) decreased dietary protein intake. Emerging data suggest that PEW may also commonly afflict children with CKD and have a negative impact on growth and development ('uremic failure to thrive'), yet it remains comparatively understudied and less well characterized in these patients. Given the challenges of applying adult-defined PEW criteria to the pediatric population, the authors of a recent study entitled 'Protein energy wasting in children with chronic kidney disease' [Abraham et al. (2014) Pediatr Nephrol 29:1231-1238] have sought to develop a scoring system and three alterative definitions for this condition using a combination of biochemical markers, clinical measurements, and subjective reporting in children in the CKiD cohort: (1) minimal PEW definition (≥2 adult-defined PEW criteria); (2) standard PEW definition (≥3 adult-defined PEW criteria); (3) modified PEW definition (≥3 adult-defined PEW criteria, plus short stature or poor growth). These authors observed that meeting the modified PEW definition was associated with a significantly increased risk of hospitalization in unadjusted analyses, i.e., a 2.2-fold higher risk, and trended towards increased risk in multivariable adjusted analyses, i.e., 2.0-fold higher risk. At the present time, future studies validating these findings and developing further refined definitions and/or scoring systems for the detection and management of PEW in children and uremic failure to thrive are urgently needed. [ABSTRACT FROM AUTHOR]

Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function. [ABSTRACT FROM AUTHOR]

Background: We examined skin autofluorescence (sAF) in chronic kidney disease children (CKD) in relation to renal function and dialysis modality. Methods: Twenty children on hemodialysis (HD), 20 on peritoneal dialysis (PD), 36 treated conservatively, and 26 healthy subjects were enrolled into the study. In all children sAF, pulse-wave velocity indexed to height (PWV/ht), left ventricular mass index (LVMI), blood pressure (BP), serum lipid profile, phosphate (P), calcium (Ca), and homocysteine were measured. Results: sAF was significantly elevated in CKD groups vs. controls and was significantly associated with PWV/ht, LVMI, BP, P, Ca × P product and homocysteine. sAF in HD and PD groups was positively correlated with dialysis vintage, and in the predialysis group negatively correlated with glomerular filtration rate (eGFR). Multiple regression analysis showed significant association of sAF with LVMI and P in the CKD patient group, and with dialysis treatment duration and BP in dialyzed children. Conclusions: In CKD children, tissue accumulation of advanced glycation end-products (AGEs) was observed. This was aggravated as eGFR declined and was related to early cardiovascular changes and some biochemical cardiovascular disease (CVD) risk markers. sAF as a non-invasive method may be a useful tool for identification of a clinical risk factors of cardiovascular disease in CKD children. [ABSTRACT FROM AUTHOR]

In the course of chronic kidney disease (CKD) the intracellular erythrocyte calcium (Ca) level increases along with the progression of the disease. The decreased activity of Ca-Mg-dependent ATP-ase (PMCA) and its endogenous modulators calmodulin (CALM), calpain (CANP), and calpastatin (CAST) are all responsible for disturbed calcium metabolism. The aim of the study was to analyze the activity of PMCA, CALM, and the CANP-CAST system in the red blood cells (RBCs) of hemodialyzed (HD) children and to estimate the impact of a single HD session on the aforementioned disturbances. Eighteen patients on maintenance HD and 30 healthy subjects were included in the study. CALM, Ca levels and basal PMCA (bPMCA), PMCA, CANP, and CAST activities were determined in RBCs before HD, after HD, and before the next HD session. Prior to the HD session, the level of Ca and the CAST activity were significantly higher, whereas bPMCA, PMCA, and CANP activities and the CALM level were significantly lower than in controls. After the HD session, the Ca concentration and the CAST activity significantly decreased compared with the basal values, whereas the other parameters significantly increased, although they did not reach the levels of healthy children. The values observed prior to both HD sessions were similar. Ca homeostasis is severely disturbed in HD children, which may be caused by the reduction in the PMCA activity, CALM deficiency, and CANP-CAST system disturbances. A single HD session improved these disturbances but the effect is transient. [ABSTRACT FROM AUTHOR]

Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nε-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P<0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P<0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabe-tic children showed significantly elevated pentosidine levels (P<0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics. [ABSTRACT FROM AUTHOR]

In adults, advanced glycation end products (AGEs) rise slowly in tissues and circulation during aging, and accumulate at an accelerated rate both in diabetes and chronic renal insufficiency (CRI). We aimed to investigate the pattern of AGE accumulation in children/adolescents with CRI and on renal replacement therapy by dialysis and transplantation. Concentrations of fluorescent AGEs, carboxymethyllysine (CML) and lipofuscin-like substance (LFLS, a marker of lipid peroxidation) were followed. Data were obtained from 11 CRI patients on conservative treatment (age 12.6±1.7 years, serum creatinine: 205.7±17.5 µmol/l), ten patients on renal replacement therapy with dialysis (13.6±1.7 years, 698.2±48.9 µmol/l) and nine patients after kidney transplantation (15.9±1.1 years, 115.9±12.0 µmol/l) and comparison made with the data from 28 healthy controls (11.8±8.2 years, 44.1±8.2 µmol/l). In controls, an age-dependent rise of fluorescent AGE and CML levels was observed. In the CRI group, fluorescent AGEs [0.38±0.03×10[sup 5] arbitrary units (AU)] and CML (369±26 ng/ml) concentrations were doubled compared with controls (0.16±0.03×10[sup 5] AU and 189±42 ng/ml, respectively) and even higher levels were revealed in dialyzed patients (0.80±0.05×10[sup 5] AU; 650±94 ng/ml). Successful kidney transplantation significantly reduced but did not normalize fluorescent AGE levels (0.39±0.03 ×10[sup 5] AU), while the decline in CML levels (550±47 ng/ml) was insignificant. Plasma LFLS was elevated in CRI (19.6± 1.7 AU) and was even higher in dialyzed children (32.0±5.3 AU) compared with healthy controls (7.1± 1.4 AU). Kidney transplantation did not normalize LFLS levels (20.3±5.3 AU), pointing to persistently enhanced lipid peroxidation. Our study provides the first data on enhanced fluorescent AGEs and CML levels in children/adolescents wit... [ABSTRACT FROM AUTHOR]

Author(s): Nuran Cetin [sup.1] , Evin Kocaturk [sup.2] , Asli Kavaz Tufan [sup.1] , Zeynep Kusku Kiraz [sup.2] , Ozkan Alatas [sup.2] Author Affiliations: (1) grid.164274.2, 0000 0004 0596 2460, [...], Background Chronic inflammation in patients with predialysis chronic kidney disease (CKD) is quite common. We aimed to investigate the relationship of the percentage of immature granulocytes (IG%) and immature granulocyte count (IGC) with inflammation in children with predialysis CKD. Methods The data from children with stage 2-4 CKD and a control group of healthy children were evaluated retrospectively. A highly-sensitive C-reactive protein (hs-CRP) level above 5 mg/dL was considered the presence of inflammation. The IGCs were calculated in the white cell differential channel of the Sysmex XN-9000 using the fluorescent flow cytometry method. The IG% was expressed as percentage of total leucocyte concentration. Results The data from 57 patients (30 stage 2 CKD, 15 stage 3 CKD, 12 stage 4 CKD) and 46 controls were analyzed. hs-CRP levels, IG%, IGC, white blood cell (WBC) and neutrophil counts, and neutrophil-to-lymphocyte ratio (NLR) were higher in patients than the control group (p < 0.000, p < 0.000, p < 0.000, p = 0.001, p = 0.002, p < 0.000, respectively). Both IG% and IGC were positively correlated with hs-CRP, WBC and neutrophil counts, and NLR (r = 0.485, p < 0.000; r = 0.379, p = 0.004; r = 0.543, p < 0.000; r = 0.628, p < 0.000 for IG%; r = 0.379, p = 0.004; r = 0.351, p = 0.007; r = 0.525, p < 0.000; r = 0.601, p < 0.000 for IGC, respectively). A ROC analysis of the relationship between IGC, IG%, and inflammation showed IGC and IG% had predictive value for the presence of inflammation (cut-off value: 0.035 x 10.sup.6/mL, AUC: 0.799 ± 0.061, sensitivity: 74.2%, specifity: 63%, p < 0.001 for IGC; cut-off value: 0.45%, AUC: 0.838 ± 0.056, sensitivity: 70.8%, specifity: 67.3%, p = 0.001 for IG%). Conclusions Immature granulocytes may be used as a biomarker of inflammation in children with predialysis CKD. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Author(s): Subhankar Sarkar [sup.1] , Rajiv Sinha [sup.1] [sup.2] , Arpita Ray Chaudhury [sup.3] , Kalana Maduwage [sup.4] , Asiri Abeyagunawardena [sup.5] , Niladri Bose [sup.2] , Subal Pradhan [sup.6] [...], Acute kidney injury (AKI) is a well-known life-threatening systemic effect of snake envenomation which commonly happens secondary to snake bites from families of Viperidae and Elapidae. Enzymatic toxins in snake venom result in injuries to all kidney cell types including glomerular, tubulo-interstitial and kidney vasculature. Pathogenesis of kidney injury due to snake envenomation includes ischaemia secondary to decreased kidney blood flow caused by systemic bleeding and vascular leakage, proteolytic degradation of the glomerular basement membrane by snake venom metalloproteinases (SVMPs), deposition of microthrombi in the kidney microvasculature (thrombotic microangiopathy), direct cytotoxic action of venom, systemic myotoxicity (rhabdomyolysis) and accumulation of large amounts of myoglobin in kidney tubules. Clinical features of AKI include fatigue, loss of appetite, headache, nausea, vomiting, oliguria and anuria. Monitoring of blood pressure, fluid balance, serum creatinine, blood urea nitrogen and serum electrolytes is useful in managing AKI induced by snake envenomation. Early initiation of anti-snake venom and early diagnosis of AKI are always desirable. Biomarkers which will help in early prediction of AKI are being explored, and current studies suggest that urinary clusterin, urinary neutrophil gelatinase-associated lipocalin, and serum cystatin C may play an important clinical role in the future. Apart from fluid and electrolyte management, kidney support including early and prompt initiation of kidney replacement therapy when indicated forms the bedrock in managing snake bite-associated AKI. Long-term follow-up is important because of chances of progression towards CKD.

Introduction Chronic kidney disease (CKD) involves intracellular calcium ([Ca.sub.i.sup.2+]) accumulation in numerous tissues, which leads to intensification of various clinical symptoms. With respect to red blood cells (RBCs), these features [...], In the course of chronic kidney disease (CKD) the intracellular erythrocyte calcium ([Ca.sub.i.sup.2+]) level increases along with the progression of the disease. The decreased activity of [Ca.sup.2+]-[Mg.sup.2+]-dependent ATP-ase (PMCA) and its endogenous modulators calmodulin (CALM), calpain (CANP), and calpastatin (CAST) are all responsible for disturbed calcium metabolism. The aim of the study was to analyze the activity of PMCA, CALM, and the CANP-CAST system in the red blood cells (RBCs) of hemodialyzed (HD) children and to estimate the impact of a single HD session on the aforementioned disturbances. Eighteen patients on maintenance HD and 30 healthy subjects were included in the study. CALM, [Ca.sub.i.sup.2+] levels and basal PMCA (bPMCA), PMCA, CANP, and CAST activities were determined in RBCs before HD, after HD, and before the next HD session. Prior to the HD session, the level of [Ca.sub.i.sup.2+] and the CAST activity were significantly higher, whereas bPMCA, PMCA, and CANP activities and the CALM level were significantly lower than in controls. After the HD session, the [Ca.sub.i.sup.2+] concentration and the CAST activity significantly decreased compared with the basal values, whereas the other parameters significantly increased, although they did not reach the levels of healthy children. The values observed prior to both HD sessions were similar. [Ca.sub.i.sup.2+] homeostasis is severely disturbed in HD children, which may be caused by the reduction in the PMCA activity, CALM deficiency, and CANP-CAST system disturbances. A single HD session improved these disturbances but the effect is transient. Keywords Children. Hemodialysis * Cytosolic calcium * [Ca.sup.2+]-[Mg.sup.2+]-dependent ATP-ase