Dorota Polak-Jonkisz

Ca2+ Influx versus Efflux during Eryptosis in Uremic Erythrocytes

its 4b isoform, being anchored in the membrane [2] . The activity of that pump is modified directly by a network of crossdependent protein, nonprotein and lipid factors. The mechanisms responsible for the regulation of PMCA activity are divided into the following two types: (1) Reversible, involving the protein kinase/phosphatase system, aggregation/ dissociation of protein molecules and calmodulin, an endogenous intracellular activator. In one of the recent issues of Blood Purification [2012; 33: 125–130], Florian Lang and Syed M. Qadri in ‘Mechanisms and Significance of Eryptosis, the Suicidal Death of Erythrocytes’ [1] , raised an important issue, concerning the mechanism of eryptosis and diseases associated with enhanced eryptosis. Eryptosis is characterized by erythrocyte shrinkage, blebbing, and phospholipid scrambling of the cell membrane and it is triggered by increased cytosolic Ca 2+ activity. This increase in cytosolic Ca 2+ concentration is a result of activation of nonselective cation channels mediating Ca 2+ entry. The quoted authors focus mainly on issues associated with the influx of calcium ions, approaching them as the leading cause of eryptosis. In our opinion, efflux processes, which are responsible for calcium ions, may also be of some significance in this particular context. Both mechanisms – influx and efflux – co-decide about cytosolic Ca 2+ concentration and thus, indirectly, about the fate of cells, or suicidal death of red blood cells (RBC). Low Ca 2+ concentrations are conditioned by undamaged erythrocyte membrane structure, low passive permeability for that ion and its active excretion, facilitated by the calcium pump Ca 2+ -Mg 2+ -dependent ATPase (PMCA, plasma membrane Ca 2+ -Mg 2+ -transporting adenosine triphosphatase: ATPase 3.6.1.38), mainly Published online: October 19, 2012

Serum VCAM-1, ICAM-1, and L-selectin levels in children and young adults with chronic renal failure.

Children and young adults with chronic renal failure (CRF) present with an impaired immune response. Our aim was to analyze whether leukocyte migration, determined by adhesion molecules, is disturbed in the course of CRF, hemodialysis (HD), and peritoneal dialysis (PD). Soluble (s) VCAM-1, ICAM-1, and L-selectin serum levels were evaluated by ELISA in 15 patients with CRF, 22 patients on cuprophane membrane HD, 24 patients on PD, and in 15 controls. The sVCAM-1 levels in all groups were significantly elevated compared with controls. The levels in HD patients were higher than in CRF patients (P <0.05), while levels in PD patients were higher than in CRF and HD (P <0.001 and P <0.01, respectively). The sICAM-1 concentrations in CRF and PD patients were significantly elevated compared with controls (P <0.001 and P <0.0001, respectively); in PD patients sICAM-1 levels were higher than in HD patients (P <0.001), but there were no differences between other groups. sL-selectin levels were decreased in all groups compared with controls. The levels in HD patients were the lowest and the differences, compared with CRF and PD patients, were significant (P <0.05 and P <0.01, respectively). Children and young adults with CRF and on maintenance dialysis have altered concentrations of soluble adhesion molecules, resulting from either inadequate clearance or disturbed synthesis and release. The differences in sVCAM-1 levels between CRF and both groups of patients on dialysis, as well as the differences in sL-selectin concentrations between HD and CRF patients, indicate that these disturbances are aggravated by maintenance dialysis, particularly HD.

Osteocalcin as a biochemical marker of bone turnover

SUMMARY: Osteocalcin is a calcium‐binding bone protein whose blood concentrations are correlated with bone synthesis and resorption. the level of blood osteocalcin is determined by several factors. Laboratory monitoring of blood osteocalcin is helpful in patient diagnosis and managment. This study presents the known biosynthesis of osteocalcin and its role as an index of bone turnover.

Soluble adhesion molecules in children and young adults on chronic hemodialysis

Children on chronic hemodialysis (HD) present with impaired immunity that may result from disturbances in leukocyte migration, caused by changes in expression of adhesion molecules on endothelium and immunocompetent cells. However, it is still not clear whether the type of dialyzer or a single dialysis session influences the concentrations of soluble adhesion molecules in these patients. We evaluated by ELISA serum levels of soluble (s) VCAM-1, ICAM-1, L-selectin, and P-selectin in 22 patients on cuprophane HD (CU), 8 on polysulfone HD (PS), 10 on vitamin E-modified cellulose HD (VE), and 15 controls. In all HD patients, sVCAM-1 levels were elevated compared with controls and were higher in CU than in VE. The sICAM-1 concentrations were increased in VE compared with controls, but remained unchanged in CU and PS. The sL-selectin levels were reduced in all HD patients. The mean values of sP-selectin were comparable in CU, PS, and controls. The lowest levels were observed in VE. In CU patients, sVCAM-1, sICAM-1, and sP-selectin concentrations rose after HD. A single PS session had no impact on adhesion molecules, whereas a VE session increased the level of sVCAM-1. The type of dialysis membrane may change the profile of adhesion molecule concentrations, thus influencing the immune system of a child on HD. The increase in levels of adhesion molecules in the course of a single HD session, which was pronounced in CU and VE patients, suggests poor biocompatibility of these dialyzers.

Nephroprotective action of sirtuin 1 (SIRT1)

Sirtuins, silent information regulator 2 (Sir 2) proteins, belong to the family of NAD+-dependent enzymes with deacetylase or mono-ADP-ribosyltransferase activity. These enzymes are responsible for processes of DNA repair or recombination, chromosomal stability and gene transcription. In mammals, sirtuins occur in seven varieties, from 1 to 7 (SIRT1–SIRT7), differing among themselves with location. SIRT1, the best known variety, exerts its effects on proteins via NAD+ coenzymes, being thus associated with cellular energetic metabolism and the ‘red–ox’ state. Its deficits are, among others, concomitant with stressful situations and associated with pathophysiologies of many medical conditions, including diabetes mellitus, cardiovascular diseases, neurodegenerative syndromes and kidney diseases. In kidney disorders, it promotes (stimulates) the survival of cells in an affected kidney by modulating their responses to various stress stimuli, takes part in arterial blood pressure control, protects against cellular apoptosis in renal tubules by catalase induction and triggers autophagy. More and more available in vitro and in vivo data indicate SIRT1 activity to be oriented, among others, towards nephroprotection. Thus, SIRT1 may become a novel element in the therapy of age-related renal diseases, including diabetic nephropathy.

The endogenous modulators of Ca2+–Mg2+-dependent ATPase in children with chronic kidney disease (CKD)

BACKGROUND Calcium homeostasis is disturbed in many ways in the course of chronic kidney disease (CKD). The concentration of free cytoplasmic calcium in erythrocytes is increased. Maintenance of a high concentration gradient (between the cystoplasmic and extracellular space) is possible only due to a finely tuned cooperation between many regulating systems in the cytoplasmic membranes and cell organelles. The aim of our study was to evaluate the activity of Ca(2+)-Mg(2+)-dependent ATPase (PMCA), calmodulin and calpain-calpastatin (CANP-CAST) system in erythrocytes of CKD children treated conservatively in the stages II-IV. METHODS A total of 36 patients with CKD were enrolled in the study. Group A contained patients with CKD stage II; group B with CKD stage III; and group C with CKD stage IV. The control group D consisted of 30 healthy subjects. In the serum, we determined the following: intact parathormon, total calcium, creatinine; in the red blood cells: free cytosolic calcium concentration (Ca(i)(2+)), activity of Ca(2+)-Mg(2+)-transporting ATPase (PMCA), basal PMCA (bPMCA), calmodulin (CALM), CANP, CAST. RESULTS In all groups, Ca(i)(2+) concentrations were significantly higher, whereas PMCA and bPMCA activity were lower than in the controls. CANP concentrations in group A were elevated compared to the controls, whereas in groups B and C they were significantly lower. In group C, the mean CAST activity reached the highest values. CALM concentrations were decreased versus controls in all groups of patients. CONCLUSIONS The intracellular Ca(i)(2+) homeostasis is disturbed in children with CKD and aggravates the deterioration of renal function as well. The reasons for the progressing increase of erythrocyte calcium concentration are multifactorial. Undoubtedly, the decreased PMCA activity, the calmodulin deficiency and the dysregulated CANP-CAST system are responsible for that phenomenon. The impact of many other biological modulators, creating a network defending the cell against the calcium accumulation, cannot be excluded.

Skin autofluorescence as a novel marker of vascular damage in children and adolescents with chronic kidney disease.

BackgroundSkin 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.MethodsA 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.ResultsCompared 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.ConclusionsThe 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.

Ca2+-Mg2+-dependent ATP-ase activity and calcium homeostasis in children with chronic kidney disease

Extracellular calcium concentrations in humans are thousands times higher than within cells. Maintenance of such gradient requires specific regulation including intracellular stores, Ca binding proteins and transmembrane protein systems. The aim of the study was to estimate PMCA (plasma membrane Ca-transporting adenosine triphosphatase; ATPase 3.6.1.38) activity and calcium homeostasis in erythrocytes of children with chronic kidney disease (CKD). Twenty-one children wth CKD stages 1–3 (group I) and 18 healthy children (group II) were examined. Group I was divided into two subgroups: Ia (8 patients with normal intact parathyroid hormone, iPTH, serum levels) and Ib (13 patients with increased iPTH). iPTH, urea, creatinine, inorganic phosphorus, cytosolic Ca2+ in red blood cells (R-Ca), and PMCA were determined. Significantly elevated R-Ca levels were observed in children from subgroup Ib in comparison with group II and subgroup Ia. The lowest activity of PMCA was found in subgroup Ia and Ib in comparison with group II. There was a negative correlation between PMCA and R-Ca in group Ia and Ib (r = −0.8, r = −0.9, respectively). In children with CKD treated conservatively, activity of PMCA in erythrocytes is disturbed. An increase in R-Ca and decrease in PMCA activity are also observed.

Usefulness of body surface potential mapping for early identification of the intraventricular conduction disorders in young patients with chronic kidney disease

BACKGROUND Cardiovascular complications are considered a significant problem in patients with chronic kidney disease (CKD). Body surface potential mapping (BSPM) is a noninvasive method that is useful in detecting early changes involving the heart. The aim of the study was to evaluate possible abnormalities within the cardiac intraventricular conduction system in young patients with CKD using the BSPM method. METHODS Based on the BSPM registrations, the QRS-T isointegral maps were created in 42 young patients with CKD (on hemodialysis, subgroup Ia; on peritoneal dialysis, subgroup Ib; on conservative treatment, group II) and in 26 healthy subjects. Serum levels of electrolytes, urea, and creatinine were also assessed in the entire study population. RESULTS In the healthy subjects, the maximums of the group mean QRS-T isointegral map were located in the left lower anterior part of the thorax, whereas in the Ia patients, the maximums were focused at the medial sternum line. The QRS-T maps, both for Ib and II groups, showed the positive integrals covering the left part of the anterior thorax. In all the patients with CKD, standard 12-lead electrocardiogram (ECG) and echocardiography findings were within the reference range. CONCLUSIONS In the hemodialyzed patients with CKD, the group-mean QRS-T isointegral map distribution suggested a significant delay of excitation propagation in the left bundle branch, although no abnormalities were found with standard ECG. In the patients with CKD treated with peritoneal dialysis or conservatively, the group-mean QRS-T isointegral maps were characteristic for the early phase of conduction disturbances within the left bundle branch, which again was not observed on the standard ECG recordings.

Effect of kidney transplantation on heart conduction disturbances in children treated with chronic hemodialysis--a pilot study.

Polak‐Jonkisz D, Laszki‐Szcząchor K, Sobieszczańska M, Makulska I, Pilecki W, Rusiecki L, Zwolińska D. Effect of kidney transplantation on heart conduction disturbances in children treated with chronic hemodialysis – A pilot study. 
Pediatr Transplantation 2011: 15: 835–843.