Krystyna Laszki-Szcząchor

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.

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.

Novel targets for pharmacological intervention in age-related diseases

In the article ‘Small molecule SIRT1 activators for the treatment of aging and age-related diseases’, Basil Hubbard and David Sinclair have presented studies showing various beneficial effects of sirtuin activation and focused on role of so-called NAD-dependent deacetylase sirtuin-1 (SIRT1) activating compounds (STACs), both natural and synthetic, in possible future therapies for various, age-related diseases [1]. While it is true that sirtuins are currently considered as potential point of pharmacological intervention in diverse areas, from the prevention of age-related diseases (such as chronic kidney disease, neurodegenerative disorders, diabetes, etc.) to lifespan extension, their beneficial role is far from being settled.

Dynamics of changes in heart conduction system in dialyzed young adults after kidney transplantation--pilot study.

BACKGROUND Cardiovascular complications are the main clinical problem in patients with end-stage renal failure (ESRF). After successful kidney transplantation, this situation improves, although cardiovascular complications remain a risk factor for increased mortality in these patients; therefore, their early identification is of key therapeutic and prognostic significance. This study was designed to determine a dynamics of changes in the heart conduction system in hemodialyzed young adult patients after kidney transplantation in a long-term follow-up, based on the body surface potential mapping (BSPM) method. METHODS The study comprised 5 patients (mean age, 20.8 ± 1.16 years) after kidney transplantation (KT) who had been chronically dialyzed before. The mean observation period was 6.7 ± 1.71 years. All of the patients were submitted to the following examinations before and after KT: 12-lead electrocardiography (ECG), echocardiography, standard biochemistry, and BSPM (isochronous maps). The mean creatinine concentration was 1.38 ± 0.05 mg/dL. The control group comprised 30 healthy persons. RESULTS BSPM maps taken from the dialyzed patients demonstrated disturbed spreading of electric impulses within the heart ventricles in a type of left bundle branch block, despite normal 12-lead ECG and echocardiography results. A relationship was demonstrated between the BSPM changes and dialysis duration. After KT, the abnormal distribution of isochrones and ventricular activation times (VAT) presented some significant and specific regression. CONCLUSIONS 1) In dialyzed patients, BSPM is a more sensitive method than ECG and enables early identification of changes in the heart conduction system presented as left bundle branch block. 2) Dialysotherapy duration before and after KT determines the extent of the BSPM changes. 3) Successful effects of KT bring about regression of intraventricular conduction disorders. 4) The observations need verification in a larger patient group.

Disturbances in intraventricular conduction in childrenwith end-stage renal disease on peritoneal dialysis:A pilot study

BACKGROUND The progression of chronic kidney disease is accompanied by multi-organ disorders, among which cardiovascular diseases have the status of a serious clinical problem. The body surface potential mapping (BSPM) technique is a non-invasive method which enables the detection of pathological changes in the bioelectrical activity of the heart. OBJECTIVES The aim of this study was to identify possible disturbances in the intraventricular conduction system in peritoneally dialyzed children. MATERIAL AND METHODS Cardiac examination consisted of 12-lead electrocardiography, echocardiography and BSPM. The evaluation of disturbances in the cardio-electrical field was performed by comparing the qualitative and quantitative features of the heart potentials on the isopotential map. RESULTS Data was collected from 10 children treated with automatic peritoneal dialysis (APD) (mean age: 13.6 ±2.3 years) and 26 healthy children. The maps of dialyzed children showed a shift in positive isopotentials toward the left lower part of the thorax, while negative values were observed in its left upper part. A distribution of lines on the isopotential maps revealed disturbances in the stimulation spread within the heart ventricles, especially within the anterior fascicle of the left bundle branch of His. CONCLUSIONS Intraventricular conduction disturbances were observed in the left bundle branch of His in the peritoneally dialyzed children. The body surface potential mapping was a more sensitive method in identifying the early stage of conduction disturbances within the heart ventricles than 12-lead electrocardiography. Further research involving a larger population of dialyzed children is planned.

Maps of Ventricular Activation Time (VAT) Differences in Children on Peritoneal Dialysis - a Pilot Study.

♦ Background: Decrement of glomerular filtration rate leads to many serious complications that cause both functional and structural impairments of the other organs. Long-term clinical observations of children and teenagers with end-stage renal disease (ESRD) showed that more than one third of those patients manifested various cardio-vascular conditions. The aim of the study was to analyze possible disturbances in the heart ventricular conduction system by using a technique of ventricular activation time (VAT) differences in ESRF children on peritoneal dialysis (PD) with normal electrocardiogram (ECG) examinations. ♦ Material and methods: The study group comprised 10 ESRD children (mean age: 13.6 ± 2.31 years) on peritoneal dialysis – group I. The control group (group II) consisted of 26 age-matched healthy children with no clinical evidence of renal or cardiac disease and with normal 12-lead ECG recordings. Each of the ESRD patients was also subjected to the standard ECG examination. In order to capture possible heart conduction abnormalities, body surface potential mapping (BSPM) recordings were performed in PD patients between the successive dwells (‘on empty abdomen’) with a HPM-7100 Fukuda Denshi system. Based on the source ECG data, the original technique of a VAT difference map was then applied. ♦ Results: Differences between VAT values for the two examined groups of children, controls and ESRD patients on PD, were significantly pronounced in the region of the right upper anterior thorax, the entire left thorax and nearly in the total back. Such a pattern of VAT delays indicates a pathological electric transmission in the intraventricular conduction system of the left anterior fascicle of His bundle. ♦ Conclusion: 1. VAT maps (isochrone maps) can be useful to detect abnormal spreading and depolarization through the heart ventricles. 2. Map of VAT value differences makes it possible to identify early disturbances in the left His bundle branch in ESRD children treated with peritoneal dialysis regardless of normal 12-lead ECG. 3. Further studies on a larger group of children with ESRD on PD are required to verify the preliminary observations presented herein.

Effects of hemodialysis on ventricular activation time in children with end-stage renal disease.

Patients with end‐stage renal disease are affected by cardiovascular complications, including disturbances of the heart intraventricular conduction. Body surface potential mapping is a non‐invasive electrocardiographic detection method of initial disturbances in heart activation propagation. A goal of the study was to analyze the effects of single hemodialysis (HD) session on ventricular activation time (VAT) maps obtained from hemodialyzed children. The study group consisted of 13 hemodialyzed children (age: 6–18 years). The control group is composed of 26 healthy subjects. In each HD patient, 12‐lead electrocardiogram and echocardiography examinations were performed. Isochrone heart maps, reflecting body surface distribution of VAT isolines, were recorded from an 87‐electrode HPM‐7100 system for body surface potential mapping, before (group B) and after HD session (group A). The distribution of isochrones and VAT values, as recorded in the HD patients, differed significantly from the reference VAT map for controls. The highest VAT maximal value was noted in group B (Me: 110 vs. 62 ms in the control group; P < 0.001), becoming significantly lower after HD session (Me: 98 ms for group A vs. 110 ms for group B; P < 0.001). Ventricular activation time maps, recorded before HD session, showed significant VAT delays with isochrone arrangement specific for the left bundle branch block. After HD session, VAT maps presented significant changes, suggesting a normalization process. Ventricular activation time maps in children with end‐stage renal disease exhibited disturbances of intraventricular conduction within the left bundle branch block, undetectable on standard electrocardiogram. A single HD session resulted in VAT map improvement related to overall HD treatment duration.

Combined Cardiac Impairments in End-Stage Renal Disease

To the Editor,We were impresses by the article published in PediatricCardiology by Kobayashi et al. [1], The Impact of Changein Volume and Left-Ventricular Hypertrophy on Left-Ventricular Mechanical Dyssynchrony in Children WithEnd-Stage Renal Disease. The study provides an importantcontribution to the scarce data on functional/organic car-diac impairments in children with end-stage renal disease(ESRD).Kobayashi et al. detected left-ventricular dyssynchrony(LVD) using real-time three-dimensional echocardiogra-phy in children with ESRD undergoing renal replacementtherapy (peritoneal dialysis or hemodialysis). The authorsstated that dyssynchrony was significantly greater in ESRDchildren, especially those on hemodialysis therapy, com-pared with controls and improved after hemodialysis. Theauthors concluded that ESRD children presented volumeload and left-ventricular hypertrophy (LVH), which wereprobably associated with increased LVD. They assumedthat cardiac dyssynchrony could be an independent pre-dictor of serious cardiac events in patients with ESRD [1].Regarding cardiac impairments in such patients, wewould like to draw attention to our findings [2, 3] showingintraventricular conduction disturbances in ESRD childrenin whom no abnormalities were observed on 12-leadelectrocardiographic and echocardiographic examinations.In our study, a noninvasive multielectrode (87-lead) bodysurface potential mapping system (Fukuda Denshi Co Ltd,Tokyo, Japan) was applied to create isochrone maps toprecisely reflect a sequence of ventricular activation time(i.e., VAT maps).In our ESRD children treated conservatively [2] or withrenal replacement [3], abnormal maps with delayed VATvalues were noted, indicating some perturbations within theintraventricular conduction pathway. Patients on hemodi-alysis for\1 year demonstrated VAT maps typical for leftbundle branch block (LBBB), which was partially allevi-ated after renal transplantation, becoming left anteriorfascicle block. In children on hemodialysis for [1 year,VAT maps showed more serious disturbances in the formof complete LBBB that was normalized to incompleteLBBB due to kidney transplantation.According to Kobayashi et al. [1], disorders of electricalactivation, consequently leading to LVD, can occur inpatients with ESRD. Multifactoral damage of the ventric-ular myocardium probably causes spatiotemporal hetero-geneity and therefore LVD, which is additionally impairedby LVH. It is supposed that LVH can be a response ofthe myocardium to numerous ‘‘cross-talking networks’’appearing both as the result of ESRD and during renal-replacement therapy.Our findings [2, 3] suggest that disturbances of theintraventricular conduction system observed in childrenwith ESRD can be a significant component of LVD, whichinevitably leads to systolic left-ventricular dysfunction.