Éva Kis

Pulse Wave Velocity in End-Stage Renal Disease: Influence of Age and Body Dimensions

Arterial stiffness increases with age. This process is accelerated by end-stage renal disease (ESRD). Pulse wave velocity (PWV) increases with arterial stiffness. In this study, PWV of 133 healthy individuals (6–23 y of age) and 11 patients on dialysis was measured to establish the normal values of PWV and to compare them with those in ESRD. Age-matched (A-C) and height- and weight-matched (H/W-C) control groups were used. Thereafter, PWV was indexed to height and the data were reevaluated. The role of the risk factors including serum calcium, phosphate, parathyroid hormone (PTH), and the time on dialysis was analyzed using a score system. PWV correlated with age, weight, height, blood pressure, and heart rate. ESRD patients were smaller than A-C and older than H/W-C. PWV of patients with ESRD did not differ from A-C; however, it was elevated in comparison to H/W-C. In both healthy and ESRD patients, the PWV/height ratio was independent of age. PWV/height was increased in ESRD. There was a correlation between PWV/height and the risk factor score. Controls matched for height and weight or PWV/height should be used in cases of growth failure. A number of risk factors responsible for increased arterial stiffness are present in ESRD.

Measurement of pulse wave velocity in children and young adults: a comparative study using three different devices

To estimate the value of pulse wave velocity (PWV) in pediatric cardiovascular disease, prospective studies are needed. Various instruments based on different measurement principles are proposed for use in children, hence the need to test the comparability of these devices in this younger population. The objective of this study was to compare PWV measured by oscillometry (Vicorder (VIC)) with the gold standard of applanation tonometry (PulsePen (PP), Sphygmocor (SC)). PWV was measured in 98 children and young adults (age: 16.7(6.3–26.6) years (median(range)) with the above three devices at the same visit under standardized conditions. Mean PWV measured by VIC was significantly lower than that measured by SC and PP. There was no difference following path length correction of the VIC measurement (using the distance between the jugular notch and the center of the femoral cuff), (PP: 6.12(1.00), SC: 5.94(0.91), VIC: 6.14(0.75) m s−1). Velocities measured by the three devices showed highly significant correlations. Bland–Altman analysis revealed excellent concordance between all three devices, however, there was a small but significant proportional error in the VIC measurements showing a trend toward lower PWV measured by VIC at higher PWV values. Our study provides data on the three most frequently used instruments in pediatrics. Following path length correction of the VIC, all three devices provided comparable results. Thus, our work allows extrapolating data between previously established normal PWV values for children and forthcoming studies using these instruments to assess children at long-term risk of cardiovascular disease. The small proportional error of VIC needs additional technical development to improve the accuracy of the measurements.

Post‐transplant diabetes mellitus in children following renal transplantation

Abstract:  PTDM plays a role in chronic allograft nephropathy and decreases graft and patient survival. Considering the serious outcome of chronic hyperglycemia, the importance of early recognition and the few data in children, in this retrospective analysis we studied the characteristics and risk factors of PTDM in 45 pediatric renal transplant recipients receiving Tac or CyA‐based immunosuppression. Fasting blood sampling and OGTT were performed. PTDM has been developed in six patients (13%), while seven children (16%) had IGT, with the overall incidence of a glucose metabolic disorder of 29% in pediatric renal transplants. Patients in the PTDM + IGT group were younger and had higher systolic blood pressure and serum triglyceride level than children with normal glucose tolerance. Multivariate analysis identified Tac treatment, Tac trough level, steroid pulse therapy and family history of diabetes to be associated with the onset of PTDM. In pediatric renal transplants, OGTT and frequent assessment of blood glucose levels might be essential not only in the post‐transplant management, but also prior to transplantation, particularly with family history of diabetes. Careful monitoring and modified protocols help to minimize the side effects of Tac and corticosteroids.

Cardiovascular risk assessment in children with chronic kidney disease.

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.

Pulse wave velocity in children following renal transplantation

BACKGROUND Arterial stiffness (ASt) increases with age, a process accelerated by uraemia and reversed by transplantation (Tx). Increased ASt results in an elevated pulse wave velocity (PWV). METHODS To compare the PWV of Tx patients (n = 25, age = 15.1/95% CI = 13.5-16.7/year) and healthy controls, three control groups were formed: matched for age (A), for height and weight (H/W) and for age and height (A/H), respectively. To avoid bias from the growth deficit of Tx, firstly Z-scores of PWV were calculated (PWV-Z). Second, the PWV/height (PWV/h) ratio was assessed. Pre-Tx serum Ca, P, PTH and the cumulative dose of calcitriol (cCTL) were also analysed. Finally, Tx patients were compared to ESRD patients (n = 11). PWV was measured by applanation tonometry. RESULTS Tx were smaller than A and older than H/W. The PWV of Tx differed only from H/W and A/H. PWV-Z and PWV/h of Tx were increased compared to all control groups. They correlated with the CaxP and cCTL before Tx and were independent of age. Patients with creatinine clearance >90 ml/min/1.73 m(2) or <1 year on dialysis had lower PWV-Z and PWV/h than ESRD. CONCLUSION Controls that matched for both age and height should be used to assess PWV in children with growth failure. PWV-Z is a universal age-independent parameter of PWV in cases of growth retardation; PWV/h is a simple alternative of PWV-Z. CaxP and cCTL are major determinants of ASt after Tx. PWV may be reduced after Tx suggesting that the uraemia-induced cardiovascular changes might be reversible.

Williams Syndrome Predisposes to Vascular Stiffness Modified by Antihypertensive Use and Copy Number Changes in NCF1

Williams syndrome is caused by the deletion of 26 to 28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln+/− mouse suggests that affected people may also have stiff vasculature, a risk factor for stroke, myocardial infarction, and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case–control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (P<0.001), with increased stiffness observed in even the youngest children with Williams syndrome. Pulse wave velocity increased with age at comparable rates in cases and controls, and although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of antihypertensive medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with antihypertensives or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive.

Cardiovascular risk assessment in children following kidney transplantation

Dégi A, Kerti A, Kis É, Cseprekál O, Tory K, Szabó AJ, Reusz GS. Cardiovascular risk assessment in children following kidney transplantation.

Ambulatory arterial stiffness index in children after kidney transplantation

Given the increase in CV morbidity after RTx and the scarcity of CV events in pediatrics, surrogate markers should be assessed to characterize CV damage in this population. AASI is a marker of arterial stiffness in adults, predicting cardio‐ and cerebrovascular morbidity. Our aim was to assess the determinants of AASI in RTx children (n = 54, 15.5 ± 3.5 yr) and to examine its relationship to central PWV. AASI was calculated from 24 h ABPM. PWV was determined by applanation tonometry, body composition by multifrequency bioimpedance measurement. The dipping state, volume overload, and time on dialysis were the main predictors of AASI (p < 0.05). Children with established HT (n = 34) had increased AASI, extracellular body water, and BNP (p < 0.05). In contrast to AASI, PWV did not differ between HT and normotensive RTx patient groups. There was no correlation between AASI and PWV. PWV was increased in children who spent more than one yr on dialysis prior to RTx. In conclusion, increased AASI in HT RTx children better characterizes the actual volume‐ and pressure‐dependent arterial rigidity rather than long‐term morphological changes in large arteries as reflected by PWV.

Immunosuppression with 4SC-101, a novel inhibitor of dihydroorotate dehydrogenase, in a rat model of renal transplantation.

Background 4SC-101 is a novel dihydroorotate dehydrogenase inhibitor and a blocker of interleukin (IL)-17 secretion with beneficial effects in experimental lupus and inflammatory bowel disease. Its immunomodulatory effect on acute kidney rejection is not known; therefore, in this study, the impact of 4SC-101 was examined in a rat model of acute kidney rejection. Methods The kidneys of Brown-Norway rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. Allograft recipients were administered with 4SC-101 at dosages of 4, 20, or 60 mg/kg per day, and survival was assessed. In the second setting, the animals were harvested 3 or 5 days after transplantation (Tx), and graft histologic diagnosis was determined. The effects of 4SC-101 on impaired renal function were examined in a model of 5/6 nephrectomy in Lewis rats. Results The recipients treated with 20-mg/kg 4SC-101 showed prolonged survival compared with placebo-treated animals (mean±SEM, 24±9.3 vs. 5.4±3 days), paralleled by less severe histologic features of acute kidney rejection such as interstitial/perivascular infiltration and tubulitis 3 and 5 days after Tx, and a lower level of IL-17 messenger RNA 5 days after Tx compared with the placebo-treated animals. In the 5/6 nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria, glomerulosclerosis, and fibrosis with decreased IL-17 messenger RNA expression. Conclusions 4SC-101 prolongs survival after Tx, paralleled by amelioration of histologic signs of acute rejection. Furthermore, it showed no worsening effects on kidney function in a remnant kidney model and even slowed the progression of proteinuria and kidney fibrosis. Therefore, 4SC-101 might be a promising pharmaceutical agent in Tx medicine for further investigations.

Inflammatory pseudotumor of the bladder in chronic granulomatous disease

Sirs, Chronic granulomatous disease (CGD) is a rare inherited (X-linked dominant 70%, or autosomal recessive 30%) disorder of the immune system, characterized by recurrent bacterial or fungal infections. The severity of the disease is not necessarily related to the pattern of inheritance. Patients present with diverse signs and symptoms, which makes CGD a difficult disease to diagnose and treat. Granuloma formation is observed in these patients, causing diagnostic and therapeutic challenges. We report a 4-year-old boy with abdominal pain and dysuria. Previously, CGD was diagnosed at 2 years of age, and trimethoprim prophylaxis had been administered for 2 years. No serious bacterial or fungal infections were detected during that time. On admission, the patient was afebrile. On rectal examination, a mass was palpated in the region of the left-side posterior bladder wall, 2×2 cm in diameter. Laboratory studies were negative (C-reactive protein 1 mg/dl, white blood cells 14,100/mm3, hemoglobin 10.5 g/dl, erythrocyte sedimentation rate 30 mm/h, urine tests negative, urine culture negative). Ultrasonography showed left-side hydronephrosis and hydroureter, and the bladder wall was irregularly thickened at the site of the trigonum (Fig. 1). Computed tomography of the tumor-like mass of the bladder showed contrast enhancement. (Fig. 2). At urethrocystoscopy under general anesthesia a granulomatous polypoid mass at the right and left sides of the bladder wall was found and biopsied. Granulomatous tissue was diagnosed by histology. Repeated ultrasonography showed bilateral hydronephrosis and hydroureter, and irregularly thickened bladder wall. Oral steroid treatment was administered for 2 weeks (prednisone 2 mg/kg). After 5 days, a quick regression of the bladder pseudotumor was detected by ultrasonography; 4 weeks later, normal bladder and kidneys were found.