Eva Šimková

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid–containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.

Control of hypertension in children after renal transplantation

Abstract: The aim of this cross‐sectional single‐center study was to investigate the efficacy of hypertension control in children who underwent transplantation using ambulatory blood pressure (BP) monitoring, and to determine the risk factors associated with poor control of hypertension. Thirty‐six children fulfilled the inclusion criteria. The mean age was 13.9±4.4 yr; the mean time after renal transplantation was 2.7±2.4 yr (0.5–10.1). Hypertension was defined as a mean ambulatory BP ≥95th centile for healthy children and/or requiring antihypertensive drugs. Hypertension was regarded as controlled if the mean ambulatory BP was <95th centile in children already on antihypertensive drugs, or uncontrolled if the mean ambulatory BP was ≥95th centile in treated children. Hypertension was present in 89% of children. Seventeen children (47%) had controlled hypertension, and 14 (39%) had uncontrolled hypertension. One child (3%) had untreated hypertension, and only four children (11%) showed normal BP without antihypertensive drugs. The efficacy of hypertensive control was 55% (17 of 31 children on antihypertensive drugs had a BP<95th centile), i.e. 45% of treated children still had hypertension. Children with uncontrolled hypertension had significantly higher cyclosporine doses (6.1 vs. 4.3 mg/kg/day, p=0.01) and tacrolimus levels (9.2 vs. 6.1 μg/L, p<0.05), and there was a tendency toward use of lower number of antihypertensive drugs (2.0 vs. 1.5 drugs/patient, p=0.06) and lower use of angiotensin‐converting enzyme (ACE) inhibitors (7 vs. 35%, p=0.09) and diuretics (29 vs. 59%, p=0.14) than in children with controlled hypertension. In conclusion, nearly 90% of our children after renal transplantation are hypertensive and the control of hypertension is unsatisfactorily low. The control of hypertension could be improved by increasing the number of prescribed antihypertensive drugs, especially ACE inhibitors, and diuretics, or by using higher doses of currently used antihypertensives.

Improved control of hypertension in children after renal transplantation: results of a two-yr interventional trial.

Abstract:  Hypertension is a frequent complication in children after renal transplantation and the control of post‐transplant hypertension is unsatisfactorily low. The aim of this prospective interventional study was to improve the control of hypertension in children after renal transplantation. Thirty‐six children fulfilled the inclusion criteria (≥6 months after transplantation and no acute rejection in the last three months). BP was measured using ABPM. Hypertension was defined as mean ambulatory BP ≥95th‐centile for healthy children and/or using antihypertensive drugs. The study intervention consisted of using intensified antihypertensive drug therapy – in children with uncontrolled hypertension (i.e., mean ambulatory BP was ≥95th centile in treated children), antihypertensive therapy was intensified by adding new antihypertensive drugs to reach goal BP <95th centile. ABPM was repeated after 12 and 24 months. Daytime BP did not change significantly after 12 or 24 months. Night‐time BP decreased from 1.57 ± 1.33 to 0.88 ± 0.84 SDS for systolic and from 1.10 ± 1.51 to 0.35 ± 1.18 SDS for diastolic BP after 24 months (p < 0.05). The number of antihypertensive drugs increased from 2.1 ± 0.9 to 2.7 ± 0.8 drugs per patient (p < 0.05), this was especially seen with the use of ACE‐inhibitors (increase from 19% to 40% of children, p < 0.05). In conclusion, this interventional trial demonstrated that, in children after renal transplantation, the control of hypertension, especially at night‐time, can be improved by increasing the number of antihypertensive drugs, especially ACE‐inhibitors.

Relapsing Peritonitis in Children Who Undergo Chronic Peritoneal Dialysis: A Prospective Study of the International Pediatric Peritonitis Registry

BACKGROUND AND OBJECTIVES The International Pediatric Peritonitis Registry (IPPR) was established to collect prospective data regarding peritoneal dialysis (PD)-associated peritonitis in children. In this report, we present the IPPR results that pertain to relapsing peritonitis (RP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was an online, prospective entry into the IPPR of data that pertain to peritonitis cases by participating centers. RESULTS Of 490 episodes of nonfungal peritonitis, 52 (11%) were followed by a relapse. There was no significant difference between RP and non-RP in distribution of causative organisms and antibiotic sensitivities. Initial empiric therapy-ceftazidime with either first-generation cephalosporin or glycopeptide (vancomycin or teicoplanin)-was not associated with relapse. Switching to monotherapy with a first-generation cephalosporin on the basis of culture results was associated with higher relapse rate (23%) than other final antibiotic therapies (0 to 9%). Culture-negative RP was less likely to have a satisfactory early treatment response than non-RP (82 versus 98%). Young age, single-cuff catheter, downward-pointing exit site, and chronic systemic antibiotic prophylaxis were additional independent risk factors for RP in the multivariate analysis. Compared with non-RP, RP was associated with a lower rate of full functional recovery (73 versus 91%), higher ultrafiltration problems (14 versus 2%), and higher rate of permanent PD discontinuation (17 versus 7%). CONCLUSIONS This is the largest multicenter, prospective study to date to examine RP in children. In addition, this is the first report in the literature to examine specifically the relationship of postempiric antibiotic treatment regimens to the subsequent risk for relapse.