Childhood onset nexilin dilated cardiomyopathy: A heterozygous and a homozygous case.

Pathogenic heterozygous NEXN variants are associated with progressive dilated cardiomyopathy (DCM) usually presenting around 50 years of age. We describe an asymptomatic boy who had transient DCM at 3 months of age, that resolved by 4 months. Presently, at 11 years of age, he has normal cardiac function with signs of mild DCM on cardiac MRI. Genetic diagnostics revealed a paternally derived, heterozygous 1949_1951del class 4 variant in NEXN. His father had mild DCM with mildly reduced systolic function. The second patient presented with fetal hydrops at 33 weeks gestation requiring emergency caesarian delivery. Postnatally she required ventilation and continuous inotropic support for left ventricle systolic dysfunction. She died after 2 weeks when therapy was withdrawn. Homozygous c.1174C > T,p.(R392*) class 4 variants in the NEXN gene were found via WES. Microscopic investigation showed endomyocardial fibroelastosis. Her parents, both heterozygous carriers, had normal cardiac function and the family history was normal. These patients show a new clinical spectrum of pediatric cardiac disease seen in heterozygous and homozygous NEXN variants, ranging from mild, transient DCM to a severe, fatal neonatal DCM. These patients support the inclusion of the NEXN gene in the investigation of pediatric patients with DCM, even in cases with transient DCM.

Infection-related hospitalizations over 30 years of follow-up in patients starting renal replacement therapy at pediatric age.

BACKGROUND: Pediatric renal replacement therapy (RRT) patients surviving long-term are at a much higher risk of mortality compared with the age-matched general population. Recently, we demonstrated a transition from cardiovascular disease to infection as the main cause of death in a long-term follow-up study of pediatric RRT. Here, we explore the burden of infections requiring hospitalization over 30 years of follow-up on RRT. METHODS: The cohort comprised all 234 Dutch patients on RRT under 15 years of age between 1972 and 1992. We analyzed infection-related hospitalizations during the period 1980­2010. We evaluated the Hospital Admission Rate (HAR) per patient-years (py) and infectious over noninfectious HAR ratio (HARR). RESULTS: The HAR decreased significantly over time for all patients. The rate of hemodialysis-related infections decreased between 1980 and 1999, but stabilized during 2000­2010, whereas peritoneal dialysis-related infections decreased progressively. Transplantation-related infections did not change, except for urinary tract infections (UTIs), which increased significantly from 3.3/100 py [95%CI 3.2­3.4] in 1980­1989 to 4.4/100 py [4.2­4.5] in 2000­2010 (p <0.001). The contribution of infection to HAR increased significantly in transplanted patients (HARR: 1980­1989: 0.25 [0.2­0.3]; 2000­2010: 1.0 [0.79­1.27], p <0.001). CONCLUSIONS: Our findings indicate a relative increase in infections requiring hospitalization over time in patients starting RRT during the pediatric age, especially severe UTIs in transplantation. More attention paid to urological abnormalities in cases of recurrent UTI and tailored adjustment of immunosuppression may reduce risk in these patients.

Mortality from infections and malignancies in patients treated with renal replacement therapy: data from the ERA-EDTA registry.

BACKGROUND: Infections and malignancies are the most common non-cardiovascular causes of death in patients on chronic renal replacement therapy (RRT). Here, we aimed to quantify the mortality risk attributed to infections and malignancies in dialysis patients and kidney transplant recipients when compared with the general population by age group and sex. METHODS: We followed 168 156 patients included in the ERA-EDTA registry who started RRT in 1993-2007 until 1 January 2012. Age- and cause-specific mortality rates per 1000 person-years (py) and mortality rate ratios (MRRs) compared with the European general population (WHO) were calculated. To identify risk factors, we used Cox regression. RESULTS: Infection-related mortality was increased 82-fold in dialysis patients and 32-fold in transplant recipients compared with the general population. Female sex, diabetes, cancer and multisystem disease were associated with an increased risk of infection-related mortality. The sex difference was most pronounced for dialysis patients aged 0-39 years, with women having a 32% (adjusted HR 1.32 95% CI 1.09-1.60) higher risk of infection-related mortality than men. Mortality from malignancies was 2.9 times higher in dialysis patients and 1.7 times higher in transplant recipients than in the general population. Cancer and multisystem disease as primary causes of end-stage renal disease were associated with higher mortality from malignancies. CONCLUSION: Infection-related mortality is highly increased in dialysis and kidney transplant patients, while the risk of malignancy-related death is moderately increased. Young women on dialysis may deserve special attention because of their high excess risk of infection-related mortality. Further research into the mechanisms, prevention and optimal treatment of infections in this vulnerable population is required.

Trend from cardiovascular to non-cardiovascular late mortality in patients with renal replacement therapy since childhood.

BACKGROUND: To evaluate transitions in causes of death in patients with renal replacement therapy (RRT) since childhood over time, we performed a 10-year extension of the Late Effects of Renal Insufficiency in Children (LERIC) study. METHODS: The LERIC cohort consisted of all 249 Dutch patients, who were born before 1979 and started RRT <15 years of age between 1972 and 1992. We collected data on mortality and causes of death over the period 2000-10 and compared them with the previously gathered data over the period 1972-99. RESULTS: The median duration of follow-up from the start of RRT was 25.5 (range 0.3-39.0 years). Overall, 97 patients died of whom 34 in 2000-10. The overall mortality rate and mortality rate ratios (MRRs) stabilized over time. The MRR for cardiovascular death decreased from 660 in 1972-89 to 70 in 1990-99 and to 20 in 2000-10. Conversely, the MRR for infectious death showed a U-shape; it decreased from 503 in 1972-89 to 102 in 1990-99 and increased again to 350 in 2000-10. In 2000-10, infections became the most prevalent cause of death (44%). In 2000-10, the cardiovascular mortality had decreased with 91% since 1972-89 [adjusted hazard ratio (HR): 0.09, 95% confidence interval (95% CI): 0.02-0.45, P = 0.003], while infectious mortality had doubled over time, although not significantly (adjusted HR: 2.12, 95% CI: 0.88-5.11, P = 0.09). CONCLUSIONS: Over the last decade, we found a substantial shift from cardiovascular disease to infections as the main cause of death at long-term follow-up in patients with chronic kidney disease since childhood and who were born before 1979.

Simultaneous reversal of risk factors for cardiac death and intensified therapy in long-term survivors of paediatric end-stage renal disease over the last 10 years.

BACKGROUND: In an extended long-term follow-up of patients on chronic renal replacement therapy (RRT) since childhood (LERIC study), we observed a substantial reduction in cardiovascular (CV) death over the last decade. In this study, we investigated the contemporaneous changes in risk factors for CV death and cardioprotective therapy. METHODS: The cohort consisted of 140 Dutch patients, who were born before 1979 and started RRT before 15 years of age between 1972 and 1992. We compared the prevalence of various factors in 2000 and 2010 by calculating matched odds ratios (OR(matched)). RESULTS: Median age of patients was 38.5 years (range 23.2-50.8) in 2010, after a median time on RRT of 28 years. The prevalence of CV risk factors decreased from 41.3% in 2000 to 18.8% in 2010. The OR(matched) in 2010 compared with 2000 for left ventricular hypertrophy, hypertension and hypercholesterolaemia were 0.26 (95% CI 0.09-0.66), 0.22 (95% CI 0.01-0.59) and 0.04 (95% CI 0.01-0.25), respectively. The rate of nonfatal CV events dropped, although not significantly, from 1.75/100 (95% CI 1.3-2.4) per patient year (py) in 1972-2000 to 0.95/100 (95% CI 0.5-1.7) py in 2000-2010. ACE inhibitors/angiotensin receptor blockers and cholesterol lowering medication were prescribed significantly more often in the period 2000-10 [OR(matched) = 7.40 (95% CI 2.90-24.10) and 11.5 (95% CI 4.20-43.90)]. Trends were similar among those who survived and those who did not survive the last decade. CONCLUSIONS: We observed a decrease in clinical CV disease synchronous to intensified antihypertensive and antidyslipidaemic therapy in long-term survivors of paediatric renal failure. This advocates a vigorous cardioprotective management in these patients.

Long-Term Risk of Cancer in Survivors of Pediatric ESRD.

BACKGROUND AND OBJECTIVES: ESRD is associated with an increased risk of malignancies. We analyzed the incidence of cancer in patients with pediatric ESRD after long-term follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All Dutch patients born before 1979 who were transplanted at age <15 years old in 1972-1992 were followed until 2010. We explored type and incidence of malignancies in patients compared with the general population using the National Cancer Registry. RESULTS: After a median of 25.3 years (1.3-37.8) of transplantation and at a median age of 33.5 years old (11.0-49.0), 105 primary malignancies had occurred in 54 of 249 patients. Among them, cutaneous squamous cell carcinoma was most frequent. Patients ages 25-30 years old had developed 16.5 times (95% confidence interval, 7.9 to 34.6) as many de novo tumors and 991 times (95% confidence interval, 313 to 3137) as many de novo cutaneous squamous cell carcinomas as their general population counterparts; in survivors ages 45-50 years old, these numbers were 81.5 (95% confidence interval, 50.7 to 131.1) and 2610 (95% confidence interval, 1596 to 4267), respectively. Cumulative incidence competing risk analysis showed that, after 30 years of transplantation, 41% of the survivors had developed cancer; 31% had developed a second de novo cancer <1 year after initial cancer diagnosis. CONCLUSIONS: Cancer is highly prevalent among patients with pediatric ESRD after 25.3 years of transplantation, with a high rate of recurrence.