Long-term outcome after pediatric renal transplantation : Endocrinologic and metabolic effects

Renal transplantation (RTx) has become an established treatment modality for end-stage renal disease in children. Along with the improvements in pre- and post-transplant care, the patient and graft outcomes have improved significantly during the past two decades. This attracts more attention to avoiding secondary complications and long-term side effects of the post-RTx immunosuppressive medication. Several risk factors cast a shadow over patients normal physical and mental development, but detailed reports on long-term outcome after pediatric RTx are scarce. This thesis was designed to investigate pubertal development and subsequent male fertility and semen quality with special emphasis on the effects of immunosuppressive medication on reproductive function. The study also aimed to analyze the prevalence of metabolic syndrome and its components in pediatric RTx patients and the association of these parameters with the long-term graft function. The onset of pubertal development occurred at the mean age of 12.7 years in boys with 22% considered delayed. In girls, however, no delayed development occurred, with the age at onset of puberty and menarche averaging 10.7 years and 12.5 years, respectively. Pubertal growth continued relatively long resulting in average final height of -1.7 height standard deviation score in boys and -1.2 in girls. The reproductive hormone levels were normal in a great majority of the patients. In young adult males who had received RTx in childhood, the free testosterone levels were lower and luteinizing hormone levels were higher in comparison with age-matched healthy controls. The RTx patients had also smaller testicular volumes and total sperm counts than the controls. Only a quarter of the RTx men who provided a semen sample had normospermia. Patients with a history of cyclophosphamide therapy had the worst outcome. Metabolic data were collected at several time points during a 13-year follow-up post-RTx. Hypertriglyceridemia associated with a worse kidney graft function at 1.5 and 5 years post-RTx, and it predicted the subsequent rate of kidney function decrease after 1.5 years post-RTx. Beyond the first postoperative year, other metabolic risk factors associated modestly with the long-term kidney graft function in pediatric RTx patients. The ambulatory BP monitoring data were retrospectively analyzed 5 to 10 years post-transplantation. The BP profiles were similar between renal, heart, and liver transplant groups. Hypertension was common especially at nighttime and the nocturnal BP dipping was often blunted. The use of antihypertensive medication did not notably change the ambulatory BP profile in RTx recipients. The BP variables correlated poorly with the metabolic parameters or kidney graft function.Elinsiirrot ovat vakiinnuttaneet asemansa monen vaikean sairauden hoitokeinona. Suomessa on tehty elinsiirto yli 400 lapselle ja nuorelle. Munuaisensiirtojen osuus kaikista lasten elinsiirroista on yli puolet. Lasten elinsiirrot on maassamme keskitetty HYKS:n Lastenklinikalle. Viimeisten kahden vuosikymmenen aikana hoitotulokset ovat parantuneet ja valtaosa siirteistä toimii kymmeniä vuosia. Munuaisensiirtopotilaiden pitkäaikaisennusteeseen vaikuttavat tekijät ovat osin selvittämättä. Elinikäinen hyljinnänestolääkitys ja ajan myötä heikentyvä siirteen toiminta uhkaavat potilaiden normaalia kehitystä ja hyvinvointia. Pitkäaikaistuloksia selvittämällä pyritään tunnistamaan suurimmassa riskissä olevat potilaat, jotta heidän hoitoaan voidaan tehostaa ja elämänlaatuaan parantaa. Tämän väitöskirjatutkimuksen tavoitteena oli analysoida lapsena munuaissiirteen saaneiden potilaiden murrosiän kehitystä, nuorten miesten hedelmällisyyttä sekä selvittää potilaiden rasva- ja sokeriaineenvaihduntaa ja verenpainetasoja pitkäaikaisseurannassa. Väitöstutkimuksen tulosten mukaan lapsena munuaissiirteen saaneiden nuorten puberteettikehitys oli viivästynyt 22 %:lla pojista, mutta normaali kaikilla tytöillä. Sukupuolihormonien tuotanto ei poikennut merkittävästi terveeseen väestöön verrattuna. Munuaissiirteen saaneiden nuorten aikuispituus oli jonkin verran lyhempi kuin terveellä suomalaisväestöllä ja se saavutettiin myöhemmin kuin keskimäärin väestössä. Tutkimuksessa selvitettiin myös nuorten aikuisten miespotilaiden kivesten koko, sukupuolihormonitasot sekä siemennesteen laatu. Tulokset osoittivat kivesten toiminnan häiriytyneeksi ja siemennesteen laadun huonoksi noin 80 %:lla potilaista, kun niitä verrattiin terveiden verrokkien vastaaviin löydöksiin. Lähes viidennes potilaista täytti metabolisen oireyhtymän kriteerit 1,5 vuotta siirron jälkeen, mutta sen esiintyvyys ei lisääntynyt seuranta-ajan kuluessa. Elinsiirronjälkeinen sokeritauti todettiin vain yksittäisillä potilailla. Rasva- ja sokeriaineenvaihduntaa kuvaavista tekijöistä ainoastaan poikkeavien triglyseridipitoisuuksien todettiin ennustavan potilaiden tutkimuksenhetkistä ja pitkäaikaista munuaissiirteen toimintakykyä. Verenpainetasoja arvioitiin 24 tunnin verenpainemonitoroinnin avulla ja kohonneita arvoja todettiin valtaosalla potilaista, etenkin yöaikaan. Vuorokauden verenpaineprofiilit munuaisen-, sydämen- ja maksansiirronsaaneilla potilailla muistuttivat toisiaan korostaen hyljinnänestolääkityksen merkitystä verenpainetasoissa. Verenpainetasot eivät assosioituneet munuaissiirteen pitkäaikaistoimintaan

Physical performance after pediatric solid organ transplantation

Introduction Low physical activity is a well-recognized problem in pediatric solid organ transplant recipients; however, little is known about the differences between transplant groups. Physical performance testing was performed in a cohort of pediatric kidney, liver, and heart transplant recipients. Methods Fifty-one patients (54.9% boys), including 17 liver, 20 kidney, 2 combined liver-kidney, and 12 heart transplant recipients, were tested at the median age of 11.5 (7.5-14.9) years. The results were compared with a control group, which consisted of 425 healthy schoolchildren. The physical performance test included six different tests of endurance, strength, flexibility, and speed. Results The transplant recipients performed worse on most tests when compared with the control subjects (leg-lift test 42.0 vs. 44.9 repetitions, p = .002; repeated squatting 21.6 vs. 23.9 repetitions, p < .001; sit-up test 9 vs. 17 vs. 9 repetitions, p < .001, back extension 20 vs. 35 repetitions, p < .001; and shuttle run test 26.5 vs. 23.7 seconds, p < .001). None of the test results differed statistically significantly between the transplant groups. Conclusion The physical performance of pediatric solid organ transplant recipients is lower than that of their healthy peers but do not differ between different transplant groups. More systematic rehabilitation programs and follow-up are needed.Peer reviewe

Anemia and low-grade inflammation in pediatric kidney transplant recipients

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p <0.001), but not with hepcidin-25, hsCRP or IL-6 levels. The levels of the major inflammatory markers IL-6 and hsCRP did not show a significant correlation with GFR at either the early maintenance phase or later. In the multivariable analysis, low Hb levels performed better than any other marker with respect to predicting concomitant and subsequent GFR. Anemia, but not elevated inflammatory indices, was associated with poor concomitant and subsequent graft function during a 10-year follow-up in pediatric RTx patients.Peer reviewe

Cancer morbidity and mortality after pediatric solid organ transplantation-a nationwide register study

Background The prevalence of malignancies after pediatric solid organ transplantation was evaluated in a nationwide study. Methods All patients who had undergone kidney, liver, or heart transplantation during childhood between the years 1982 and 2015 in Finland were identified. The inclusion criteria were age under 16 years at transplantation and age over 18 years at the last follow-up day. A total of 233 (137 kidney, 53 liver, and 43 heart) transplant recipients were enrolled. Controls (n = 1157) matched by the year of birth, gender, and hometown were identified using the Population Register Center registry. The cancer diagnoses were searched using the Finnish Cancer Registry. Results Altogether 26 individuals diagnosed with cancer were found, including 18 transplant recipients. Cancer was diagnosed at a median of 12.0 (IQR 7.8-17.8) years after the transplantation. The transplant recipients' risk for cancer was significantly higher when compared with the controls (HR 14.7; 95% CI 6.4-33.9). There was no difference for different graft types. Sixty-one percent of cancers among the transplant recipients were diagnosed at age older than 18 years. Conclusion The risk for cancer is significantly higher among young adults having undergone solid organ transplantation during childhood in comparison with population controls. Careful follow-up and attention to prevent cancers throughout adulthood are warranted.Peer reviewe

Long-term outcome of biopsy-proven idiopathic tubulointersitial nephritis with or without uveitis in children-a nationwide follow-up study

Background Only a few studies reporting the long-term outcome of children with idiopathic tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are available. We studied the long-term kidney and ocular outcome in a nationwide cohort of children with TIN or TINU.Methods All patients followed up for a minimum of 1 year by a paediatrician and an ophthalmologist were enrolled. The data on plasma creatinine (P-Cr), estimated glomerular filtration rate (eGFR), proteinuria, hypertension and uveitis were collected retrospectively.Results Fifty-two patients were studied. Median age at time of diagnosis was 13.1 (1.8-16.9) years and median follow-up time was 5.7 (1.1-21.2) years. Forty-five (87%) patients were initially treated with glucocorticoids. The median of the maximum P-Cr was 162 mu mol/l (47-1,016) and that of eGFR 47 ml/min/1.73m(2) (8-124). Uveitis was diagnosed in 33 patients (63%) and 21 (40%) patients developed chronic uveitis. P-Cr normalised in a median of 2 months. Eleven (21%) patients had nephritis recurrence during or after discontinuation of glucocorticoids. At the latest follow-up, 13 (25%) patients had eGFR Conclusions Our study questions the previously reported good long-term kidney and ocular outcome of patients with TIN/TINU. Decreased kidney function and/or ocular co-morbidities may persist for several years; thus, both kidney and ocular follow-up for at least 1 year is warranted.</div

Impact of borosilicate bioactive glass scaffold processing and reactivity on in-vitro dissolution properties

In this study, bulk borosilicate glasses and 3D scaffolds (processed by the burn-off technique and by robocasting) were synthesized to investigate the impact of the manufacturing method, glass composition and preincubation time on in vitro dissolution and cell response. The studied compositions are based on commercial bioactive glass S53P4 (BonAlive) where 12.5% SiO2 has been replaced by B2O (labelled B12.5), and part of the CaO is replaced with MgO and SrO (labelled B12.5-Mg-Sr). First, the impact of the processing and glass composition, on the dissolution rate, was assessed. As expected, scaffolds were found to exhibit faster dissolution, due to the increased surface area, when compared to the bulk glass. Furthermore, the 3D printed scaffolds were found to dissolve faster than the burn-off scaffolds. Moreover, scaffolds made from B12.5-Mg-Sr glass composition exhibited slower ion release and precipitation of calcium phosphate (CaP) layer, when compared to B12.5, due to the stabilizing effect of Mg and Sr. Finally, dynamic condition produces lower ion releases that static condition and could be more optimal for in vitro cell growth. Secondly, in culture with murine MC3T3-E1 cells, it was shown that 3 days preincubation would be optimal to decrease the burst of ions that is known to lead to cell death. However, it was found that MC3T3-E1 survived and proliferated only in presence of B12.5-Mg-Sr scaffolds. Finally, it was shown that despite scaffolds having different porosities, they had no significant difference on human adipose-derived stem cells (hADSCs) survival. This manuscript brings new information on 1) the impact of material design (porosity) and composition on dissolution kinetic sand reactivity, 2) the impact of static vs dynamic testing on in-vitro dissolution and 3) the impact of materials’ pre-incubation on cell behavior.publishedVersionPeer reviewe

Lasten ja nuorten verenpainetauti

Vertaisarvioitu. Näin hoidan. Teema : verenpainetautiLapsuus- tai nuoruusiällä alkavalla korkealla verenpaineella on kauaskantoiset vaikutukset aikuisiän hypertensioon ja sydän- ja verenkiertoelimistön sairauksiin. Vaikka hypertension kohde-elinvaurioita ei lapsuudessa yleensä todeta, on lisääntyvän tutkimustiedon valossa perusteltua seuloa ja seurata verenpainetta jo varhaisesta iästä alkaen. Alle kouluikäisillä hypertensiolle löydetään usein sekundaarinen syy tutkimuksissa, joita toisaalta voidaan tehdä harkiten etenkin ylipainoisilla, hypertension suhteen sukurasitteisilla potilailla, joilla tiedetään korkean verenpaineen olevan yleisempää. Lasten verenpaineelle ei ole osoitettavissa yhtä raja-arvoa, vaan mitattua verenpainetasoa verrataan terveen väestön sukupuolen, iän ja pituuden mukaisiin viitearvoihin. Koska lapset ja nuoret usein jännittävät verenpaineen mittaamista, on verenpaineen mittaaminen riittävän rauhoittumisen jälkeen useaan kertaan ja useina eri ajankohtina ensiarvoisen tärkeää ennen lisätutkimusten ohjelmoimista, diagnoosin asettamista tai lääkehoidon aloittamista

Physical performance capacity after pediatric kidney transplant and clinical parameters associated with physical performance capacity

Background History of chronic kidney disease and kidney transplantation is known to influence physical performance capacity. The aim of this study was to compare the physical performance of pediatric kidney transplant recipients to healthy controls and to find possible correlations between clinical parameters and physical performance capacity.Methods Twenty-four pediatric kidney transplant recipients (62.5% boys) were tested at a median age of 10.8 years. Physical performance capacity was tested with a test set including six different components assessing muscle endurance, strength, speed, and flexibility. The control group consisted of 273 healthy age-matched schoolchildren. Clinical parameters were collected as part of routine follow-up protocol. The majority of patients (62.5%) had congenital nephrotic syndrome of Finnish type (CNS) as primary diagnosis, and therefore, the results of CNS recipients were compared to the other disease groups.Results The physical performance capacity in pediatric kidney transplant recipients was lower compared to healthy controls. Surprisingly, no statistically significant correlation was found between graft function and physical performance capacity. The CNS patients scored worse than patients with other diagnoses in all test domains except for sit-and-reach and shuttle run, but the differences did not reach statistical significance.Conclusion The physical performance of pediatric kidney transplant recipients is reduced, especially in those with congenital nephrotic syndrome. Clinical parameters, including graft function, did not predict physical performance capacity, suggesting that the reduced physical performance seems to be of multivariable cause.Peer reviewe

Renal function and inflammatory response in neonates undergoing cardiac surgery with or without antegrade cerebral perfusion - A post hoc analysis

Publisher Copyright: © 2021 Annals of Cardiac Anaesthesia.Background: Cardiopulmonary bypass (CPB) may lead to tissue hypoxia, inflammatory response, and risk for acute kidney injury (AKI). We evaluated the prevalence of AKI and inflammatory response in neonates undergoing heart surgery requiring CPB with or without antegrade cerebral perfusion (ACP). Methods: Forty neonates were enrolled. The patients were divided into two groups depending on the use of ACP. AKI was classified based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Inflammatory response was measured using plasma concentrations of interleukins 6 (IL-6) and 10 (IL-10), white blood cell count (WBC), and C-reactive protein (CRP). Results: Eight patients (20%) experienced AKI: five (29%) in the ACP group and three (13%) in the non-ACP group (P = 0.25). Postoperative peak plasma creatinine and urine neutrophil gelatinase-associated lipocalin were significantly higher in the ACP group than in the non-ACP group [46.0 (35.0-60.5) vs 37.5 (33.0-42.5), P = 0.044 and 118.0 (55.4-223.7) vs 29.8 (8.1-109.2), P = 0.02, respectively]. Four patients in the ACP group and one in the non-ACP group required peritoneal dialysis (P = 0.003). Postoperative plasma IL-6, IL-10, and CRP increased significantly in both groups. There were no significant differences between the ACP and non-ACP groups in any of the inflammatory parameters measured. Conclusions: No significant difference in the AKI occurrence or inflammatory response related to CPB modality could be found. In our study population, inflammation was not the key factor leading to AKI. Due to the limited number of patients, these findings should be interpreted with caution.Peer reviewe