Browsing by Subject "Kidney"

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  • Smyth, L. J.; Kilner, J.; Nair, V.; Liu, H.; Brennan, E.; Kerr, K.; Sandholm, N.; Cole, J.; Dahlström, E.; Syreeni, A.; Salem, R. M.; Nelson, R. G.; Looker, H. C.; Wooster, C.; Anderson, K.; McKay, G. J.; Kee, F.; Young, I.; Andrews, D.; Forsblom, C.; Hirschhorn, J. N.; Godson, C.; Groop, P. H.; Maxwell, A. P.; Susztak, K.; Kretzler, M.; Florez, J. C.; McKnight, A. J. (2021)
    Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.
  • Smyth, L. J; Kilner, J.; Nair, V.; Liu, H.; Brennan, E.; Kerr, K.; Sandholm, N.; Cole, J.; Dahlström, E.; Syreeni, A.; Salem, R. M; Nelson, R. G; Looker, H. C; Wooster, C.; Anderson, K.; McKay, G. J; Kee, F.; Young, I.; Andrews, D.; Forsblom, C.; Hirschhorn, J. N; Godson, C.; Groop, P. H; Maxwell, A. P; Susztak, K.; Kretzler, M.; Florez, J. C; McKnight, A. J (BioMed Central, 2021)
    Abstract Background A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.
  • Alyodawi, Khalid; Vermeij, Wilbert P.; Omairi, Saleh; Kretz, Oliver; Hopkinson, Mark; Solagna, Francesca; Joch, Barbara; Brandt, Renata M. C.; Barnhoorn, Sander; van Vliet, Nicole; Ridwan, Yanto; Essers, Jeroen; Mitchell, Robert; Morash, Taryn; Pasternack, Arja; Ritvos, Olli; Matsakas, Antonios; Collins-Hooper, Henry; Huber, Tobias B.; Hoeijmakers, Jan H. J.; Patel, Ketan (2019)
    Background One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit. Methods To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone. Results We show that muscle of Ercc1(Delta/-) progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.14 mm(3) in untreated mice, cortical bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.22 mm(3) in untreated mice). The onset of neurological abnormalities was delayed (by similar to 5 weeks) and their severity reduced, overall sustaining health without affecting lifespan. Conclusions This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.
  • Leppävirta, Jussi; Kallionpaa, Roope A.; Uusitalo, Elina; Vahlberg, Tero; Pöyhönen, Minna; Peltonen, Juha; Peltonen, Sirkku (2018)
    Background: Neurofibromatosis type 1 (NF1) is a dominantly inherited Rasopathy caused by mutations in the NF1 gene on chromosome 17. NF1 has been connected to congenital anomalies, e.g., in the skeletal and cardiovascular systems, but the overall incidence of anomalies is unknown. In this retrospective register-based total population study conducted in Finland, the congenital anomalies in NF1 were evaluated. Methods: One thousand four hundred ten patients with NF1 were identified by searching the medical records related to inpatient and outpatient hospital visits of patients with an associated diagnosis for NF1 in 1987-2011. Each diagnosis was confirmed by a thorough review of the medical records. Ten non-NF1 control persons per NF1 patient were collected from the Population Register Centre. NF1 patients and controls were linked to the Medical Birth Register and the Register of Congenital Malformations. Odds ratios (OR) and 95% confidence intervals (95% CI) for major congenital anomalies (MCA) were calculated. Results: The OR for at least one MCA among NF1 children was almost threefold (adjusted OR 2.78, 95% CI 1.71-4.54) compared to controls matched for age, sex and municipality. NF1 children had a significantly increased risk of congenital anomalies in the circulatory (adjusted OR 3.35, 95% CI 1.64-6.83), urinary (adjusted OR 4.26, 95% CI 1.36-13.35) and musculoskeletal (adjusted OR 2.77, 95% CI 1.09-7.02) systems. Also, anomalies of the eye, ear, head and neck were more common among NF1 children than controls (adjusted OR 4.66, 95% CI 1.42-15.31). Non-NF1 children of mothers with NF1 did not have more anomalies than controls (adjusted OR 0.53, 95% CI 0.13-2.21). Conclusions: Children with NF1 have more MCAs than controls and close follow-up during pregnancy and the neonatal period is required if the mother or father has NF1. Non-NF1 children of mothers with NF1 do not have an increased risk for anomalies.
  • Raatesalmi, Oliver (Helsingin yliopisto, 2019)
    Suomessa tehdään vuosittain noin 240 munuaissiirtoa ja siirtojen määrä on kasvamassa. Verrattuna dialyysihoitoon munuaisensiirto antaa potilaalle pidemmän elinajanennusteen sekä paremman elämänlaadun. Munuaisensiirto on lisäksi kustannustehokasta dialyysihoitoon verrattuna. Suomessa suurin osa (85%) munuaissiirteistä tulee aivokuolleelta elinluovuttajalta. Loput siirteet tulevat eläviltä luovuttajilta, mutta maailmalla käytetään myös verenkierron pysähtymiseen menehtyneitä elinluovuttajia. Aivokuolema aiheuttaa elinluovuttajalle verenkierronsäätelyn häiriöitä sekä muutoksia immuuni- ja hyytymisjärjestelmiin. Lisäksi munuaissiirteen kylmä- ja lämminsäilytys sekä verenkierron palauttaminen aiheuttavat siirteelle iskemia-reperfuusio vaurion. Tämä voi aiheuttaa munuaissiirteen hidastuneen käynnistymisen (delayed graft function, DGF) aiheuttaen dialyysihoidon tarpeen. Munuaissiirteen hidastuneen käynnistymisen yleisyys Suomessa on tällä hetkellä noin 25%. Tässä tutkielmassa on analysoitu 100 munuaissiirtopotilaan muodostama aineisto. 89 munuaissiirteistä oli Suomesta ja 11 munuaissiirrettä saatiin Pohjoismaisen jakeluverkoston kautta. Munuaissiirrot on tehty vuosina 2015-2016. Tutkimuksen tavoitteena on selvittää, mitkä elinluovuttajaan liittyvät tekijät vaikuttavat DGF:n kehittymiseen. 30%:lle aineiston potilaista kehittyi DGF. Tilastollisesti merkittäviä tekijöitä DGF:n kehittymiselle olivat elinluovuttajan BMI ja verenpainetauti. Tutkimus tuo vahvistusta jo aikaisemmin tiedossa olleille DGF:n riskitekijöille suomalaisessa aineistossa. DGF lisää munuaissiirtoon liittyviä kustannuksia ja huonontaa siirteen pitkäaikaisennustetta. DGF:lle altistavat tekijät ovat suurelta osin elinluovuttajaan liittyviä (64%). Tämä puoltaa ajantasaisten ja yhtenäisten elinluovuttajan hoito-ohjeiden käyttöä.
  • Taskinen, Seppo; Lohi, Jouko; Koskenvuo, Minna; Taskinen, Mervi (2018)
    Purpose: To evaluate usefulness of cutting needle biopsy (CNB) to recognize pediatric renal tumors and to predict the evolution of histology during preoperative chemotherapy of Wilms tumors. Methods: Ninety pediatric patients were operated for renal tumors at our institution in 1988-2015. We included all 64 patients who had undergone CNB at diagnosis and whose CNB and nephrectomy samples were available for re-evaluation. Results: The CNB was diagnostic in all 59 Wilms tumors but only in two out of live non-Wilms tumors. Anaplasia was missed by CNB in one of three with diffuse anaplasia in nephrectomy specimens. In Wilms tumors the proportions of the blastemal, stromal and epithelial components were 55% (IQR 25-85), 28% (IQR 10-58) and 2% (IQR 0-10) in CNB samples and 5% (IQR 0-64), 15% (IQR 0-50) and 15% (IQR 0-44) in the nephrectomy specimens (p-values 0.002,0.599 and 0.005 respectively). The degree of tumor necrosis was in median 80% (IQR 21-97), after preoperative chemotherapy. The degree of tumor necrosis after chemotherapy had a positive correlation with the proportion of blastemal component (p = 0.008) and a negative correlation with proportion of epithelial component in pre-chemotherapy CNB samples (p <0.001). Conclusions: Wilms tumors are usually recognizable unlike non-Wilms tumors in CNB at diagnosis. In Wilms tumors, high blastemal cell content is associated with significant tumor necrosis during pre-operative chemotherapy. Our results do not support routine use of CNB in diagnosis of renal tumors. Type of study: Retrospective review. (C) 2017 Elsevier Inc. All rights reserved.
  • Achhra, Amit C.; Mocroft, Amanda; Ross, Michael; Ryom-Nielson, Lene; Avihingsanon, Anchalee; Bakowska, Elzbieta; Belloso, Waldo; Clarke, Amanda; Furrer, Hansjakob; Lucas, Gregory M.; Ristola, Matti; Rassool, Mohammed; Ross, Jonathan; Somboonwit, Charurut; Sharma, Shweta; Wyatt, Christina; INSIGHT START Study Grp (2017)
    The impact of early ART initiation (versus deferring) on kidney function has not been studied. START was a randomised comparison of immediate versus deferred ART initiation among HIV-positive persons with CD4(+) (cellsimm(3)) counts >500. Serum creatinine and urine dipstick protein were measured at Months 0, 1, 4, 8 and 12, and annually thereafter. The two arms were compared for changes in eGFR (mL/min/1.73 m(2), calculated by CI94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 056 (95% CI 0.003-1.11) higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or bPI use (1.85, 95% CI 1.21-2.50) and in Black participants (30.1% overall) (3.90, 95% CI 2.84-4.97) versus non-Blacks (1.05, 95% CI 0.33-1.77) (P <0.001 for interaction). Relative risk for proteinuria in the immediate versus deferred arm was 0.74 (95% CI 0.55-1.00) (P = 0.049). In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower proteinuria risk versus deferring ART (more pronounced in Black participants). Whether this early benefit translates into a lower risk of CKD requires further follow-up. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
  • Ylinen, Elisa; Merras-Salmio, Laura; Gunnar, Riikka; Jahnukainen, Timo; Pakarinen, Mikko P. (2018)
    Objective: Although impaired renal function has been a frequent finding among adults with intestinal failure (IF), the data on children is scarce. The aim of this study was to assess renal function in pediatric-onset IF. Methods: Medical records of 70 patients (38 boys) with pediatric-onset IF due to either short bowel syndrome (n = 59) or primary motility disorder (n = 11) and a history of parenteral nutrition (PN) dependency for >= 1 mo were evaluated. Renal function at the most recent follow-up was studied using plasma creatinine, cystatin C, and urea concentrations and estimated glomerular filtration rate (eGFR). Results: At a median age of 5.7 y and after PN duration of 3.2 y, 20 patients (29%) had decreased eGFR and higher cystatin C and urea concentrations. Patients with decreased renal function had significantly longer duration of PN (3.2 versus 0.9 y; P = 0.030) and shorter percentage of age adjusted small bowel length remaining (22 versus 32%; P = 0.041) compared with patients with preserved renal function. No other predisposing factors for decreased eGFR were identified. Conclusions: Patients with pediatric-onset IF are at significant risk for impaired renal function, which is associated with the duration of PN and the length of the remaining small bowel. In the present study, no other predisposing factors for decreased eGFR were found. Further studies using measured GFR are needed. (C) 2017 Elsevier Inc. All rights reserved.
  • WSES-AAST Expert Panel; Coccolini, Federico; Moore, Ernest E.; Kluger, Yoram; Leppäniemi, Ari; Catena, Fausto (2019)
    Renal and urogenital injuries occur in approximately 10-20% of abdominal trauma in adults and children. Optimal management should take into consideration the anatomic injury, the hemodynamic status, and the associated injuries. The management of urogenital trauma aims to restore homeostasis and normal physiology especially in pediatric patients where non-operative management is considered the gold standard. As with all traumatic conditions, the management of urogenital trauma should be multidisciplinary including urologists, interventional radiologists, and trauma surgeons, as well as emergency and ICU physicians. The aim of this paper is to present the World Society of Emergency Surgery (WSES) and the American Association for the Surgery of Trauma (AAST) kidney and urogenital trauma management guidelines.
  • Wang, Yilin; Strassl, Robert; Helanterä, Ilkka; Aberle, Stephan W.; Bond, Gregor; Hedman, Klaus; Weseslindtner, Lukas (2019)
    Background: While the pathogenicity of the two initially identified Human Polyomaviruses (HPyVs), BK Virus (BKPyV) and JC Virus (JCPyV) has been intensely studied, there is only limited data, on whether the occurrence of the recently discovered HPyVs correlates with high level BKPyV replication and progression towards Polyomavirus associated nephropathy (PVAN). Methods: Therefore, we performed a comprehensive longitudinal genoprevalence analysis of 13 HPyVs using a novel multiplex assay including 400 serum and 388 urine samples obtained from 99 kidney transplant recipients (KTRs), grouped by quantitative BKPyV DNA loads and evidence of manifest BKPyV associated disease (histologically verified PVAN, high urinary decoy cell levels and concurrent decrease of renal function). Results: In total, 3 different non-BKPyV/JCPyV HPyVs, Human Polyomavirus 9, Merkel Cell Polyomavirus (MCPyV) and Trichodysplasia Spinulosa associated Polyomavirus were detected in 11 blood and 21 urine samples from 21 patients. Although DNAemia of these viruses occurred more frequently during high level BKPyV DNAemia and PVAN, the increase of the detection frequency due to progression of BKPyV replication did not reach statistical significance for blood samples. The positive detection rate of MCPyV in urine, however, was significantly higher during BKPyV DNAemia in 19 KTRs of our cohort who suffered from histologically verified PVAN (p=0.005). In one individual with PVAN, continuous long-term shedding of MCPyV in urine was observed. Conclusion: In our cohort the recently discovered HPyVs HPyV9, TSPyV and MCPyV emerged in blood from KTRs with variable kinetics, while detection of MCPyV DNAuria occurred more frequently during BKPyV DNAemia in patients with PVAN.
  • Finne, Patrik; Helanterä, Ilkka; Lempinen, Marko (2019)
    Odotusajan lyheneminen vaikuttaisi suotuisasti potilaiden elämään.
  • Sivunen, Johanna; Karlberg, Susann; Lohi, Jouko; Karlberg, Niklas; Lipsanen-Nyman, Marita; Jalanko, Hannu (2017)
    Background Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Methods Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Results Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, a-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Conclusions Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.
  • Metsähonkala, Liisa; Alapulli, Heikki; Arvio, Maria; Hiippala, Anita; Hodgson, Ulla; Immonen, Arto; Kananen, Kristiina; Karvonen, Marjo; Kataja, Janne; Kälviäinen, Reetta; Leppävirta, Jussi; Lähdesmäki, Tuire; Nisen, Harry; Pöyhönen, Minna; Vanninen, Ritva; Vasara, Kristiina; Vieira, Päivi (2017)
    •Tuberoosiskleroosia sairastavat potilaat tarvitsevat systemaattista, monen erikoisalan seurantaa läpi elämän. •Tavoitteena on haitallisten tai jopa hengenvaarallisten elinmuutosten varhainen toteaminen ja hoito. •Epilepsian tehokkaalla hoidolla ja kehityksen oikea-aikaisella tuella pyritään vaikuttamaan potilaiden kehitys¬ennusteeseen ja neuropsykiatristen häiriöiden esiintymiseen. •Tässä suosituksessa esitetään diagnosointi- ja seurantavaiheessa tarvittavat tutkimukset ja niiden toteutus, jossa hyödynnetään sekä erikoissairaanhoidon että perusterveydenhuollon palveluja.