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1.
Artigo em Inglês | MEDLINE | ID: mdl-38632055

RESUMO

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

2.
Transpl Infect Dis ; 26(1): e14233, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38180168

RESUMO

BACKGROUND: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug-induced side effects and dose reduction due to decline in kidney function. METHOD: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections. RESULTS: In the studied cohort, 18.7% of patients showed a high-risk (HR) constellation (D+/R-) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients. CONCLUSION: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post-KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Humanos , Antivirais/uso terapêutico , Antivirais/farmacologia , Citomegalovirus , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Viremia/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/prevenção & controle , Valganciclovir/uso terapêutico , Transplantados , Ganciclovir/uso terapêutico , Ganciclovir/farmacologia
3.
Nephrol Dial Transplant ; 39(1): 141-150, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-37391381

RESUMO

BACKGROUND: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. METHODS: The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. RESULTS: Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P = .041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. CONCLUSIONS: With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).


Assuntos
Transplante de Rim , Idoso , Humanos , Anticorpos Monoclonais , Basiliximab , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Ácido Micofenólico/uso terapêutico , Esteroides , Tacrolimo/efeitos adversos
4.
Int J Mol Sci ; 24(3)2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36768831

RESUMO

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.


Assuntos
Senilidade Prematura , Insuficiência Renal Crônica , Feminino , Camundongos , Animais , Gravidez , Humanos , Senilidade Prematura/metabolismo , Obesidade/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Envelhecimento/genética
5.
Graefes Arch Clin Exp Ophthalmol ; 259(4): 941-948, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33258999

RESUMO

PURPOSE: To assess corneal densitometry in patients with Fabry disease (FD) and to compare corneal densitometry differences in FD patients to different corneal manifestations. METHODS: Ten participants (20 eyes) with FD and 10 age-matched healthy volunteers (20 eyes) were recruited. All participants were assessed by standardized ophthalmic examinations and the corneal densitometry analysis by Pentacam HR. Densitometry measurements were analyzed in standardized grayscale units. RESULTS: Seven patients developed conjunctival vessel tortuosity, cornea verticillata appeared in 6 patients, and two patients had Fabry cataract. Retinal vessel tortuosity occurred in 4 patients, and dilation of retinal vessels appeared in 3 patients, all symptoms occurred in both eyes. The first diagnosis of FD up to examination was 4.7 ± 3.23 years, and first ERT up to examination was 2.6 ± 2.27 years. The initial time to diagnosis was negatively related to the corneal densitometry value of the 0-2-mm (r = - 0.556, p = 0.011) and 2-6-mm (r = - 0.482, p = 0.032) zones in the posterior layer. FD group have significantly higher corneal densitometry in anterior 0-2-mm zone and 2-10-mm zone anterior and posterior layer than the control group (p ≤ 0.035, respectively). When divided into two groups by the existence of cornea verticillata, there was a statistically significant difference in the anterior layer, 6-10-mm zone (p = 0.031); in the central layer, 0-2 mm (p = 0.012), 2-6 mm (p = 0.001), 6-10 mm (p = 0.002), and total (p = 0.002); and in the posterior layer, 6-10 mm (p = 0.004) and total (p = 0.002). CONCLUSIONS: FD patients show higher corneal densitometry, and corneal densitometry may have potential for early diagnosis and reminding progress of FD.


Assuntos
Doença de Fabry , Túnica Conjuntiva , Córnea , Densitometria , Diagnóstico Precoce , Doença de Fabry/diagnóstico , Humanos
6.
Cell Physiol Biochem ; 52(5): 1139-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30990584

RESUMO

BACKGROUND/AIMS: Fabry disease (FD) is a lysosomal storage disorder characterized by impaired alpha-galactosidase A (α-Gal A) enzyme activity due to mutations in the GLA gene. While virtually all tissues are affected, renal damage is particularly critical for the patients' outcome. Currently, powerful diagnostic tools and in vivo research models to study FD in the kidney are lacking, which is a major obstacle for further improvements in diagnosis and therapy. The present study focuses on the effects of enzyme replacement therapy on a previously established podocyte cell culture model of Fabry disease. METHODS: We investigated the effect of in vitro application of α-Gal A on Fabry podocytes for 3 days, mimicking enzyme replacement therapy. We studied reduction of Gb3 levels and dysregulated molecular pathways such as autophagy, mTOR/AKT signaling and pro-fibrotic signaling by employing immunofluorescence, electron microscopy, tandem mass spectrometry and western blot. RESULTS: We detected complete resolution of Gb3 accumulation in Fabry podocytes upon α-Gal A treatment. Despite robust Gb3 clearance, dysregulation of the signaling pathways investigated was not reversed. CONCLUSION: This study presents first evidence for Gb3-independent effects regarding dysregulation of signal transduction mechanisms in FD not recovering upon α-Gal A treatment. We assume that intracellular alterations observed in FD may have a point of no return after which a reversal of dysregulated cellular signal transduction by α-Gal A treatment is not effective, despite Gb3 clearance. Our observations suggest further research on signal transduction mechanisms altered in Fabry podocytes and on determining the appropriate time for initiation of Fabry therapy.


Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry , Modelos Biológicos , Podócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triexosilceramidas/metabolismo , alfa-Galactosidase/uso terapêutico , Técnicas de Cultura de Células , Linhagem Celular Transformada , Doença de Fabry/tratamento farmacológico , Doença de Fabry/metabolismo , Doença de Fabry/patologia , Humanos , Podócitos/patologia
7.
BMC Nephrol ; 20(1): 296, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382904

RESUMO

BACKGROUND: Transplant failure requires the consideration of numerous potential causes including rejection, acute tubular necrosis, infection, and recurrence of the original kidney disease. Kidney biopsy is generally required to approach these differential diagnoses. However, the histopathological findings on their own do not always lead to a definite diagnosis. Consequently, it is crucial to integrate them with clinical findings and patient history when discussing histopathological patterns of injury. The histopathologic finding of a membranoproliferative glomerulonephritis (MPGN) is one of the most challenging constellations since it does not refer to a specific disease entity but rather reflects a pattern of injury that is the result of many different causes. Whilst MPGN is occasionally classified as immune complex mediated, careful evaluation usually reveals an underlying disorder such as chronic infection, plasma cell dyscrasia, complement disorders, and autoimmune disease. CASE PRESENTATION: We describe the case of a 43-year-old woman who was referred to us because of a slowly rising serum creatinine 4 years after kidney transplantation. As in the native kidney, the biopsy revealed an MPGN pattern of injury. The cause of this finding had not been established prior to transplantation leading to a classification as idiopathic MPGN in the past. Further workup at the time of presentation and allograft failure revealed chronic infection of a ventriculoatrial shunt as the most probable cause. CONCLUSION: This case underlines the fact that MPGN is not a disease but a histopathological description. Consequently, the causative disorder needs to be identified to avoid kidney failure and recurrence after transplantation.


Assuntos
Derivações do Líquido Cefalorraquidiano/efeitos adversos , Glomerulonefrite Membranoproliferativa/etiologia , Transplante de Rim , Complicações Pós-Operatórias/etiologia , Infecções Estafilocócicas/complicações , Adulto , Biópsia , Creatinina/sangue , Feminino , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Hidrocefalia/sangue , Hidrocefalia/cirurgia , Rim/patologia , Recidiva , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis , Staphylococcus hominis , Derivação Ventriculoperitoneal
8.
J Am Soc Nephrol ; 28(10): 2867-2878, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28724775

RESUMO

Regulated intracellular proteostasis, controlled in part by proteolysis, is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. We applied a novel proteomics technology that enables proteome-wide identification, mapping, and quantification of protein N-termini to comprehensively characterize cleaved podocyte proteins in the glomerulus in vivo We found evidence that defined proteolytic cleavage results in various proteoforms of important podocyte proteins, including those of podocin, nephrin, neph1, α-actinin-4, and vimentin. Quantitative mapping of N-termini demonstrated perturbation of protease action during podocyte injury in vitro, including diminished proteolysis of α-actinin-4. Differentially regulated protease substrates comprised cytoskeletal proteins as well as intermediate filaments. Determination of preferential protease motifs during podocyte damage indicated activation of caspase proteases and inhibition of arginine-specific proteases. Several proteolytic processes were clearly site-specific, were conserved across species, and could be confirmed by differential migration behavior of protein fragments in gel electrophoresis. Some of the proteolytic changes discovered in vitro also occurred in two in vivo models of podocyte damage (WT1 heterozygous knockout mice and puromycin aminonucleoside-treated rats). Thus, we provide direct and systems-level evidence that the slit diaphragm and podocyte cytoskeleton are regulated targets of proteolytic modification, which is altered upon podocyte damage.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Nefropatias/metabolismo , Podócitos/metabolismo , Proteólise , Animais , Células Cultivadas , Humanos , Masculino , Camundongos Knockout , Proteoma , Proteômica/métodos , Ratos
9.
Internist (Berl) ; 59(8): 861-867, 2018 08.
Artigo em Alemão | MEDLINE | ID: mdl-29671012

RESUMO

This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.


Assuntos
Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistina/sangue , Cistina/metabolismo , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Adulto , Criança , Pré-Escolar , Cisteamina/administração & dosagem , Eliminadores de Cistina/administração & dosagem , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/etiologia , Humanos , Rim/patologia , Lisossomos/metabolismo , Masculino , Qualidade de Vida
10.
Am J Pathol ; 186(5): 1128-39, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27105734

RESUMO

Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein. Immunofluorescence and immunogold labeling detected PHB2 at mitochondrial membranes and at the slit diaphragm, a specialized cell junction at the filtration slit of glomerular podocytes. PHB2 coprecipitated with podocin, another SPFH domain-containing protein, essential for the assembly of the slit diaphragm protein-lipid supercomplex. Consistent with an evolutionarily conserved extra-mitochondrial function, the ortholog of PHB2 in Caenorhabditis elegans was also not restricted to mitochondria but colocalized with the mechanosensory complex that requires the podocin ortholog MEC2 for assembly. Knockdown of phb-2 partially phenocopied loss of mec-2 in touch neurons of the nematode, resulting in impaired gentle touch sensitivity. Collectively, these data indicate that, besides its established role in mitochondria, PHB2 may have an additional function in conserved protein-lipid complexes at the plasma membrane.


Assuntos
Mitocôndrias/fisiologia , Podócitos/fisiologia , Proteínas Repressoras/deficiência , Animais , Proteínas de Caenorhabditis elegans , Células Cultivadas , Células HEK293 , Humanos , Junções Intercelulares/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/fisiologia , Mecanorreceptores/fisiologia , Mecanotransdução Celular/fisiologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/etiologia , Doenças Mitocondriais/fisiopatologia , Membranas Mitocondriais/fisiologia , Membranas Mitocondriais/ultraestrutura , Podócitos/ultraestrutura , Proibitinas , Proteinúria/etiologia , Proteinúria/fisiopatologia , Tato/fisiologia
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