1,720,968 research outputs found
New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers.
No full textMedullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET–GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers
Pharmacogenetics: a promising tool to personalize immunosuppressive therapy in renal transplantation.
No full textIl trapianto renale rappresenta la terapia d’elezione per la malattia renale allo stadio terminale, una condizione clinica caratterizzata da gravi alterazioni biologiche/biochimiche che richiedono una terapia sostitutiva della funzione renale per garantire la sopravvivenza dei pazienti. Il trapianto è seguito, nella maggior parte dei casi, da un significativo miglioramento della qualità di vita dei pazienti, da una riduzione delle spese mediche e da un prolungamento della vita. Tuttavia i pazienti nefro-trapiantati devono assumere diversi farmaci immunosoppressori (inibitori della calcineurina, inibitori di mTOR e antimetaboliti) caratterizzati da un basso indice terapeutico, che, in alcuni casi, potrebbero determinare importanti effetti collaterali. Per evitare tossicità e reazioni avverse al farmaco, è importante che gli immunosoppressori siano somministrati correttamente sulla base dei livelli ematici degli stessi. Tuttavia questa metodologia risulta spesso poco riproducibile e poco efficiente. Inoltre, come in gran parte descritto, differenze ereditarie nel metabolismo e nella disposizione dei farmaci, e la variabilità genetica nei bersagli terapeutici (es recettori) possono inficiare significativamente i loro effetti e la tossicità. Pertanto, numerosi studi si stanno focalizzando sulla identificazione di biomarcatori utili per personalizzare la terapia sulla base delle caratteristiche genetiche dei pazienti. In questo contesto, riteniamo che le tecniche "omiche" potrebbero rappresentare in futuro potenti strumenti che, se impiegate regolarmente, potrebbero contribuire a raggiungere questo obiettivo
Very low levels of vitamin D in systemic sclerosis patients
No full textVitamin D displays many extraosseous immunomodulatory effects. The aim of the study was to evaluate the level of vitamin D in patients with systemic sclerosis (SSc) and to analyze the associations between the concentration of the vitamin and clinical manifestations. In March-April 2009, 65 consecutive SSc patients underwent evaluation of vitamin D concentrations by the LIAISON immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency, while concentrations <10 ng/ml as vitamin D deficiency. None of the patients were receiving vitamin D supplementation at the time of or during the year prior to study entry. The mean level of vitamin D was 15.8 +/- 9.1 ng/ml. Only three cases showed normal values; vitamin D insufficiency and deficiency were found in 43 and 19 cases, respectively. Patients with vitamin D deficiency showed longer disease duration (13.1 +/- 6.8 versus 9.4 +/- 5.5 years, P = 0.026), lower diffusing lung capacity for carbon monoxide (63.7 +/- 12.4 versus 76.4 +/- 20.2, P = 0.014), higher estimated pulmonary artery pressure (28.9 +/- 9.9 versus 22.8 +/- 10.4, P = 0.037) and higher values of ESR (40 +/- 25 versus 23 +/- 13 mm/h, P = 0.001) and of CRP (7 +/- 7 and 4 +/- 2 mg/l, P = 0.004) in comparison with patients with vitamin D insufficiency; moreover, late nailfold videocapillaroscopic pattern was more frequently found (52.6% versus 18.6%, P = 0.013). None of the patients showed evidence of overt mal-absorption. Low levels of vitamin D are very frequent in patients with SSc. Intestinal involvement is not likely the cause of vitamin D deficit; other factors such as skin hyperpigmentation and reduced sun exposition for psychological and social reasons may be implicated. Patients with vitamin D deficiency showed more severe disease in comparison with patients with vitamin D insufficiency, above all concerning lung involvement. Further trials are awaited to determine whether vitamin D could represent a modifiable factor able to interfere with SSc evolution
Severe vascular complications in patients affected by systemic sclerosis cyclically treated with iloprost
No full textThe objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 ± 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 ± 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy
Mitochondria: a new therapeutic target in chronic kidney disease
Full text linkCellular metabolic changes during chronic kidney disease (CKD) may induce higher production of oxygen radicals that play a significant role in the progression of renal damage and in the onset of important comorbidities. This condition seems to be in part related to dysfunctional mitochondria that cause an increased electron "leakage" from the respiratory chain during oxidative phosphorylation with a consequent generation of reactive oxygen species (ROS). ROS are highly active molecules that may oxidize proteins, lipids and nucleic acids with a consequent damage of cells and tissues. To mitigate this mitochondria-related functional impairment, a variety of agents (including endogenous and food derived antioxidants, natural plants extracts, mitochondria-targeted molecules) combined with conventional therapies could be employed. However, although the anti-oxidant properties of these substances are well known, their use in clinical practice has been only partially investigated. Additionally, for their correct utilization is extremely important to understand their effects, to identify the correct target of intervention and to minimize adverse effects. Therefore, in this manuscript, we reviewed the characteristics of the available mitochondria-targeted anti-oxidant compounds that could be employed routinely in our nephrology, internal medicine and renal transplant centers. Nevertheless, large clinical trials are needed to provide more definitive information about their use and to assess their overall efficacy or toxicity
Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in "Omics" Medicine.
Full text linkRenal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies
Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.
Full text linkThe gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group).A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective
Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease
Full text linkChronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The "omics" techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other "omics" methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients
Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects
Full text linkSirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific "SRL/EVR genes-focused pathway", possibly employable as a starting point for future in-depth research projects
The nephrologist of tomorrow: towards a kidney-omic future
No full textOmics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called “Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment” (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function
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