Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in "Omics" Medicine.

Renal 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

Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease.

Chronic 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

Mitochondria: a new therapeutic target in chronic kidney disease.

Cellular 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

Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects

Sirolimus (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

Fitoderivati e dieta mediterranea: armi naturali contro la disfunzione mitocondriale e la progressione del danno renale cronico

Abstract non disponibil

Pharmacogenetics: a promising tool to personalize immunosuppressive therapy in renal transplantation

Il 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

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.

Medullary 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\u2013GDNF 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.

Il trapianto renale rappresenta la terapia d\u2019elezione 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 \ue8 seguito, nella maggior parte dei casi, da un significativo miglioramento della qualit\ue0 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 tossicit\ue0 e reazioni avverse al farmaco, \ue8 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 variabilit\ue0 genetica nei bersagli terapeutici (es recettori) possono inficiare significativamente i loro effetti e la tossicit\ue0. 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

Sulodexide alone or in combination with low doses of everolimus inhibits the hypoxia-mediated epithelial to mesenchymal transition in human renal proximal tubular cells

BACKGROUND: Prolonged cold ischemia time, the period from the start of perfusion with cold preservation fluid after cessation of circulation due to arterial clamping until transplantation in the recipient, could induce epithelial-to-mesenchymal transition (EMT) in renal tubular cells, a process associated with chronic graft damage. In this context, everolimus (EVE) and sulodexide (SUL) could potentially slow down this process. METHODS: To assess whether SUL (50 \u3bcg/ml), EVE (at 5, 10, 100 nM) or their combination were able to inhibit EMT in human renal epithelial proximal tubular cells (HK-2) reoxygenated after 24 h under hypoxic conditions, we used classical biomolecular strategies. RESULTS: Hypoxia induced upregulation of alpha smooth muscle actin (\u3b1-SMA), fibronectin (FN) and vimentin at gene-expression and \u3b1-SMA and FN at protein levels. However, the addition, after reoxygenation, of SUL plus low-dose EVE (5 nM) to the cell culture reversed this condition. Moreover, SUL and EVE were able to inhibit the hypoxia-induced Akt phosphorylation in HK2 cells and their morphological changes. Similarly, SUL was able to reverse the hyper-expression of EMT markers induced by high EVE dosage (100 nM) in cells cultured under both normoxic and hypoxic conditions. CONCLUSIONS: Our data reveal, for the first time, that sulodexide, alone or combined to low doses of everolimus, may hinder EMT in renal cells following hypoxia or minimize fibrotic complications due to high dosage of mammalian target of rapamycin inhibitors

The nephrologist of tomorrow: towards a kidney-omic future

Omics 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