Contributions to nephrology
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The parathyroid gland plays a central role in the regulation of mineral metabolism. In patients with chronic kidney disease (CKD), circulating levels of parathyroid hormone (PTH) are progressively increased as kidney function declines, as a result of phosphate retention, hypocalcemia, decreased production of 1,25-dihydroxyvitamin D [1,25(OH)2D], endogenous changes within the parathyroid gland, and skeletal resistance to the actions of PTH. In addition, the identification of fibroblast growth factor 23 (FGF23) and its cofactor Klotho offers important implications for the deeper understanding of disordered mineral metabolism in CKD. ⋯ FGF23 also acts directly on the parathyroid to decrease PTH synthesis and secretion, but this effect is blunted in advanced stages of CKD, due to decreased expression of the Klotho-FGF receptor 1 complex and increased concentrations of C-terminal FGF23 that competes with full-length FGF23 for binding to the receptor complex. Recent clinical studies also reported that high levels of FGF23 are associated with morbidity and mortality as well as treatment resistance to active vitamin D, suggesting the potential of FGF23 as a novel biomarker to guide treatment of disordered phosphate metabolism in CKD. This review will discuss the pathogenesis of secondary hyperparathyroidism, particularly focusing on the emerging role of the FGF23-Klotho axis in patients with CKD.
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Various drugs have been used for the treatment of focal segmental glomerular sclerosis (FSGS) or minimal change disease (idiopathic nephrotic syndrome, INS) including methylprednisolone pulses, alkylating agents and calcineurin inhibitors, often without a strong rationale. For some drugs the rationale has been recently provided by the identification of mechanisms regulating proteinuria. The characterization of molecules acting as permeability factors, including hemopexin, soluble urokinase receptor and cardiotrophin-like cytokine-1, supports plasma exchange in severe cases of INS, particularly in patients at high risk of recurrence of FSGS after transplantation. ⋯ Using saquinavir associated with small doses of calcineurin inhibitors, we treated a small series of very difficult cases of INS with insufficient response to steroid therapy and multiple immunosuppressive drugs. Saquinavir allowed a significant reduction of steroid cumulative doses and disappearance of features of steroid toxicity. In conclusion, recent reports have allowed a new insight into the pathogenetical mechanism regulating proteinuria in INS, offering new targets for treating severe cases.
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In order to prevent a disease, its temporal nature (or at least when it starts) needs to be clearly defined. In acute kidney injury (AKI), this is usually not possible because the current diagnostic criteria are retrospective. Contrast-induced nephropathy (CIN) and cardiac surgery-associated acute kidney injury (CSA-AKI) are both thought of as potentially preventable acute renal lesions because the timing of the insult is known precisely. ⋯ Despite this, progress in prevention has been slow, and to date there are no therapies indicated for preventing either CIN or CSA-AKI. The best we can currently do is to recommend aggressive parenteral hydration, avoid compounds we know are nephrotoxic, and avoid unnecessary hypoxia and hypotension. While there is still clearly a long way to go before either of these acute kidney conditions can be described as preventable, the use of major adverse kidney events - death, dialysis and incident or progressive chronic kidney disease at 90 days - as a composite endpoint in clinical trials of putative prevention agents would represent a significant step forwards.
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Review Comparative Study
Acute kidney injury, acute lung injury and septic shock: how does mortality compare?
Acute kidney injury (AKI), acute lung injury (ALI) and sepsis are all commonly encountered in critically ill patients. Although considered as separate conditions, largely for therapeutic purposes, a common inflammatory response is often implicated in their pathophysiologies and they are frequently present simultaneously. Mortality rates in critically ill patients suffering from renal failure, respiratory failure or severe sepsis are quite similar at about 40%, and all increase substantially when these conditions coexist. Most intensive care unit patients will die from multiple rather than individual organ failure, and further research is needed to evaluate the patterns of organ failure in surviving and nonsurviving critically ill patients, as well as the importance and mechanisms of organ-organ crosstalk in such patients.
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The pathogenesis of sepsis-induced acute kidney injury (AKI) is not fully understood, and may involve altered systemic hemodynamics and renal circulation, renal hypoxia and perhaps direct tubular toxicity. Oxidative stress, induced by systemic and intrarenal generation of reactive oxygen species (ROS) can directly exert renal parenchymal damage and may intensify renal microvascular and functional dysregulation, with a feedforward loop of hypoxia and ROS generation. Herein we review compelling evidence that sepsis is associated with systemic and intrarenal intense oxidative and nitrosative stress with a depletion of antioxidant capacity. ⋯ Though oxidative and nitrosative stress are likely to participate in the pathogenesis of sepsis-induced AKI, it is impossible to clearly identify their isolated independent role and renal-specific effect since there are complex interactions involved linking various affected organs, ROS generation with altered systemic hemodynamics, compromised microcirculation, hypoxia and distorted cellular function. Facing this complex disease entity, alleviation of oxidative stress single-handedly is unlikely to be effective in the prevention of sepsis-associated renal dysfunction. However, the addition of antioxidants to a comprehensive treatment strategy seems a reasonable approach.