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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Acute kidney injury (AKI) is a common but complex clinical syndrome with multiple etiologies. These etiologies target different sites and pathways within the kidney. Novel biomarkers of 'kidney damage' (which can be tubular or glomerular) can be used to diagnose AKI, even in the absence of an increase in serum creatinine or oliguria. ⋯ The presence of underlying CKD or of sepsis poses additional challenges in differential diagnosis, since these conditions alter both baseline biomarker excretion and biomarker performance. We recommend that biomarkers be validated within the clinical context in which they are to be used. Within that context, combinations of biomarkers may, in the future, allow differentiation of the site, mechanism and phase of injury.
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Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and strongly associates with morbidity and mortality. The clinical benefits of a timely and definitive diagnosis of AKI have not been fully realized due to limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. These restrictions often lead to diagnostic delays, potential misclassification of actual injury status, and provide little information regarding underlying cause. ⋯ Promising diagnostic injury markers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and liver-type fatty acid binding protein (L-FABP). However, there are currently insufficient data on damage biomarkers to support their use for AKI staging. Rigorous validation studies measuring the association between the novel damage biomarker(s) and clinically relevant outcomes are needed.
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Several new biomarkers of kidney damage have been characterized and are being validated in clinical studies. These damage biomarkers complement existing conventional biomarkers of kidney function (e.g. serum creatinine, serum urea, and urine output) that are currently utilized to diagnose and stage acute kidney injury (AKI). Both functional and damage biomarkers provide an opportunity to identify patients with AKI who are at risk for a less favorable prognosis in terms of worsening damage or further declines in kidney function and likelihood of need for renal replacement. ⋯ Set cut-offs for various biomarkers and their bedside utility are forthcoming and will be in part determined by regulatory intended use guidelines, platform standardization, and inter-laboratory calibration. There remain many unresolved areas of AKI biomarker use in selected syndromes of AKI (e.g. cardiorenal syndrome, hepatorenal syndrome). As clinicians gain experience with AKI biomarkers, clinical care plans that incorporate them into routine care will shortly follow.