Nephron Clinical Practice最新文献

Oxygen is vital to mammalian survival. Oxygen deprivation, defined as hypoxia, elicits adaptive responses in cells and tissues, a process regulated by proteins known as hypoxia-inducible factors (HIF). Animal studies have provided compelling data to demonstrate a pivotal role for the HIF pathway in the pathogenesis of acute kidney injury (AKI) that have led to initial human clinical trials examining this pathway in ischemia-reperfusion injury in various organ systems, including the kidney. HIF are master regulators and mediate adaptive responses to low oxygen in tissues and cells. This review will summarize recent key advances in the field highlighting preclinical and clinical studies relevant to the HIF pathway in the pathophysiology of AKI.

The clinical implementation of urinary and plasma renal injury biomarkers has been hampered by the variability associated with nonstandardized commercially available biomarker assays, uncertainty and variations in patient selection criteria, and the absence of context-specific cutoffs for biomarker concentrations. These limitations are increased by comparison with serum creatinine to define acute kidney injury. The critical problem affecting biomarker performance is patient heterogeneity involving the cause, context (including comorbidity and baseline renal function), and timing of the injury. We suggest strategies for stratifying subjects to provide appropriate context, and illustrate a creatinine-independent method for defining thresholds for biomarker concentrations in these contexts which utilizes the same sensitivity for the clinical outcomes of dialysis or death. Large multicenter cohort studies are needed to validate the proposed cutoffs.

Diabetes is the single largest contributor to the growing prevalence of chronic kidney disease (CKD), and episodes of acute kidney injury (AKI) increase the risk of advanced CKD in diabetic patients. Here we discuss whether the pathophysiological changes that occur in the tubular system of the diabetic kidney affect the intrinsic susceptibility to AKI. There is abundant data showing that drug-induced nephrotoxicity is attenuated in rodents with experimental diabetes mellitus, and some mechanistic explanations have been provided, in particular in response to aminoglycosides. Besides downregulation in proximal tubular megalin, which mediates the aminoglycoside uptake in proximal tubules, a role for hyperglycemia-induced activation of regenerative mechanisms has been proposed. The available clinical data, however, indicates that diabetes is a risk factor for AKI, including aminoglycoside nephrotoxicity. While much needs to be learned about this disconnect, the isolated induction of diabetes in otherwise healthy young adult rodents may simply not fully mimic the influence that diabetes exerts in the setting of a critically ill and often elderly patient. We speculate that diabetic tubular growth and the associated molecular signature (including upregulation of TGF-β, senescence, and inflammation) set up the development of diabetic nephropathy and renal failure in part by increasing the susceptibility to AKI, which further promotes hypoxia and apoptosis. Considering the strong association between AKI episodes and the cumulative risk of developing advanced CKD in diabetes, strategies that reduce AKI in these patients are expected to help reduce the growing burden of end-stage renal disease.

While the field of acute kidney injury (AKI) research has undergone exponential growth over the past 15 years, the topic of renal recovery has only recently garnered much attention. Both lack of standardized renal recovery definitions and lack of systematic assessment of AKI survivors for chronic kidney disease development pose barriers to the complete understanding of the renal recovery epidemiology. In addition, evaluation of pediatric AKI renal recovery is further complicated by the potential AKI effects on renal development as well as a relatively greater renal reserve for younger children. The aims of this review are to review the current state of knowledge in pediatric AKI renal recovery.

Background/aims: β2-Microglobulin (β2-MG) is a major protein component of dialysis-related amyloidosis. In long-term hemodialysis (HD) patients, β2-MG amyloid deposits not only in osteoarticular tissues, but also in systemic tissues, including the heart. The purpose of this study was to investigate the relationship between serum β2-MG concentrations and echocardiographic parameters in long-term HD patients in a cross-sectional study.

Methods: Measurement of serum β2-MG concentrations and echocardiography were performed in 251 patients who had undergone HD therapy for more than 10 years.

Results: The left ventricular mass index (LVMI) of the higher serum β2-MG (≥30 mg/l) group was significantly higher than that of the lower serum β2-MG (<30 mg/l) group (151.5 ± 45.7 vs. 137.0 ± 44.5 g/m(2), p = 0.020). In simple regression analyses, serum β2-MG concentrations correlated significantly and positively with interventricular septum thickness (IVST) (r = 0.215, p < 0.001), posterior left ventricular wall thickness (PWT) (r = 0.249, p < 0.001), left ventricular wall thickness (LVWT) (r = 0.252, p < 0.001), relative wall thickness (RWT) (r = 0.153, p = 0.015) and LVMI (r = 0.171, p = 0.007). Multiple regression analyses revealed that serum β2-MG concentrations correlated significantly and positively with IVST, PWT, LVWT and RWT.

Conclusion: Serum β2-MG concentrations correlated significantly and positively with the echocardiographic parameters of left ventricular hypertrophy (LVH) in long-term HD patients. Thus, deposition of β2-MG amyloid in the heart may be associated with LVH progression.

Background/aims: Cerebrovascular diseases such as stroke are increased in dialysis patients, and haemodiafiltration has been reported to reduce cerebrovascular mortality compared to haemodialysis. We wished to determine whether haemodiafiltration improves arterial stiffness.

Methods: We audited aortic pulse wave velocity (PWV) measurements 6 months apart in 3 cohorts of patients: 69 treated with haemodialysis, 78 who converted from haemodialysis to haemodiafiltration and 142 treated with haemodiafiltration.

Results: Cohorts were well matched for age (means ± SD: haemodialysis 64 ± 15 years vs. haemodialysis to haemodiafiltration 64 ± 17 years vs. haemodiafiltration 67 ± 16 years), sex (male 65 vs. 59 vs. 63%), diabetes (45 vs. 56.4 vs. 44%) and body mass index (26 ± 6 vs. 26 ± 5 vs. 26 ± 5), respectively. Systolic blood pressure did not differ over time (haemodialysis 143 ± 25 vs. 146 ± 27 mm Hg, haemodialysis to haemodiafiltration 153 ± 26 vs. 154 ± 25 mm Hg, haemodiafiltration 149 ± 31 vs. 148 ± 30 mm Hg) or between groups. Aortic PWV significantly increased in the haemodialysis group (9.5 ± 1.9 vs. 10.2 ± 2.2 m/s, p < 0.01) and haemodialysis to haemodiafiltration group (9.4 ± 1.9 vs. 10.1 ± 2.2 m/s, p < 0.01), but did not change with haemodiafiltration (9.9 ± 2.1 vs. 10.1 ± 2.2 m/s).

Conclusions: Aortic PWV, a measure of vascular stiffness, stabilised with haemodiafiltration. Our preliminary findings require further investigation to determine how haemodiafiltration may potentially improve vascular stiffness.

The spectrum of polycystic kidney disease (PKD) comprises a family of inherited syndromes defined by renal cyst formation and growth, progressive renal function loss and variable extrarenal manifestations. The most common form, autosomal-dominant PKD is caused by mutations in one of two genes, PKD1 or PKD2. Recent developments in genomic and proteomic medicine have resulted in the discovery of novel genes implicated in the wide variety of less frequent, recessive PKD syndromes. Cysts are the disease, and overall cystic burden, measured by MRI as total kidney volume, is being established as the best available biomarker of disease progression. Current state-of-the-art therapy is aimed at quality treatment for chronic renal insufficiency and cyst-related complications. Recent therapeutic studies have focused on mechanisms reducing intracellular cyclic AMP levels, blocking the renin-angiotensin-aldosterone system and inhibiting the mTOR-signaling pathway. PKD therapies with vasopressin antagonists and somatostatin analogues result in the reduction of intracellular cAMP levels and have shown limited clinical success, but side effects are prominent. Similarly, mTOR pathway inhibition has not shown significant therapeutic benefits. While the HALT-PKD study will answer questions by the end of 2014 about the utility of renin-angiotensin-aldosterone system blockade and aggressive blood pressure control, the next generation of PKD therapy studies targeting proliferative mechanisms of cyst expansion are already under way. Advances in research on the molecular mechanisms of cystogenesis will help design novel targeted PKD therapies in the future.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.

Background/aims: Lupus nephritis is an organ manifestation of systemic autoimmunity. Current treatment algorithms are still based on unselective immunosuppressive drugs. There is hope that highly selective biological drugs could be as or even more effective but less toxic. A profound understanding of the pathogenesis of lupus nephritis is necessary to identify the optimal molecular targets.

Methods: PubMed and www.clincialtrials.gov were searched using 'lupus nephritis' as the key word.

Results: The pathogenesis of lupus nephritis is based (1) on the mechanisms that lead to loss of tolerance against nuclear autoantigens, i.e. systemic lupus, and then (2) on the mechanisms of immune complex-induced intrarenal inflammation. Systemic lupus develops when genetic variants allow autoimmunization against nuclear autoantigens, e.g. by impairing lymphocyte depletion via apoptosis, opsonization, and rapid phagocytic clearance. This allows endogenous nucleic acids to directly activate Toll-like receptors on dendritic cells or B cells, a process that drives IFN-α-driven immunity, antigen presentation, and the activation of autoreactive lymphocyte subsets. Activation of B cells and their maturation to plasma cells promotes autoantibody production and subsequent immune complex glomerulonephritis. Complement and numerous proinflammatory cytokines drive the inflammatory process that can cause kidney injury, scarring, and chronic kidney disease.

Conclusion: Systemic lupus is more a variable syndrome than a single disorder based on heterogeneous genetic variants and complex aberrant immune alterations. This makes it less likely that a single specific biological drug will be as efficient as currently used unselective immunosuppressive drugs. Autoantibody production and intrarenal immune complex formation are the hallmark of lupus nephritis. However, kidney injury and scarring also result from local amplification of tissue inflammation. Therefore, a combination of unselective immunosuppressive and biological drugs that block immune cell recruitment or proinflammatory cytokines may be promising to improve disease outcomes in lupus nephritis.