PURPOSE OF REVIEW: The review will examine clinically relevant advances in the area of polycystic kidney disease (PKD), mainly focusing on autosomal dominant polycystic kidney disease (ADPKD). Discussion will focus on predicting the course of ADPKD, clinical trials and new research endeavors. RECENT FINDINGS: During the past several years PKD research has been one of the most prolific areas in investigative nephrology. Research endeavors have focused on decreasing cyst proliferation and cyst fluid formation based on an understanding of the pathophysiology of these processes. If cysts can be prevented from growing, kidney function can be better preserved. SUMMARY: Progression of this most common inherited kidney disorder can be altered by understanding that cysts are the disease in ADPKD. Assessing total kidney volume and noting its relationship to glomerular filtration rate is key in predicting the course of the disease and will aid in the evaluation of the new research initiatives that are designed to stop cyst proliferation and fluid secretion into the kidney cysts. The role of biomarkers is an advancement in predicting PKD progression and can potentially be used in evaluation of treatments for this disease. Complications of PKD alter the course and prognosis; hence management approaches will be addressed.
PMID: 22274800 [PubMed - as supplied by publisher]
The kidney and hypertension: novel insights from transgenic models.
Curr Opin Nephrol Hypertens. 2012 Jan 20;
Authors: Herrera M, Coffman TM
Abstract
PURPOSE OF REVIEW: Despite decades of study, the pathogenesis of essential hypertension remains obscure, but the kidney appears to play a central role. Technology for manipulation of the mouse genome has been immensely valuable in dissecting pathways involved in blood pressure control. This review summarizes recent studies employing this technology to understand signaling pathways and specific cell lineages within the kidney that are involved in the regulation of sodium excretion impacting blood pressure homeostasis. RECENT FINDINGS: We review a series of recent studies of regulatory pathways affecting sodium excretion by the kidney including the renin-angiotensin system, the mineralocorticoid receptor, the endothelin system, nitric oxide, and the with-no-lysine (K)/sterile 20-like kinase pathway. We have specifically highlighted studies utilizing transgenic mouse models, which provide a powerful mechanism for defining the role of proteins and pathways on sodium balance and blood pressure in the intact organism. SUMMARY: These studies underscore the importance of the kidney in regulation of blood pressure and the pathogenesis of hypertension. Transgenic mouse models provide a powerful approach to identifying key cell lineages and molecular pathways causing hypertension. These pathways represent potential targets for novel antihypertensive therapies.
PMID: 22274801 [PubMed - as supplied by publisher]
PURPOSE OF REVIEW: The purpose of this review of the vascular biology of endothelin-1 (ET-1) is the presentation of recent data including the use of endothelin-receptor antagonists for the treatment of hypertension. RECENT FINDINGS: Recent discoveries regarding the pharmacology of ET-1 in the vascular wall and its effect on signalling transduction and gene expression in vascular smooth muscle cells are reviewed, as well as mechanisms controlling blood pressure in normal conditions and in hypertension, discovered using genetically modified models. Finally, studies of endothelin antagonists for treatment of hypertension will be summarized. SUMMARY: Pharmacological studies demonstrate that calcitonin gene-related peptide is a physiological antagonist of ET-1 that terminates the long-lasting contraction induced by ET-1. ET-1-induced rise in [Ca]i involves the newly described stromal-interaction molecule-1/orai1 pathway to increase store-operated calcium entry. Sensitization of contractile proteins to calcium during ET-1-induced contraction of vascular smooth muscle cells includes activation of p63Rho guanine nucleotide exchange factor and increase in O-GlcNAcylation, a form of posttranslational modification. Genetically modified mice have demonstrated that endothelial ET-1 is involved in the regulation of normal blood pressure and development of vascular disease. Gene expression induced by endothelial overexpression of ET-1 in mice demonstrated upregulation of lipid metabolism, inflammatory and signal transduction genes. Crossing these mice with apoE mice was associated with acceleration of atherosclerosis on a high-fat diet and blood pressure elevation. Finally, the DORADO clinical trial has demonstrated that the ETA-receptor antagonist darusentan is able to decrease the blood pressure of patients with refractory hypertension.
PMID: 22257795 [PubMed - as supplied by publisher]
Endothelin as a final common pathway in the pathophysiology of preeclampsia: therapeutic implications.
Curr Opin Nephrol Hypertens. 2012 Jan 17;
Authors: George EM, Palei AC, Granger JP
Abstract
PURPOSE OF REVIEW: Preeclampsia remains a major health concern in the United States and worldwide. Recent research has begun to shed light on the underlying mechanisms responsible for the symptoms of preeclampsia, and may provide new avenues for therapy for the preeclamptic patient. RECENT FINDINGS: The central role of placental ischemia in the manifestation of preeclampsia has provided new understanding for the origin of pathogenic factors in the preeclamptic patient. The release of soluble factors into the maternal bloodstream from the ischemic placenta is now recognized as a central mechanism in disease manifestation. Specifically, the importance of the vascular endothelial growth factor antagonist soluble fms-like tyrosine kinase and immune factors as factors regulating maternal endothelial dysfunction has become widely acknowledged. Furthermore, mounting evidence implicates the signaling protein endothelin-1 as the final converging factor in the multifaceted cascades that are responsible for the symptomatic manifestation of preeclampsia. Endothelin-1, as a final common pathway in the pathogenic cascade of preeclampsia, presents an intriguing new therapeutic approach for preeclamptic patients. SUMMARY: Identification of antiangiogenic, autoimmune, and inflammatory factors produced in response to placental ischemia have provided potential new avenues for future research into novel therapies for the preeclamptic patient, and suggest new therapeutic avenues for the treatment of preeclampsia.
PMID: 22257796 [PubMed - as supplied by publisher]
Challenges in the diagnostic and therapeutic approach to nephrolithiasis.
Curr Opin Nephrol Hypertens. 2012 Jan 17;
Authors: McMahon GM, Seifter JL
Abstract
PURPOSE OF REVIEW: The incidence of renal stones is rising along with the costs and morbidity associated with this condition. With careful evaluation and management, the great majority of recurrent stones are preventable. The cornerstone of this evaluation remains the 24-h urine collection. This review details the physiological rationale for commonly requested urine studies and details how these results should guide therapy with special emphasis on recent advances in the understanding of risk factors for stone disease. Challenges associated with the complicated patient will be addressed. RECENT FINDINGS: Long-term follow-up and repeated evaluations are effective at preventing recurrent stones and increasing patient satisfaction. There is growing appreciation of the complexity of dietary risks for stone disease, and traditional risk-factors such as dietary oxalate must be reevaluated. SUMMARY: The key to stone prevention is the individualization of therapy to specific patient risk factors with a recognition that these factors can change over time leading to a need for alterations in preventive therapies.
PMID: 22257797 [PubMed - as supplied by publisher]
PURPOSE OF REVIEW: We review recent work on the genetic basis of kidney disease in African Americans and its relationship to variation in the APOL1 gene. RECENT FINDINGS: People of recent African ancestry develop kidney disease at rates 4-5 times higher than most other groups. This observation holds for kidney disease attributed to hypertension, as well as focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Recent work suggests that the high risk for all of these forms of kidney disease in African Americans is conferred by the same genetic risk factors, specifically two coding sequence variants in the APOL1 gene. SUMMARY: Future studies aimed at understanding the clinical implications of APOL1 genotype in the setting of HIV infection, proteinuria, and hypertension-associated kidney disease will help clarify how these recent findings should influence a nephrologist’s decisions about patient care. Studies exploring the cellular and molecular mechanisms of APOL1-associated disease may lead to new methods of treatment.
PMID: 22257798 [PubMed - as supplied by publisher]
Authors: Steckelings UM, Paulis L, Namsolleck P, Unger T
Abstract
PURPOSE OF REVIEW: Research about the angiotensin AT2 receptor (AT2R) has been hampered in the past by the lack of a specific and selective agonist with in-vivo stability. Such an eagerly awaited agonist, compound 21, has recently become available, giving momentum to AT2R research which so far has resulted in 14 original publications. This article is intending to review those publications which address AT2R function by direct in-vivo stimulation instead of indirect approaches such as receptor blockade or genetic alteration of AT2R expression. RECENT FINDINGS: Studies reviewed in this article looked at the effect of AT2R stimulation in disease models of hypertension, renal disease, stroke, Alzheimer’s disease and myocardial infarction. AT2R stimulation does not have an antihypertensive effect, but promoted tissue protection in all models in which it was tested. Antiinflammation and antiapoptosis seem important features of the AT2R underlying improved outcome in experimental disease models. SUMMARY: Availability of nonpeptidic, orally active AT2R agonists will facilitate future AT2R research and hopefully contribute to the clarification of many still open questions regarding AT2R signalling and function. Furthermore, AT2R agonists represent a potential novel class of drugs and are expected to enter a phase I clinical study in 2012.
PMID: 22257799 [PubMed - as supplied by publisher]
PURPOSE OF REVIEW: The renal distal tubule has been considered for a long time as the main cellular target of aldosterone, where the hormone enhances sodium reabsorption and potassium secretion. However, other cell types in nonepithelial tissues, such as the heart, the vessels, adipose tissue, and macrophages, are now also recognized as targets for aldosterone. The functions that aldosterone exerts in these nonclassical target tissues are still a matter of debate. This review will highlight the recent findings on the extrarenal effects of aldosterone. RECENT FINDINGS: Numerous studies showed that aldosterone exerts profibrotic and proinflammatory effects, but one or more cofactors such as salt, angiotensin II, and oxidative stress are required. Moreover, inflammation and macrophage infiltration are a prerequisite to aldosterone-induced cardiac fibrosis. This underlines a key role for aldosterone and the mineralocorticoid receptor in macrophages. Inflammatory effects of aldosterone in vascular smooth muscle cells involve trafficking to lipid rafts/caveolae through receptor tyrosine kinases. Finally, a growing body of evidence indicates a prominent role of aldosterone/mineralocorticoid receptor in the metabolic syndrome, in insulin resistance, and in adipocyte biology. SUMMARY: The idiom from Socrates, ‘the more we learn, the less we know’, can be applied to aldosterone with its different facets and its pleiotropic effects. There is clear evidence for rapid nongenomic effects of aldosterone, mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent signaling, in the heart, the vessels, and other nonepithelial tissues, leading to inflammation, fibrosis, and progression of cardiovascular diseases including hypertension and metabolic syndrome.
PMID: 22240440 [PubMed - as supplied by publisher]
Novel antimicrobial-resistant bacteria among patients requiring chronic hemodialysis.
Curr Opin Nephrol Hypertens. 2012 Jan 11;
Authors: Snyder GM, D’Agata EM
Abstract
PURPOSE OF REVIEW: Antimicrobial-resistant bacteria (ARB) including resistant strains of Staphylococcus aureus, enterococci, and Gram-negative bacteria have the potential to cause serious infections among patients requiring chronic hemodialysis (CHD). The purpose of this article is to review novel ARB, which have emerged in this patient population, their mechanisms of transmission, and preventive efforts aimed at limiting their dissemination. RECENT FINDINGS: New strains of ARB, including community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility to vancomycin, vancomycin-resistant S. aureus and multidrug-resistant Gram-negative bacteria (MDRGN), are emerging among the CHD population. Extended-spectrum β-lactamase Gram-negative bacteria (ESBLGN) are among the most common MDRGN strains. These ESBLGN are resistant to the great majority of antimicrobials. The carbapenems remain the only optimal antimicrobial choice to treat ESBLGN infections. Intrafacility spread of ARB in dialysis units occurs between patients through contaminated hands and clothes of healthcare workers (HCWs), as well as contaminated inanimate surfaces. Spread of ARB to family members of both patients and HCWs has also been documented. SUMMARY: Colonization and infection with ARB continues to present a significant threat to patients receiving CHD. Interventions to reduce the spread of ARB should include infection control measures and judicious use of antimicrobials.
PMID: 22240441 [PubMed - as supplied by publisher]
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