Abstract:
:Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Bierzynska A,McCarthy HJ,Soderquest K,Sen ES,Colby E,Ding WY,Nabhan MM,Kerecuk L,Hegde S,Hughes D,Marks S,Feather S,Jones C,Webb NJ,Ognjanovic M,Christian M,Gilbert RD,Sinha MD,Lord GM,Simpson M,Koziell AB,Welshdoi
10.1016/j.kint.2016.10.013subject
Has Abstractpub_date
2017-04-01 00:00:00pages
937-947issue
4eissn
0085-2538issn
1523-1755pii
S0085-2538(16)30612-3journal_volume
91pub_type
杂志文章abstract:BACKGROUND:The National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) clinical practice guidelines have suggested minimal weekly Kt/V urea and creatinine clearance goals for peritoneal dialysis patients maintained on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1046/j.1523-1755.2000.00120.x
更新日期:2000-06-01 00:00:00
abstract:BACKGROUND:Familial nephrotic syndrome (NS) has both autosomal dominant and recessive forms of inheritance. Recent studies in families with an autosomal dominant form of focal segmental glomerulosclerosis (FSGS) have been at odds concerning linkage to chromosome 19q13 (Mathis et al, Kidney Int 53:282-286, 1998; Winn et...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.057003875.x
更新日期:2000-03-01 00:00:00
abstract::As new components of the renin-angiotensin system (RAS) are elucidated, our understanding of the complexities of their interactions also advances. Previous studies have determined that podocytes possess a local RAS that can generate angiotensin II. Podocytes have also been shown to express angiotensin-converting enzym...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2012.127
更新日期:2012-08-01 00:00:00
abstract::Interstitial monocytic infiltration of the kidney occurs within hours of acute kidney injury and is an important determinant of functional decline and fibrosis. Li et al. used several surface markers to distinguish between dendritic cells and inflammatory monocytes following acute kidney injury and to identify two che...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2008.555
更新日期:2008-12-01 00:00:00
abstract:BACKGROUND:The fibrinolytic system plays an important role in degrading fibrin-rich thrombi and in vascular and tissue remodeling. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) can reduce the efficiency of the endogenous fibrinolytic system. Angiotensin (Ang) has been shown to regulate PAI-1 expression v...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00160.x
更新日期:2000-07-01 00:00:00
abstract::Whole-genome microarrays identify large numbers of gene expression changes that appear specifically related to disease states such as antineutrophil cytoplasmic autoantibody (ANCA) and systemic lupus erythematosus. Although understanding this enormous volume of esoteric data is difficult, a few basic concepts regardin...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/sj.ki.5002492
更新日期:2007-10-01 00:00:00
abstract::Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated rena...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.215
更新日期:1991-08-01 00:00:00
abstract::In his hypothesis of the evolution of renal functions Homer Smith proposed that the formation of glomerular nephron and body armor had been adequate for the appearance of primitive vertebrates in fresh water and that the adaptation of homoiotherms to terrestrial life was accompanied by the appearance of the loop of He...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.1996.220
更新日期:1996-06-01 00:00:00
abstract:BACKGROUND:Microalbuminuria (MA) is a strong predictor of cardiovascular disease, but its causes are incompletely understood. Hyperhomocysteinemia is a recently recognized risk factor for cardiovascular disease independent of established risk factors. It is not known whether hyperhomocysteinemia is associated with MA, ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.4495353
更新日期:1998-07-01 00:00:00
abstract:BACKGROUND:The renin-angiotensin system has been known to regulate blood pressure and body fluid homeostasis. Several lines of evidence have shown that renin gene expression and release are up-regulated by beta-adrenergic stimulation, sodium depletion, and angiotensin converting enzyme inhibition, but down-regulated by...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00209.x
更新日期:1998-12-01 00:00:00
abstract::Functional and morphological changes developed rapidly in rats after the intravenous administration of the organic nephrotoxin p-aminophenol. Proximal intratubular pressure remained close to its mean control value of 14.9 +/- 0.9 mm Hg up to 40 min after injection of the nephrotoxin then rose rapidly over the followin...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1983.221
更新日期:1983-12-01 00:00:00
abstract::Insulin resistance from chronic kidney disease (CKD) stimulates muscle protein wasting but mechanisms causing this resistance are controversial. To help resolve this, we used microarray analyses to identify initiators of insulin resistance in the muscles of mice with CKD, glucose intolerance, and insulin resistance. C...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2013.97
更新日期:2013-08-01 00:00:00
abstract:BACKGROUND:The aim of this study was to determine the glucose-dependent regulation of the sodium-proton-antiporter (Na+/H+ antiporter) in patients with mild chronic renal failure (CRF). METHODS:We measured plasma glucose concentrations, plasma insulin concentrations, plasma C peptide concentrations, arterial blood pre...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00510.x
更新日期:1999-07-01 00:00:00
abstract::The selective vasopressin V2-receptor antagonist tolvaptan is eliminated almost exclusively by non-renal mechanisms. As renal impairment can influence the pharmacokinetics of drugs even when eliminated by non-renal mechanisms, we evaluated the effect of renal insufficiency on the pharmacokinetics/pharmacodynamics of t...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1038/ki.2013.350
更新日期:2014-04-01 00:00:00
abstract:BACKGROUND:Cisplatin (CP) induced polyuria in rats is associated with a reduction in medullary hypertonicity, normally generated by the thick ascending limb (TAL) salt transporters, and the collecting duct urea transporters (UT). To investigate the molecular basis of this abnormality, we determined the protein abundanc...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.00048.x
更新日期:2001-12-01 00:00:00
abstract:BACKGROUND:Cardiovascular disease is known to be the most important complication among patients with renal failure, and oxidative stress has been proposed to play a major role as the source of such complications. Human serum albumin (HSA) is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00969.x
更新日期:2004-11-01 00:00:00
abstract::An expression profile is a list based on a large scale sequencing of 1000 cDNA clones, showing the expressed genes and the abundance of their transcripts in a given cell or tissue (Okubo K et al: Nature Genet 2:173, 1992). We constructed an expression profile of mouse renal proximal tubules (PT) carefully isolated by ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00808.x
更新日期:1998-03-01 00:00:00
abstract::The plasminogen activators (PA), which are regulated by their specific inhibitor, PAI-1, convert the zymogen plasminogen to plasmin, a protease involved in fibrinolysis and extracellular matrix turnover. Interleukin 1 beta (IL-1) is a key cytokine released from infiltrating monocytes/macrophages during the initial sta...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1996.159
更新日期:1996-04-01 00:00:00
abstract::Residual renal function is a major survival determinant for peritoneal dialysis patients. Hypovolemia can cause acute kidney injury and loss of residual renal function, and it has been suggested that patients receiving peritoneal dialysis should preferably be maintained hypervolemic to preserve residual renal function...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2013.273
更新日期:2014-01-01 00:00:00
abstract::Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammaso...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2014.271
更新日期:2015-01-01 00:00:00
abstract::Recent studies including the current article by Sawinski et al. demonstrate that hepatitis C virus (HCV) infection is associated with worse outcomes in kidney transplant recipients with and without HIV infection. We comment on the significance of these findings in the context of newer options for the treatment of HCV ...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2015.180
更新日期:2015-08-01 00:00:00
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journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2009.345
更新日期:2009-12-01 00:00:00
abstract::The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; ca...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000116
更新日期:2006-02-01 00:00:00
abstract::Class II gene products of the major histocompatibility complex (MHC) are not expressed usually in abundance on normal epithelium. The cell surface visibility of such proteins for the immune system is thought to be limited protectively in order to minimize inflammation consequent to the recognition of self-antigens in ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.191
更新日期:1991-07-01 00:00:00
abstract::The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel throm...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1016/j.kint.2016.06.026
更新日期:2017-01-01 00:00:00
abstract:BACKGROUND:Prolonged antihypertensive therapy might be less effective in reversing the left ventricular hypertrophy (LVH) in uremics bearing the deleted (DD) allele of the angiotensin converting enzyme (ACE) gene than in patients with the inserted (II) allele or in those heterozygous (ID) for the gene. METHODS:Thirtee...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00027.x
更新日期:1998-08-01 00:00:00
abstract::In organ transplantation, ischemia/reperfusion (I/R) results in damage that may affect cell viability and lead to organ failure. I/R injury involves a complex cascade of events, including loss of energy, derangement of the ionic hemostasis, production of reactive oxygen species, and cell death. In this context, mitoch...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1111/j.1523-1755.2004.761_9.x
更新日期:2004-08-01 00:00:00
abstract::Progressive glomerulonephritis and attendant end-stage renal disease (ESRD) result from antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The optimum time of kidney transplantation in patients with ESRD due to ANCA-associated vasculitis (AAV) and the risk of renal or nonrenal recurrence of vasculitis a...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5002244
更新日期:2007-06-01 00:00:00
abstract:BACKGROUND:Renal salt wasting and hypotension are some of the frequent complications in patients treated with cis-diamminedichloroplatinum (II) (cDDP), and it is suggested that cDDP produces an abnormality in the renin-angiotensin system. However, not only the underlying mechanism but also prophylactic treatment of thi...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00307.x
更新日期:2000-10-01 00:00:00
abstract:BACKGROUND:alpha 2 Macroglobulin (alpha 2M), a protease inhibitor, is often increased in plasma of patients with the nephrotic syndrome. Although it has been speculated that synthesis is increased, no direct measurements have been performed. METHODS:alpha 2M synthesis in both normal subjects (N = 4) and nephrotic pati...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00018.x
更新日期:1998-08-01 00:00:00