- Prospects for Precision Medicine in Glomerulonephritis Treatment. [Review]
- CJCan J Kidney Health Dis 2018; 5:2054358117753617
- CONCLUSIONS: With advances in data collection, technologies, and experimental model systems, we now have vast tools available to pursue precision medicine in GN. We anticipate a growing number of studies integrating data from high-throughput analysis with the development of diagnostic tools and targeted therapies for GN in the near future.
- The Role of Trio, a Rho Guanine Nucleotide Exchange Factor, in Glomerular Podocytes. [Journal Article]
- IJInt J Mol Sci 2018 Feb 06; 19(2)
- Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called "podocytes" within the filtration unit of the kidney, glomerulu...
Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called "podocytes" within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte injury and glomerulosclerosis (accumulation of extracellular matrix in the glomerulus). However, the mechanism by which Rac1 is activated during podocyte injury is unknown. Trio is a guanine nucleotide exchange factor (GEF) known to activate Rac1. By RNA-sequencing, we found that Trio mRNA is abundantly expressed in cultured human podocytes. Trio mRNA was also significantly upregulated in humans with minimal change disease and focal segmental glomerulosclerosis, two representative causes of nephrotic syndrome. Reduced expression of Trio in cultured human podocytes decreased basal Rac1 activity, cell size, attachment to laminin, and motility. Furthermore, while the pro-fibrotic cytokine, transforming growth factor β1 increased Rac1 activity in control cells, it decreases Rac1 activity in cells with reduced Trio expression. This was likely due to simultaneous activation of the Rac1-GTPase activation protein, CdGAP. Thus, Trio is important in the basal functions of podocytes and may also contribute to glomerular pathology, such as sclerosis, via Rac1 activation.
- GeneReviews® [BOOK]
- BOOKUniversity of Washington, Seattle: Seattle (WA)
- PAX2- related disorder is an autosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characteri...
PAX2- related disorder is an autosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characterized by renal hypodysplasia and abnormalities of the optic nerve; with improved access to molecular testing, a wider range of phenotypes has been recognized in association with pathogenic variants inPAX2. Abnormal renal structure or function is noted in 92% of affected individuals and ophthalmologic abnormalities in 77% of affected individuals. Renal abnormalities can be clinically silent in rare individuals. In most individuals, clinically significant renal insufficiency / renal failure is reported. End-stage renal disease requiring renal transplant is not uncommon. Uric acid nephrolithiasis has been reported. Ophthalmologic abnormalities are typically described as optic nerve coloboma or dysplasia. Iris colobomas have not been reported in any individual withPAX2–related disorder. Ophthalmologic abnormalities may significantly impair vision in some individuals, while others have subtle changes only noted after detailed ophthalmologic examination. Additional clinical findings include high-frequency sensorineural hearing loss, soft skin, and ligamentous laxity.PAX2pathogenic variants have been identified in multiple sporadic and familial cases of nonsyndromic renal disease including renal hypodysplasia and focal segmental glomerulosclerosis.
- Activation of podocyte Notch mediates early Wt1 glomerulopathy. [Journal Article]
- KIKidney Int 2018 Feb 02
- The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the...
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
- Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. [Journal Article]
- KIKidney Int 2018 Feb 02
- HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid ...
HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.
- End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population. [Journal Article]
- MCMayo Clin Proc 2018 Jan 09
- CONCLUSIONS: Our findings from a real-world clinical environment revealed significant differences in eGFR decline and ESRD risk among patients with 5 glomerulonephropathies. These variations in presentation and outcomes warrant different management strategies and expectations.
- Quantification of cancer risk in glomerulonephritis. [Journal Article]
- BNBMC Nephrol 2018 02 02; 19(1):27
- CONCLUSIONS: Cancer rates are increased for many cancer and most GN diagnoses. Cancer screening for patients < 45 years and for patients without nephrosis or uraemia may not be necessary. The findings suggest that screening programs for specific GN diagnoses can be extended to other GN forms.
- Steroid-resistant nephrotic syndrome: past and current perspectives. [Review]
- PHPediatric Health Med Ther 2017; 8:29-37
- Patients with steroid-resistant nephrotic syndrome (SRNS) represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of ...
Patients with steroid-resistant nephrotic syndrome (SRNS) represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of progressing to end-stage renal disease. Appropriate treatment of SRNS requires an adequate understanding of the historical treatment, renal histopathology, and genetics associated with the disease. The aim of this review is to present a comprehensive appraisal of the history, role of renal biopsy, genetics, and treatment of SRNS.
- The effect of peri-transplant plasmapheresis in the prevention of recurrent FSGS. [Journal Article]
- PTPediatr Transplant 2018 Feb 01
- Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post-transplant. But the effectiveness of this expensive, time-consuming pr...
Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post-transplant. But the effectiveness of this expensive, time-consuming process of plasmapheresis in the prevention of FSGS recurrence is still unclear. We retrospectively reviewed all pediatric cases of FSGS in our center that received a kidney transplant and compared the transplant and patient outcomes of those transplanted after 2006 who received pretransplant plasmapheresis to those prior to 2006 who did not. Of the 57 children with FSGS, 31 and 26 were transplanted before and after 2006, respectively. The cohorts differed significantly in keeping with the center immunosuppression protocol changes, and prior to 2006, the recipients were significantly younger. All children with FSGS transplanted after 2006 underwent three and one sessions of 1.0 plasma volume/exchange plasmapheresis with fresh frozen plasma replacement prior to the transplant in living and deceased donors, respectively, in addition to five sessions of every other day post-transplant pheresis. The incidence (27% vs 26%, P = 1.0) and time to recurrence of FSGS in the kidney allograft (P = .22) were not significantly different in patients that did and did not undergo prophylactic plasmapheresis. We need to re-evaluate the role of preemptive plasmapheresis in the prevention of FSGS recurrence in a prospective multicenter study.
New Search Next
- Coenzyme Q10 supplementation therapy for 2 children with proteinuria renal disease and ADCK4 mutation: Case reports and literature review. [Case Reports]
- MMedicine (Baltimore) 2017; 96(47):e8880
- CONCLUSIONS: Based on the cases we reported and from the literature, recognition of ADCK4 mutation through early and accurate genetic screening could be helpful in avoiding unnecessary toxicities and in preventing complications arising in mitochondrial nephropathy.