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Recent studies in experimental animals and clinical studies suggest that alkali therapy may be a powerful suppressor of CKD progression. There is a need for well controlled studies and using alkali formulations that are more palatable than existing ones to enhance patient compliance.
Before we can think about stem cells or iPS cell based therapies, we need to understand how renal epithelial cells are programmed. Basic studies in development and differentiation will help to identify factors that could be used for reprogramming. We may find that it is easier to reprogram a renal fibroblast or myofibroblast into an epithelial cell if we introduce the right combination of factors. These ideas are being ...more »
Before we can think about stem cells or iPS cell based therapies, we need to understand how renal epithelial cells are programmed. Basic studies in development and differentiation will help to identify factors that could be used for reprogramming. We may find that it is easier to reprogram a renal fibroblast or myofibroblast into an epithelial cell if we introduce the right combination of factors. These ideas are being pursued in the pancreas and other tissues. Pushing forward with stem cell based therapies without a basic understanding of development is potentially dangerous. Of course this is a biased view from a basic scientist.
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To take advantage of the rapidly emerging approaches in genomic medicine to define disease on the molecular level, cohorts of patients with large-scale molecular and clinical data sets on the same individual are be the rate-limiting step. Establishing these cohorts requires a long-term effort, but renal disease offer a unique advantage compared to other chronic diseases as we have access to the primary disease mechanism ...more »
To take advantage of the rapidly emerging approaches in genomic medicine to define disease on the molecular level, cohorts of patients with large-scale molecular and clinical data sets on the same individual are be the rate-limiting step. Establishing these cohorts requires a long-term effort, but renal disease offer a unique advantage compared to other chronic diseases as we have access to the primary disease mechanism in humans via renal biopsy and urine derived biofluids.
Technologies are emerging to obtain comprehensive genome wide information spanning genotype, tissue compartment specific epigenetic, transcriptional, proteomic and metabolomic datasets from blood, urine and renal tissue. Matching this information with in vivo imaging, digital histopathology and prospective clinical disease course including drug and environmental exposures can aid to define underlying molecular events of phenotypic measures. Systems biology approaches can be employed across the entire genotype – phenotype continuum to redefine renal diseases on the molecular level and identify the key regulatory hubs most amendable to therapeutic manipulations. These data sets will be a reference base to test novel hypotheses and model systems for human disease relevance.
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How can nephrology identify, attract and retain outstanding junior investigators?
Voting reflects the current makeup of our community and defines the common denominator of our imagination. Because we (scientists, administrators, politicians) cannot predict future need nor can we predict which idea will get us to any desired therapy, a certain amount of investment in avant garde hypotheses is essential to our continued success. The NIH has tried its best to put money to good and efficacious use but ...more »
Voting reflects the current makeup of our community and defines the common denominator of our imagination. Because we (scientists, administrators, politicians) cannot predict future need nor can we predict which idea will get us to any desired therapy, a certain amount of investment in avant garde hypotheses is essential to our continued success. The NIH has tried its best to put money to good and efficacious use but in doing so, efforts that do not fall within mission relevance and topic areas mandated by the congress, the administration or the "community vote" became a casualty of over-investment in near horizon projects. We must improve the balance between "community selected topics" and investigator initiated ideas. This will ensure the innovation pipeline continues as long as RO1s adhere to strict "best science" criteria (innovative, hypothesis driven, and evidence-based investigation into the mechanisms of development and disease; all broadly defined, whether or not included in a topic area listed to the left of this post). We should leave open a window for the unexpected as we all know that serendipity is the mother of invention.
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To improve the health outcomes of adolescents and emerging adults with CKD/ESKD as they transfer to adult-focused providers, a successful health care transition (HCT) process needs to take place. This preparation from parent-directed care to disease self management should be planned and monitored longitudinally. Tools to measure and monitor the HCT process need to be developed and validated.
Do we need a set of validated tools for mouse models of kidney disease (and development), available to all, for example Cre/CreER drivers for the major relevant differentiated cell types in adult kidney (endothelial, nephron epithelia by segment, fibroblast, macrophage etc...)?
This is an important area for mechanistic insights to further elucidate understanding of how the kidney elicits repair and regenerative processes in response to injury.
Currently disease analyses studies use 2D cell culture studies. Recent advances have shown that they do not mimic physiological conditions. Developing models using tissue engineering technologies allows better understanding of diseases while reducing time and money invested in animal models. These efforts could ultimately lead to regeneration of kidney.
Many younger investigators are drawn to big science labs where large scale GWAS, genomic, proteomic and other 'omic studies are performed. The expertize for teasing out defined physiological mechanisms is slowly but surely being lost. We need to ensure that funding is distributed in such a way that precious resources are not consumed generating mountains of data that may never be appropriately analyzed - we don't even ...more »
Many younger investigators are drawn to big science labs where large scale GWAS, genomic, proteomic and other 'omic studies are performed. The expertize for teasing out defined physiological mechanisms is slowly but surely being lost. We need to ensure that funding is distributed in such a way that precious resources are not consumed generating mountains of data that may never be appropriately analyzed - we don't even know what CFTR and PKD proteins really do, despite their discovery years go!
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At the current time, we only have RAAS blockade and hypertension control to slow progression to ESRD. What mechanisms should be targeted to slow progression (loss of GFR) in diabetic nephropathy?
There are fewer and fewer nephrology trainees opting for a career in laboratory based kidney research. In our own training program the vast majority of renal fellows who want an academic career pursue training in clinical science. There are many reasons for this including (but not limited to) an extended training period in a field in which they may have little prior experience, the perceived uncertainty of maintaining ...more »
There are fewer and fewer nephrology trainees opting for a career in laboratory based kidney research. In our own training program the vast majority of renal fellows who want an academic career pursue training in clinical science. There are many reasons for this including (but not limited to) an extended training period in a field in which they may have little prior experience, the perceived uncertainty of maintaining adequate funding over the long haul and the difficulty inherent in "wearing many hats". Another observation is that lab based science is like a cottage industry with each investigator ultimately working independently. There is less of a role for group interactions that might provide a more supportive environment for physicians who are under a lot of pressure to obtain salary support. If the community believes that practicing M. D.s can make valuable contributions to basic research, what do we need to do to recruit, train and retain these individuals? Should all M. D.s who choose a lab based career obtain a Ph.D.? Should M. D.s who want to do basic research participate in larger cooperative groups? How are M. D.s doing in comparison to M. D./Ph.Ds and, Ph. D.s in terms of R01 grant funding?
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Several candidate biomarkers have been proposed for the early diagnosis of forms of AKI. Are these biomarkers sufficiently sensitive and specific to guide therapeutic interventions? Do they provide robust prognositc information
A convergence of data suggests that cilia are important in the pathogenesis of PKD. Despite intense investigation, the precise nature of this relationship remains unclear. It has been suggested that the the PKD1/PKD2 receptor channel complex acts as a flow sensor on renal epithelial cells. When this complex is inactivated (for any reason), cyst formation occurs. However, disruption of TRPV4 in MDCK cells results in ...more »
A convergence of data suggests that cilia are important in the pathogenesis of PKD. Despite intense investigation, the precise nature of this relationship remains unclear. It has been suggested that the the PKD1/PKD2 receptor channel complex acts as a flow sensor on renal epithelial cells. When this complex is inactivated (for any reason), cyst formation occurs. However, disruption of TRPV4 in MDCK cells results in absence of flow mediated signaling yet TRPV4 Knock out mice do not develop cysts. We need to understand the precise relationship of cilia to cystogenesis.
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The mechanisms by which obesity and metabolic syndrome influence kidney function has not been well elucidated. Studies to investigate potential pathways are needed
What does happen to the normal kidney across the lifetime of a human (i.e what usually happens with aging? Is this simply a result of accumulated insults or not? How does the kidney maintain function across time)? How is this informed by the pathways involved in kidney development?
The value of currently available urine biomarkers that identify those at risk for diabetic nephropathy is increasingly called into question. The development of new urine and plasma biomarkers to predict diabetic nephropathy may shed light on disease mechanisms. Also, rational clinical trial design will be made possible by such markers.
Over the past 20 years, the developing kidney has received recognition as a powerful model system to investigate the molecular regulation of several developmental programs including mesenchymal-to-epithelial conversions, branching morphogenesis, and segmentation of tubular structures into functional domains. This is due, in large part, to the generous support of the NIH in funding fundamental scientific research. This ...more »
Over the past 20 years, the developing kidney has received recognition as a powerful model system to investigate the molecular regulation of several developmental programs including mesenchymal-to-epithelial conversions, branching morphogenesis, and segmentation of tubular structures into functional domains. This is due, in large part, to the generous support of the NIH in funding fundamental scientific research. This research justified the use of several model organisms to study kidney development and generated the large number of mutant mouse lines with kidney defects that are now available for analysis. Most importantly it has provided novel insight into the development of kidney structure. It is now timely to address the development of renal function. Although there is a rich literature on adult renal function, it is a complex subject and may be intimidating to young investigators lacking a strong physiology background. I propose that the NIDDK organize a course on renal physiology for these investigators and encourage them to expand their thoughts and studies towards the acquisition of renal function during embryogenesis. This paradigm shift towards physiology would bring adult kidney disease into the field of developmental biology. It is likely to be more effective, in the long run, than targeting research towards a specific diseased state, which may or may not be due to primary defects in kidney function.
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For patients with AKI, should dialysis be started early versus late? How should early and late be defined - based on novel biomarkers, volume status, or "conventional" parameters (eg, BUN/Cr)?
Identify role of environmental exposures, i.e., viruses, toxins, and effect on dysregulation of the epigenome in the development of glomerular diseases without genetic mutations.
Characterize an individual's genetic propensity for adverse epigenomic changes.
Chronic kidney disease disproportionately affects racial and ethnic minorities, but little is known about the determinants and consequences of decreased GFR (45-75 ml/min/1.73 m2) in these populations. Current studies are limited by non-representative populations, and gaps in knowledge about normal levels of measured GFR, appropriate methods to estimate GFR, associations of decreased GFR with development and progression ...more »
Chronic kidney disease disproportionately affects racial and ethnic minorities, but little is known about the determinants and consequences of decreased GFR (45-75 ml/min/1.73 m2) in these populations. Current studies are limited by non-representative populations, and gaps in knowledge about normal levels of measured GFR, appropriate methods to estimate GFR, associations of decreased GFR with development and progression of CKD and CVD, and effect modification by other biomarkers. Measurement of GFR in an ongoing longitudinal study of a representative, multi-racial and multi-ethnic population, with utilization of stored serum and urine for investigation of emerging biomarkers, is required to address these questions.
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Development and validation of noninvasive imaging techniques to study microstructural and/or physiologic changes associated with chronic kidney disease progression.
Investigate the role of epigenome disruptors that change gene activity and alter stem cell activity resulting in gene dysregulation. (Science 29 Oct 2010 330) “Epimutations” can pass through germ line to the gametes and affect heredity. Stem cells display developmental plasticity and offer opportunity to examine epigenetic peturbations during normal development such as DNA methylation as well as their response to injurious ...more »
Investigate the role of epigenome disruptors that change gene activity and alter stem cell activity resulting in gene dysregulation. (Science 29 Oct 2010 330)
“Epimutations” can pass through germ line to the gametes and affect heredity.
Stem cells display developmental plasticity and offer opportunity to examine epigenetic peturbations during normal development such as DNA methylation as well as their response to injurious agents (epigenetic reprogramming?)
Identify mechanisms responsible for the plasticity of epigenetic states that may be operative in dysregulation in disease.
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Most of the 20 million Americans with chronic kidney disease (CKD) die before commencing dialysis. One of every five dialysis patients dies each year in the United States. Although cardiovascular disease is the most common cause of death in CKD, conventional cardiovascular risk factors such as hypercholesterolemia, hypertension and obesity are paradoxically associated with better survival at least consistently in hemodialysis ...more »
Most of the 20 million Americans with chronic kidney disease (CKD) die before commencing dialysis. One of every five dialysis patients dies each year in the United States. Although cardiovascular disease is the most common cause of death in CKD, conventional cardiovascular risk factors such as hypercholesterolemia, hypertension and obesity are paradoxically associated with better survival at least consistently in hemodialysis patients. Emerging data indicate the existence of this ‘reverse epidemiology’ even in earlier stages of CKD. These survival paradoxes might evolve progressively over the natural course of CKD as a result of time differential of the competing risk factors and the overwhelming contribution of malnutrition, inflammation and wasting. Reversal of the reverse epidemiology upon successful kidney transplantation underscores the role of nutritional status and kidney function in engendering these paradoxes. These observations, if indicative of biologically plausible and causal associations, may lead to emergence of new paradigms and potential management strategies to improve survival in CKD patients. Such movement away from use of targets derived from general populations (e.g. Framingham) would represent a major paradigm shift in clinical medicine and public health.
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Progressive decline of function in CKD is common and for some/many patients inevitable. We need to develop therapies that will improve GFR and tubular function, not just slow the deterioration.
