Rationale and design of the Kidney Precision Medicine Project

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Residual Kidney Function: Implications in the Era of Personalized Medicine

The association of residual kidney function (RKF) with improved outcomes in peritoneal dialysis and hemodialysis patients is now widely recognized. RKF provides substantial volume and solute clearance even after dialysis initiation. In particular, RKF provides clearance of nonurea solutes, many of which are potential uremic toxins and not effectively removed by conventional hemodialysis. The presence of RKF provides a distinct advantage to incident dialysis patients and is an opportunity for nephrologists to individualize dialysis treatments tailored to their patients’ unique solute, volume, and quality of life needs. The benefits of RKF present the opportunity to personalize the management of uremia.     

Human Kidney Cell Reprogramming: Applications for Disease Modeling and Personalized Medicine

The ability to reprogram fully differentiated cells into a pluripotent embryonic state, termed induced pluripotent stem cells (iPSCs), has been met with great excitement. iPSC technology has advanced the fundamental study of disease modeling with the potential for cell-replacement therapy, especially in the neuronal and cardiac fields. However, renal medicine as of yet has not benefited from similar advancements. This review summarizes the unique characteristics of iPSCs and their potential applications for modeling kidney disease. Pioneering such endeavors could yield constructs that recapitulate disease phenotypes, open avenues for more targeted drug development, and potentially serve as replenishable sources for replacement of kidney cells in the setting of human disease.Through experimentation involving nuclear fusion came the realization that differentiated somatic cells have potential to show a plasticity that is not unidirectional.^1–3 Subsequent studies suggested the transfer of a single somatic cell nucleus into an enucleated unfertilized egg possessed the ability to not only form all three germ layers but also produce viable offspring.^4–6 Decades later, the direct reprogramming of fibroblasts into a pluripotent state, so-called induced pluripotent stem cells (iPSCs),^7,8 has renewed interest in what constitutes the reprogramming process. An explosion of subsequent studies confirms that a large variety of somatic cells can be efficiently reprogrammed into iPSCs^9–13 and subsequently redifferentiated into other cell types that recapitulate disease phenotypes.^14–16 Such information offers proof-of-principle for the use of iPSCs as useful in vitro modeling systems that could ultimately lead to novel drug development and testing. Additionally, as iPSCs are produced from individual patients, the derivation of patient-specific stem cell lines could provide a limitless source of clinically useful immune and genetically matched cells.Since the pioneering discovery by Takahashi and Yamanaka,^7,8 iPSCs have now been successfully generated from a wide array of human tissues.^14,16–20 Despite such advances, cell reprogramming with respect to the kidney remains in its infancy. Only recently has it been possible to derive iPSCs from kidney mesangial cells²¹ or epithelial cells sourced from urine.²² Furthermore, the directed differentiation of mesangial cell-derived iPSCs to podocyte-like cells (iPSC-podocyte)²³ and the generation of iPSCs from kidney disease patients has only recently been reported.²⁴Here we review our current knowledge regarding the use of pluripotent stem cells targeted at kidney disorders. Specifically, it will address certain shortcomings of traditional model systems, current knowledge regarding the differentiation of pluripotent stem cells into the kidney mesodermal lineage, and the advantages of reprogramming for in vitro disease modeling and therapeutic interventions. Finally, the efficiency and safety of iPSC technology that governs the prospective applications and clinical promise for kidney regeneration will also be discussed.     

Recognition of Chronic Kidney Disease in a General Medicine Outpatient Clinic

Abstract

Chronic kidney disease (CKD) is a major health problem. Recent emphasis has been to prevent the progression of CKD. We used chart audits to see if CKD was an under-recognized condition in a general medicine resident clinic. Data focused on recognition of CKD, 3 or 4, evaluation of metabolic bone disease, and anemia. A multifaceted educational initiative was developed and occurred between 2005 and 2010. Three retrospective chart audits were performed, in 2005 prior to the education and again in 2007 and 2010. In 2005, less than one-fifth of patients were identified as CKD, 3 or 4. Evaluation of bone disease and anemia is similar. Initial results were reviewed with the residents and handouts for metabolic bone monitoring were developed. Wall charts of the handouts were also posted. In 2007, CKD recognition increased slightly, but more patients had bone disease and anemia evaluations. After 2007, the only educational intervention was a CKD lecture given yearly. In 2010, the audit saw decreased recognition of CKD and a decline in metabolic bone monitoring. Although complete blood count (CBC) monitoring decreased, iron studies increased to 50% of patients. We conclude that despite educational initiatives and re-enforcement efforts with the internal medicine residents and attending staff, major issues related to CKD are not being recognized or addressed. With an increasing CKD population, attempts must be made to improve recognition and management. Novel strategies need to be developed.