The bridge between transplantation and regenerative medicine: Beginning a new Banff classification of tissue engineering pathology.

The science of regenerative medicine is arguably older than transplantation-the first major textbook was published in 1901-and a major regenerative medicine meeting took place in 1988, three years before the first Banff transplant pathology meeting. However, the subject of regenerative medicine/tissue engineering pathology has never received focused attention. Defining and classifying tissue engineering pathology is long overdue. In the next decades, the field of transplantation will enlarge at least tenfold, through a hybrid of tissue engineering combined with existing approaches to lessening the organ shortage. Gradually, transplantation pathologists will become tissue-(re-) engineering pathologists with enhanced skill sets to address concerns involving the use of bioengineered organs. We outline ways of categorizing abnormalities in tissue-engineered organs through traditional light microscopy or other modalities including biomarkers. We propose creating a new Banff classification of tissue engineering pathology to standardize and assess de novo bioengineered solid organs transplantable success in vivo. We recommend constructing a framework for a classification of tissue engineering pathology now with interdisciplinary consensus discussions to further develop and finalize the classification at future Banff Transplant Pathology meetings, in collaboration with the human cell atlas project. A possible nosology of pathologic abnormalities in tissue-engineered organs is suggested.

Implanted renal replacement for end-stage renal disease.

The nearly 400000 American patients on dialysis suffer high cardiovascular and infectious mortality, but there is now evidence that this morbid phenotype can be rescued by intensive dialytic therapy. Self-care dialysis at home is limited by patient fears about skill and safety. An implanted artificial kidney would provide the benefits of intensive therapy while avoiding the focal points of patient concern. Hollow fiber polymer membranes and dialytic waste removal are lifesaving innovations but are difficult to adapt to implantable therapies. Biomimetic membranes and living cells can replicate the native kidney's strategy for waste removal. Three key technology developments are necessary for implementation of an implantable artificial kidney: high efficiency ultrafiltration membranes, control of blood-materials interactions such as thrombosis and fouling, and stable differentiated function of renal proximal tubule cells in an engineered construct. There has been significant progress in demonstrating proof-of-concept experiments in each key technology area.

Middle-molecule clearance at 20 and 35 ml/kg/h in continuous venovenous hemodiafiltration.

BACKGROUND: Of 5 clinical trials testing dose response of continuous renal replacement therapy (CRRT) in acute kidney injury, 2 showed a benefit, 2 showed none, and 1 appeared equivocal. However, blood-membrane interactions may dominate macromolecule transport in continuous venovenous hemodiafiltration, reducing the impact of dose adjustment. The dosing arms in the Acute Renal Failure Trial Network (ATN) study may have delivered similar clearances for middle molecules. METHODS: We simulated the 2 CRRT doses in the ATN study using a synthetic polydisperse macromolecular probe in bovine blood. Clearance of tracers between 10 and 100 kDa molecular weight was measured during 6 h of therapy. RESULTS: Middle-molecule clearance differed by less than 2 ml/min between the 2 dosing arms. CONCLUSION: The CRRT prescription used in the ATN study appears to have achieved dose separation for small molecules while holding middle-molecule clearance nearly constant. This may explain the outcome difference between the ATN study and earlier studies, and suggests subsequent trial designs.

New insights into mechanisms of glomerular permselectivity.

Proteinuria has emerged as a key predictor of progression from renal insufficiency to end-stage renal disease, and clearly plays a pathogenic role in loss of renal function. Control of proteinuria is seen as critical to delaying disease progression, and myriad treatments which appear to reduce proteinuria have been reported and have entered clinical practice. Despite the increasing emphasis on control of proteinuria, the precise mechanism by which the kidney retains proteins in the blood remains a subject of dispute in the literature. In the past decade, mechanisms for protein retention by the kidney which transcend simple molecular sieve heuristics have been proposed. This renewed interest in renal physiology is exciting, as new insights may drive forward mechanism-based treatments for renal disease. In this review article, four schools of thought on renal protein retention are described, including three from other groups and our own hypothesis. Arguments and data supporting and refuting each paradigm are discussed without the intent or effect of supporting one to the exclusion of others.

Dialysis and nanotechnology: now, 10 years, or never?

Nanotechnology, defined as the science of material features between 10(-9) and 10(-7) of a meter, has received extensive attention in the popular press as proof-of-concept experiments in the laboratory are published. The inevitable delay between feature articles and clinical endpoints has led to unwarranted skepticism about the applicability of the technology to current medical therapy. The theoretic advantages of micro- and nanometer scale engineering to renal replacement include the manufacture of high-hydraulic permeability membranes with implanted sensing and control structures. Recent data in membrane design and testing is presented, with a review of the challenges remaining in implementation of this technology.

The future of hemodialysis membranes.

Hemodialytic treatment of patients with either acute or chronic renal failure has had a dramatic impact on the mortality rates of these patients. Unfortunately, this membrane-based therapy is still incomplete renal replacement, as the mortality and morbidity of these patients remain unacceptably high. Much progress must be made to improve the biocompatibility of hemodialysis membranes as well as their hydraulic and permselective properties to remove small solutes and 'middle molecules' in compact cartridges. The next directions of development will leverage materials and mechanical engineering technology, including microfluidics and nanofabrication, to further improve the clearance functions of the kidney to replicate glomerular permselectivity while retaining high rates of hydraulic permeability. The extension of membrane technology to biohybrid devices utilizing progenitor/stem cells will be another substantive advance for renal replacement therapy. The ability to not only replace solute and water clearance but also active reabsorptive transport and metabolic activity will add additional benefit to the therapy of patients suffering from renal failure. This area of translational research is rich in creative opportunities to improve the unmet medical needs of patients with either chronic or acute renal failure.

Cell therapy of renal failure.

The kidney is unique in that it is the first organ for which long-term ex vivo substitutive therapy has been available. The first hemodialyzer was successfully applied to a human patient with acute renal failure in 1948, and the first successful allograft transplantation was performed with a kidney in 1951. Both treatments are used today. There is ample evidence that the small solute clearance function provided by hemodialysis does not confer the same survival advantage as a functional kidney, both in acute and in chronic renal failure. To mimic the metabolic, endocrine, and immunologic functions of the kidney, our group has successfully engineered a bioartificial device that includes a conventional dialysis filter and a bioreactor containing 10(9) renal proximal tubule cells. We have demonstrated differentiated activity of these cells both in vitro and ex vivo in a large animal model. The bioreactor has been shown to confer a survival advantage in two large animal models of gram-negative sepsis, seemingly due to modulation of inflammatory mediators. This bioartificial kidney has now completed a Phase I clinical trial in acute renal failure.

The role of a bioengineered artificial kidney in renal failure.

Renal failure continues to carry substantial burden of morbidity and mortality in both acute and chronic forms, despite advances in transplantation and dialysis. There is evidence to suggest that the kidney has metabolic, endocrine, and immune effects transcending its filtration functions, even beyond secretion of renin and erythropoietin. Our laboratory has developed experience in the tissue culture of renal parenchymal cells, and has now been able to demonstrate the metabolic activity of these cells in an extracorporeal circuit recapitulating glomerulotubular anatomy. We have observed active transport of sodium, glucose, and glutathione. We describe the design and initial preclinical testing of the bioartificial kidney, as well as future directions of our research.