The Diabetic Kidney
http://www.100md.com
《新英格兰医药杂志》
Pandemic diabetes mellitus, predominantly type 2 diabetes, gained front-page recognition in the New York Times and other major print media this year after the ominous prediction by Dr. Martin Silink, president-elect of the International Diabetes Federation, that diabetes, "one of the biggest health catastrophes the world has ever seen," is an epidemic that "will overwhelm health care resources everywhere if governments do not wake up and take action now." Industrialized nations in Europe, Asia, and South America report diabetes as the leading cause of end-stage renal disease (ESRD). Of 92,469 patients who began treatment for ESRD in the United States during 2004, 44,160 (47.8%) had diabetes, an incidence rate in the U.S. population of 147 per million. Clinical nephrology is fundamentally dominated by efforts to detect, delay, reverse, and treat renal injury resulting from diabetes. In The Diabetic Kidney, Pedro Cortes and Carl Erik Mogensen offer a compendium of what is known about this multifaceted disorder and present algorithms for protecting and salvaging renal integrity in the patient with diabetes.
Part 1 covers pathophysiology and biochemical perturbations in diabetes and consists of 18 chapters that contain 326 of the book's 564 pages. The mechanisms by which cytokines, chemokines, and growth factors govern glomerular and tubular function in health are clearly reviewed. Elevated glucose levels increase intracellular angiotensin II levels, thereby promoting the expansion of the glomerular mesangial cell matrix and the accumulation of collagen, as well as increasing the production of reactive oxygen species and the ensuing oxidative stress. Internationally established investigators update the reader on the perturbed biochemical and physiological processes involved in diabetes, providing rationales for the promotion of euglycemia, normotension, and blockage of excess angiotensin activity as objectives in contemporary diabetes treatment. Proteinuria, which when detected in small amounts (urinary excretion of 30 to 200 mg per day) is termed "microalbuminuria," is portrayed as the sentinel event in which albumin, as a tubular toxin, is the "culprit," activating transcription factors that ultimately induce tubular destruction and interstitial fibrogenesis. The concept of defective podocyte structure and function as the consequence of proteinuria, causing apoptosis, alterations in intracellular microfilaments, and detachment from the glomerular basement membrane, is lucidly presented. Loss of podocytes is described as "a major potential starting point for glomerular injury" in diabetes.
(Figure)
A Glomerulus in a Kidney from a Patient with Diabetes.
Nodular and diffuse intercapillary glomerulosclerosis (also referred to as nodular glomerulosclerosis or the Kimmelstiel–Wilson lesion) is apparent in the upper left part of the specimen, and afferent and efferent arteriolosclerosis is present in the bottom left and right arterioles, respectively (hematoxylin and eosin).
Courtesy of Dr. Eli A. Friedman.
Several chapters explore the putative steps between the onset of hyperglycemia in diabetes and end-organ damage, updating the reader's understanding of perturbed carbohydrate metabolism in mesangial and renal tubular cell glucose transporters and cell signaling pathways. Diabetes alters the interrelationships between the hexosamine biosynthesis pathway and nonenzymatic glycation, producing advanced glycation end products that lead to oxidative stress. Evidence is presented regarding the known and suspected contributions to kidney damage by connective tissue growth factor (a member of the CCN family of genes), vascular endothelial growth factor, and transforming growth factor . A central theme is that modulating these cytokines in animal models of diabetes identifies attractive potential "molecular targets for therapeutic intervention." Especially appealing is an introduction of proteomics, the examination of "proteomes" (proteins encoded by the genome) in subjects with and those without diabetes. An emerging technique, the proteomic study of kidney tissue from mice with either type 1 or type 2 diabetes, holds the promise of the discovery of new biomarkers and therapeutic targets in diabetic nephropathy.
Part 2 of the book, in 12 chapters, translates insights from basic science to clinical syndromes resulting from progressive organ damage in diabetes, ranging from histopathological findings in renal and retinal tissue to the replacement of renal function by dialysis or by kidney and pancreas transplantation. Interventions applicable in background and proliferative retinopathy, coexisting conditions that occur in nearly all persons with diabetes who have clinical nephropathy, are concisely explained. By contrast, renal transplantation, the preferred management option for ESRD, is superficially discussed, with no mention of whether the risk of recurrent diabetic nephropathy in renal allografts can be reduced. Beyond deployment as a research tool, the utility of renal biopsy in patients with diabetes and proteinuria is not considered. Admittedly, full exploration of the medical and surgical effects of diabetic nephropathy would have transformed this book into a weighty encyclopedia in need of a library shelf.
Cortes and Mogensen and their contributors succeed in portraying the complexities of, enigmas of, and probable imminent successes in the field for those striving to understand and treat diabetic nephropathy, the preeminent kidney disease of the 21st century. One hundred years ago, Sir William Osler enjoined physicians to "know syphilis in all its manifestations and relations, and all other things clinical will be added unto you" — advice that should now be recast, with diabetes mellitus as the "open sesame" to the wonders of evidence-based medicine.
Eli A. Friedman, M.D.
Downstate Medical Center
Brooklyn, NY 11203
elifriedmn@aol.com((Contemporary Diabetes.) )
Part 1 covers pathophysiology and biochemical perturbations in diabetes and consists of 18 chapters that contain 326 of the book's 564 pages. The mechanisms by which cytokines, chemokines, and growth factors govern glomerular and tubular function in health are clearly reviewed. Elevated glucose levels increase intracellular angiotensin II levels, thereby promoting the expansion of the glomerular mesangial cell matrix and the accumulation of collagen, as well as increasing the production of reactive oxygen species and the ensuing oxidative stress. Internationally established investigators update the reader on the perturbed biochemical and physiological processes involved in diabetes, providing rationales for the promotion of euglycemia, normotension, and blockage of excess angiotensin activity as objectives in contemporary diabetes treatment. Proteinuria, which when detected in small amounts (urinary excretion of 30 to 200 mg per day) is termed "microalbuminuria," is portrayed as the sentinel event in which albumin, as a tubular toxin, is the "culprit," activating transcription factors that ultimately induce tubular destruction and interstitial fibrogenesis. The concept of defective podocyte structure and function as the consequence of proteinuria, causing apoptosis, alterations in intracellular microfilaments, and detachment from the glomerular basement membrane, is lucidly presented. Loss of podocytes is described as "a major potential starting point for glomerular injury" in diabetes.
(Figure)
A Glomerulus in a Kidney from a Patient with Diabetes.
Nodular and diffuse intercapillary glomerulosclerosis (also referred to as nodular glomerulosclerosis or the Kimmelstiel–Wilson lesion) is apparent in the upper left part of the specimen, and afferent and efferent arteriolosclerosis is present in the bottom left and right arterioles, respectively (hematoxylin and eosin).
Courtesy of Dr. Eli A. Friedman.
Several chapters explore the putative steps between the onset of hyperglycemia in diabetes and end-organ damage, updating the reader's understanding of perturbed carbohydrate metabolism in mesangial and renal tubular cell glucose transporters and cell signaling pathways. Diabetes alters the interrelationships between the hexosamine biosynthesis pathway and nonenzymatic glycation, producing advanced glycation end products that lead to oxidative stress. Evidence is presented regarding the known and suspected contributions to kidney damage by connective tissue growth factor (a member of the CCN family of genes), vascular endothelial growth factor, and transforming growth factor . A central theme is that modulating these cytokines in animal models of diabetes identifies attractive potential "molecular targets for therapeutic intervention." Especially appealing is an introduction of proteomics, the examination of "proteomes" (proteins encoded by the genome) in subjects with and those without diabetes. An emerging technique, the proteomic study of kidney tissue from mice with either type 1 or type 2 diabetes, holds the promise of the discovery of new biomarkers and therapeutic targets in diabetic nephropathy.
Part 2 of the book, in 12 chapters, translates insights from basic science to clinical syndromes resulting from progressive organ damage in diabetes, ranging from histopathological findings in renal and retinal tissue to the replacement of renal function by dialysis or by kidney and pancreas transplantation. Interventions applicable in background and proliferative retinopathy, coexisting conditions that occur in nearly all persons with diabetes who have clinical nephropathy, are concisely explained. By contrast, renal transplantation, the preferred management option for ESRD, is superficially discussed, with no mention of whether the risk of recurrent diabetic nephropathy in renal allografts can be reduced. Beyond deployment as a research tool, the utility of renal biopsy in patients with diabetes and proteinuria is not considered. Admittedly, full exploration of the medical and surgical effects of diabetic nephropathy would have transformed this book into a weighty encyclopedia in need of a library shelf.
Cortes and Mogensen and their contributors succeed in portraying the complexities of, enigmas of, and probable imminent successes in the field for those striving to understand and treat diabetic nephropathy, the preeminent kidney disease of the 21st century. One hundred years ago, Sir William Osler enjoined physicians to "know syphilis in all its manifestations and relations, and all other things clinical will be added unto you" — advice that should now be recast, with diabetes mellitus as the "open sesame" to the wonders of evidence-based medicine.
Eli A. Friedman, M.D.
Downstate Medical Center
Brooklyn, NY 11203
elifriedmn@aol.com((Contemporary Diabetes.) )