The

n e w e ng l a n d j o u r na l

of

m e dic i n e

b o ok r e v ie w s

The Diabetic Kidney

(Contemporary Diabetes.) Edited by Pedro Cortes and Carl
Erik Mogensen. 564 pp., illustrated. Totowa, NJ, Humana
Press, 2006. $175. ISBN 1-58829-624-5.

andemic 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 books 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 objec-

n engl j med 355;17

tives 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.
Several chapters explore the putative steps between the onset of hyperglycemia in diabetes and
end-organ damage, updating the readers 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

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1837

The

new england journal of medicine

Microvascular Research:
Biology and Pathology
Edited by David Shepro, Patricia DAmore, Carol M. Black, and
others. 1187 pp., in two volumes, illustrated. San Diego, CA,
Elsevier Academic Press, 2006. $299. ISBN 0-12-639510-1.

Courtesy of Dr. Eli A. Friedman.

A Glomerulus in a Kidney from a Patient with Diabetes.

Nodular and diffuse intercapillary glomerulosclerosis
(also referred to as nodular glomerulosclerosis or the
KimmelstielWilson 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).

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

1838

n engl j med 355;17

t is difficult to think of a single physiologic or pathologic process that is not dramatically influenced by the microcirculation, the smallest functional unit of the cardiovascular system.
The microcirculation is where the interaction between blood and tissue creates the environment
necessary for cell function; when functioning normally, it is a remarkable ensemble of signaling
pathways that direct the many interacting cell
types that regulate blood flow through networks
of staggering complexity. The medical community is now beginning to understand and accept
the importance of this vital system in the pathogenesis of a wide variety of diseases.
This book comes at a critical time in the history of microcirculation research, which can trace
its origins to the ancient philosophical writings
in the Yellow Emperors Classic of Internal Medicine and,
later, to the first direct observations of microvascular blood flow by Marcello Malpighi in 1661.
With the advent of clinically relevant methods to
assess and image circulatory function in the smallest vessels, an understanding of the basic physiology of the microcirculation is now relevant to
the practicing physician and the basic scientist
alike. It is no small task to assemble this information, simply because a textbook on the microcirculation must cover material from dynamic
cell and network function to vessel growth and
development the ability of the microcirculation to grow new blood vessels is crucial in the
recovery of vital organs from stroke and heart
attack. David Shepro and his group of experts
are uniquely qualified for this task. More than
300 persons have contributed to this 2-volume,
167-chapter work.
In volume 1, with each of the 83 chapters
written by experts in the field, the fundamental
groundwork is presented. It explains the function
of the cells, tissues, and networks that make up
the microcirculation. In volume 2, 84 chapters do
the same for diseases, therapies, and methods. The
authors are leaders in their respective fields and
have written the most up-to-date reviews available on their topics. Shepro himself, the founding editor and former editor in chief of the inter-

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