Paraproteinemic renal diseases that involve the tubulo-interstitium.
ABSTRACT The renal response to deposition of monoclonal light chains represents a spectrum of pathologic changes that can be divided into glomerular or tubulo-interstitial processes. Involvement of the tubulo-interstitium can include activation of the proximal tubule, proximal tubule injury/cell death, and cast nephropathy. In these diseases, the culprit is not the intact immunoglobulin protein but instead the immunoglobulin light chain. Recent noninvasive tests, including immunofixation electrophoresis or quantification of serum free light chains, have increased the sensitivity for detection of an abnormality in circulating free light chains and are invaluable ancillary tools, but short of renal biopsy, the diagnosis of these diseases can prove challenging. A description of the pathobiology and overview of the approach to management of these light chain-mediated renal lesions is provided.
The Kidney in Plasma Cell Dyscrasias
Contributions to Nephrology
Claudio Ronco Vicenza
The Kidney in Plasma
Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney
Guillermo A. Herrera
St. Louis, Mo.
61 figures, 29 in color and 13 tables, 2007
Saint Louis University School of Medicine
Department of Pathology
1402 South Grand Blvd.
St. Louis, MO 63104 (USA)
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© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
Library of Congress Cataloging-in-Publication Data
The kidney in plasma cell dyscrasias / volume editor, Guillermo A.
p. ; cm. – (Contributions to nephrology ; v. 153)
Includes bibliographical references and indexes.
ISBN-13: 978-3-8055-8178-3 (hard cover : alk. paper)
ISBN-10: 3-8055-8178-5 (hard cover : alk. paper)
1. Plasma cell diseases–Complications.
–Immunological aspects. 3. Amyloidosis–Complications.
I. Herrera, Guillermo A., MD.
globulin Light Chains. W1 CO778UN v.153 2007 / WJ 300
2. Paraproteinemias. 3. Immuno-
Contributions to Nephrology
(Founded 1975 by Geoffrey M. Berlyne)
1 The Kidney in Plasma Cell Dyscrasias: A Current View
and a Look at the Future
Herrera, G.A. (Saint Louis, Mo.)
5 A History of the Kidney in Plasma Cell Disorders
Steensma, D.P.; Kyle, R.A. (Rochester, Minn.)
25 Pathologic Studies Useful for the Diagnosis and
Monitoring of Plasma Cell Dyscrasias
Veillon, D.M.; Cotelingam, J.D. (Shreveport, La.)
44 Serum Free Light Chains in the Diagnosis and
Monitoring of Patients with Plasma Cell Dyscrasias
Mayo, M.M.; Schaef Johns, G. (St. Louis, Mo.)
66 Mechanisms of Renal Damage in Plasma Cell Dyscrasias:
Merlini, G. (Pavia); Pozzi, C. (Lecco)
87 Proximal Tubular Injury in Myeloma
Batuman, V. (New Orleans, La.)
105 Paraproteinemic Renal Diseases that Involve the Tubulo-Interstitium
Herrera, G.A. (St. Louis, Mo.); Sanders, P.W. (Birmingham, Ala.)
116 The Mesangium as a Target for Glomerulopathic Light and Heavy Chains:
Pathogenic Considerations in Light and Heavy Chain-Mediated
Keeling, J.; Herrera, G.A. (St. Louis, Mo.)
135 Immunoglobulin Light and Heavy Chain Amyloidosis AL/AH:Renal
Pathology and Differential Diagnosis
Picken, M.M. (Maywood, Ill.)
156 Diversity and Diversification of Light Chains in Myeloma:
The Specter of Amyloidogenesis by Proxy
Gu, M.; Wilton, R.; Stevens, F.J. (Argonne, Ill.)
182 High-Dose Therapy in Patients with Plasma Cell Dyscrasias
and Renal Dysfunction
Pineda-Roman, M.; Tricot, G. (Little Rock, Ark.)
195 Current and Emerging Views and Treatments of Systemic
Immunoglobulin Light-Chain (AL) Amyloidosis
Comenzo, R.L. (New York, N.Y.)
211 Author Index
212 Subject Index
Herrera GA (ed): The Kidney in Plasma Cell Dyscrasias.
Contrib Nephrol. Basel, Karger, 2007, vol 153, pp 1–4
The Kidney in Plasma Cell
Dyscrasias: A Current View and
a Look at the Future
Guillermo A. Herrera
Department of Pathology, Saint Louis University School of Medicine,
Saint Louis, Mo., USA
A book with an identical title to the one now compiled: The kidney in
plasma cell dyscrasias was edited by Minetti, D’Amico and Ponticelli and pub-
lished in 1988 by Kluwer Academic Publishers . The book is a collection of
manuscripts compiling the presentations at a meeting by the same name held in
Milan in 1987 in which the leading researchers and clinicians in the field par-
ticipated. The book provides a rather comprehensive state of the art of the sub-
ject summarizing knowledge available two decades ago.
In the last chapter of this book titled Conclusions, Dr. J.S. Cameron makes
a number of interesting comments worth reflecting on 18 years later. When he
discusses mechanisms of renal damage, there is ample information provided
regarding proximal and distal tubular nephrotoxicity. Mechanisms involved in
these are summarized and; although the refined molecular understanding of the
pathological processes that we command today did not exist then, the overall
conceptual mechanistic views as to how damage occurs is quite similar to our
current perception. What is remarkable is that he clearly stated that there was no
idea as to how glomerular damage occurred in these monoclonal light chain-
related disorders. The readers will observe as they peruse and read this book, that
our understanding of how glomerular damage occurs has remarkably improved
in the last two decades. The present book devotes several chapters to various
glomerulopathies associated with deposition of immunoglobulin light and heavy
chains, including those associated with amyloidosis, highlighting sequential
events that take place and delineating crucial steps and key molecules involved
amenable to modulation or control. Another notable difference is that there has
been significant improvement in the therapy of these conditions using innovative
means. Likewise, the increased sophistication in therapy is highlighted in the
book chapters dealing with this subject. Although the emphasis in these chapters
addressing the therapy is placed on the management of cases with renal involve-
ment, a distinct focus in addressing the diseases as a whole as they impact the
patients’general health and prognosis has been maintained in the discussions.
The chapters in this book address the entire pathological spectrum of mono-
clonal light chain-related renal diseases and provide a comprehensive up to date
compendium of information that should be valuable to a variety of disciplines.
Drs. Steeusma and Kyle provide a historical account of how throughout the years
we have increased our understanding of these diseases highlighting the key devel-
opments that have taken place in the field. This chapter provides a wonderful intro-
duction to the entire book and clearly provides a historical account dealing with the
sequence of events that have taken place throughout the years culminating in our
current knowledge. Cotelingam and Veillon address the diagnosis of plasma cell
dyscrasias in the anatomic and pathology laboratories. Significant advances in this
area now permit a rather sophisticated and accurate evaluation of paraproteins in
the serum and urine, not only for diagnostic purposes, but also to follow these
patients and to assess pertinent prognostic and therapeutic issues. Mayo and Johns
address in their chapter the use of serum free light chains in the diagnosis and
monitoring of patients with plasma cell dyscrasias. They summarize the current
knowledge regarding the applications of this relatively new test in clinical practice.
Merlini summarizes in a succinct yet lucid fashion the main mechanisms involved
in the pathogenesis of the various renal manifestations of plasma cell dyscrasias.
The type of renal damage in these conditions is quite broad and heterogeneous.
Understanding mechanisms involved not only clarifies how it happens mechanisti-
cally, but it also delineates basic science considerations that serve to explain why
renal alterations can be so diverse, a good example of how research can translate
from the bench to the bedside to enhance patients’management. Dr. Batuman has
spent a significant amount of this career in deciphering how proximal tubular dam-
age occurs in some patients with monoclonal light chain-associated diseases. His
chapter provides a translational approach to the understanding of this subject.
Likewise, Dr. Sanders has conducted sophisticated and elegant research in the area
of distal nephron obstruction associated with myeloma. In his chapter, he outlines
how crucial is for particular structurally abnormal light chains to interact with
Tamm-Horsfall protein as they engage in creating distal tubular casts. My labora-
tory has been engaged in the study of the pathogenesis of glomerular damage in
monoclonal light chain related renal diseases for the last 15 years. Dr. Keeling has
been involved in defining how crucial are interactions between some light chains
and mesangial cells resulting in the pathological alterations that we observe in
these conditions and how functional alterations of mesangial cells inevitably affect
the surrounding mesangial matrix. Dr. Picken’s chapter provides an in-depth
Kidney in Plasma Cell Dyscrasias3
excursion into light and heavy chain associated amyloidosis with emphasis on
diagnostic aspects and pathogenesis. Dr. Steven’s group has conducted seminal
research dealing with the characterization of abnormal light chains and the impact
of this biochemical characterization on the pathogenicity (including nephrotoxic-
ity) of these monoclonal light chains. They provide us with a detailed summary of
their research and how this information fits into the understanding of renal damage
in plasma cell dyscrasias. Finally, the chapters by Roman-Pineda and Tricot, as
well as Comenzo, leaders in the clinical management of these patients, detail cur-
rent therapeutic protocols used, particularly in those patients with renal involve-
ment. These two chapters clearly show the great advances that have taken place in
the last 20 years in the treatment of these conditions.
It should be noted that heavy chain-associated renal diseases were not
known until the 1990s, so it is in this book (not in the previously published) that
conditions such as heavy chain deposition disease and heavy chain-related amy-
loidosis are discussed as specific entities. While our understanding of the
pathogenesis of heavy chain-associated disorders is still primitive, we are
becoming proficient at diagnosing them accurately.
Much has been done in the biochemical characterization of pathogenic light
chains. This work has clearly shown that these pathological light chains exhibit
peculiar amino acid alterations in the variable portion of the light chain molecule.
While those alterations in some instances are quite characteristic (i.e. the amino
acid substitution in position 30 of the variable portion of the ? 1 light chain mole-
cule on acquired renal Fanconi’s syndrome), in other monoclonal light chains-asso-
ciated conditions the structural changes noted are significantly more variable and
complex. The abnormality in the light chains associated with the Fanconi’s syn-
drome has been shown to render the altered light chain resistant to catabolism, thus
crystalline structures are formed in the cytoplasm of the proximal tubular cells.
Animal models of these diseases have not been easy to create. Recent devel-
opments have resulted in the creation of an animal model of acquired renal
Fanconi’s syndrome . This exciting discovery should lead the way for other
models of these diseases to be developed. Animal models are most useful to test
new therapeutic interventions and provide a solid platform to test the clinical
importance what has been observed in vitro. Undoubtedly, animal models bridge
the gap between experimental work and reality. As demonstrated by Sirac et al.
in their seminal paper, design of therapeutic interventions leading to reversibility
of these disorders is possible once their pathogenesis is clearly elucidated [2, 3].
In the era of molecular understanding of diseases, monoclonal light chain-
related renal disorders have not been left behind. These diseases are understood
with much better details at the present time. While advances in molecular-
targeted pharmacotherapy for renal disorders have taken place relatively slowly,
it is anticipated that new therapeutic interventions will be designed at a much
faster pace in the near future. Obviously designing such therapeutic avenues is
only possible because we have acquired a sound and comprehensive molecular
understanding of the pathogenesis of these disorders.
1 Cameron JS: Conclusions; in Minetti L, D’Amico G, Ponticelli C (eds): The Kidney in Plasma
Cell Dyscrasias. Dordrecht, The Netherlands, Kluwer Academic Publishers, 1988, pp 291–299.
Sirac C, Bridoux F, Carrion C, et al: Role of the monoclonal k chain V domain and reversibility of
renal damage in a transgenic model of acquired Fanconi syndrome. Blood 2006;108:536–543.
Herrera GA: Animal models: a pot of gold. Blood 2006;108:414.
Prof. Guillermo A. Herrera, MD
Saint Louis University School of Medicine, Department of Pathology
1402 South Grand Blvd.
St. Louis, MO 63104 (USA)
Tel. ?1 314 577 8475, Fax ?1 314 268 5478, E-Mail Guillermo.Herrera@tenethealth.com
Herrera GA (ed): The Kidney in Plasma Cell Dyscrasias.
Contrib Nephrol. Basel, Karger, 2007, vol 153, pp 5–24
A History of the Kidney in Plasma
David P. Steensma, Robert A. Kyle
Mayo Clinic, Rochester, Minn., USA
Background: The kidneys are commonly injured in plasma cell dyscrasias. Methods:
We reviewed the pertinent medical literature related to the historical development of clinical
nephrology and diagnostic renal pathology; early case reports of patients with plasma cell dis-
orders; and historical descriptions of multiple myeloma, amyloidosis, and the renal disorders
that are associated with these conditions. Results: Medieval uroscopists recognized protein-
uria, and in 1827 Richard Bright first linked proteinuria to both dropsy (edema) and the
autopsy finding of chronically diseased, scarred kidneys. In the 1840s, Henry Bence Jones
and William Macintyre described a peculiar form of proteinuria in a middle-aged English gro-
cer with fragile, tumor-riddled bones; this proteinuria became known as ‘Bence Jones type’. It
was initially believed that Bence Jones proteins were harmless to the kidney, but after 1899
(when myeloma cast nephropathy was recognized), investigators observed numerous renal
injury patterns associated with plasma cell dyscrasias. Gross observations of ‘waxy degenera-
tion’or ‘lardaceous change’in organs including the kidney yielded to the misnomer ‘amyloid’
in 1854, when iodine staining suggested to Rudolf Virchow that the strange material present in
these conditions was a form of starch or cellulose. During the 20th century, biochemists and
physicians carefully studied patients with myeloma, in order to better define the nature and
structure of normal and pathological immunoglobulins. Conclusion: Historical understand-
ing of the kidney in plasma cell disorders reflects developments in understanding of the
anatomy and physiology of the kidneys in health and in disease.
Copyright © 2007 S. Karger AG, Basel
General Considerations:Evolution of Clinical
Nephrology and Diagnostic Renal Pathology
Physicians have been interested in the role of the kidney in human disease
since antiquity, yet clinical nephrology and diagnostic renal pathology are
relatively new biomedical disciplines, formalized only in the second half of the
20th century [1, 2]. In the early 19th century, abnormalities in the gross appear-
ance of the urine and the kidney were first reported in association with the clin-
ical conditions now grouped together as plasma cell disorders. In contrast,
microscopic descriptions of specific renal disease patterns in the monoclonal
gammopathies only began with the recognition of myeloma cast nephropathy in
1899, and most reports belong to the late 20th century [3, 4]. Advances in our
collective understanding of the various renal injuries complicating plasma cell
dyscrasias are best understood within the context of more general insights into
the anatomy and physiology of the kidney, both in health and disease.
Many ancient texts contain observations of the kidneys and theories about
their afflictions, but the first major treatise devoted solely to diseases of the kid-
neys and urinary tract was probably that of Rufus of Ephesus . Rufus was
a leading Greek physician who flourished during the reign of the Roman
Emperor Trajan (98–117 AD) . Later writers referenced Rufus extensively,
including Claudius Galen (129–199 AD), and Rufus was especially influential
among the medieval Islamic physicians, who translated more than 50 of his
works into Arabic . Rufus of Ephesus was appreciated for the richness of his
clinical descriptions, and some credit him with being the first to notice the
hardened, shrunken kidneys of what is now referred to as ‘end stage’renal dis-
ease. Little else is known of Rufus, and only fragments of his original works
have survived . In the centuries after Rufus, many major authorities
addressed urolithiasis and hematuria, but the kidneys themselves remained
mysterious and received relatively little attention.
Uroscopy, the practice of carefully examining the appearance of patients’
urine – known colloquially as ‘water gazing’ performed by ‘piss-prophets’
(fig. 1) – was advocated by many historical medical authorities, including both
Hippocrates (cf. 460–377 BCE) and Galen. In his famous Canon of Medicine,
the Persian physician and philosopher Avicenna (Ibn Sina; 980–1037 AD)
insisted that physicians should routinely examine their patients’urine. The prac-
tice of uroscopy reached its zenith during the time of French physician and
humanist Pierre Gilles de Corbeil (Aegidius Corboliensis; 1165–1223) (fig. 2),
whose influential treatise De urinis, de pulsibus, de virtutibus, et laudibus
compositorum medicamentorum includes observations on dozens of subtly dis-
tinct physical states of urine. Frequently, uroscopy substituted for a physical
examination, which many academic doctors in this era considered improper or
A History of the Kidney7
Medical practitioners in the Middle Ages practiced uroscopy so often that
the icon of the glass urine flask became identified with physicians as closely as
the image of the stethoscope would in the 20th century (fig. 1). Geoffrey
Chaucer’s physician-pilgrim – who esteemed Rufus of Ephesus as one of the
many authorities supporting his opinions – is depicted gazing at a urine flask in
the illuminated Ellesmere manuscript of the 14th-century Canterbury Tales, in
the rather unlikely position of practicing uroscopy while riding on horseback
(fig. 3). Chaucer’s Host praises the physician for his storytelling by blessing his
urine examinations and his flasks:
Fig. 1. A classic image of uroscopy: ‘The Physician’ by Gerrit Dou (1613–1675), a
Dutch painter who was a pupil of Rembrandt van Rijn. Dated 1653, oil on oak,
49.3 ? 37cm, Kunsthistorisches Museum, Vienna. In this case, the reddish color of the liq-
uid in the flask and the imagery suggest that the physician was performing a pregnancy test.
In the 17th century, urine was sometimes mixed with red wine for this purpose, a procedure
that altered the appearance of urine proteins observed in many pregnant women.
Fig. 2. A 1967 semipostal stamp from Belgium illustrating
Pierre Gilles de Corbeil (1140–1224), also known as Aegidius
Corboliensis, who distinguished more than 19 substances in
urine, separating them by consistency, sedimentation, quantity,
and quality. Author’s collection.
I pray to God so save thy gentil cors,
And eek thyne urynals and thy jurdones,
Thyn ypocras, and eek thy galiones,
And every boyste ful of thy letuarie,
God blesse hem, and oure lady Seinte Marie!
(Introduction to The Pardoner’s Tale, lines 304–308) 
Gross observation of urine has been practiced for millennia, but chemical
analysis of the urine was first systematized in the early 1800s. During this
period, the rise of ‘animal chemistry’ (i.e., what is now called clinical chemis-
try) in British, French and German hospitals facilitated detailed analyses of all
body excreta, especially the urine. Richard Bright (1789–1858), an energetic
and enormously popular physician at Guy’s Hospital in London, was not the
first to recognize albumin in the urine, but he did develop a simple test for pro-
teinuria in 1827: holding a small quantity of urine in a spoon over a candle .
Bright was the first to connect urine that curdled when treated in this way with
the clinical condition of dropsy (edema) and the autopsy finding of shriveled,
scarred kidneys (fig. 4). For more than a century after his work, all chronic kid-
ney diseases, especially progressive parenchymal renal disorders, were grouped
together and called ‘Bright’s disease’. Bright also clearly distinguished renal
edema from the forms of edema associated with heart and liver disease,
although he was not the first to do so . The same milieu of exhaustive chem-
ical analysis that Bright worked in also made possible the description of the
Bence Jones protein in the 1840s , the landmark event in the history of the
plasma cell dyscrasias (described in more detail below).
Marcello Malpighi (1628–1694) of Bologna, one of the founders of micro-
scopical anatomy and a contemporary of the Dutchman who invented the