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554 Arch Pathol Lab MedVol 134, April 2010 Classification of
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The Classification of Renal Cystic Diseases and OtherCongenital
Malformations of the Kidney and
Urinary TractStephen M. Bonsib, MD
Context.Renal cystic diseases and congenital abnor-malities of
the kidney and urinary tract comprise a hetero-geneous group of
lesions whose pathogenesis has eludedphysicians for centuries.
Recent advances in molecular andgenetic understanding of these
diseases may provide thesolution to this riddle.
Objective.The formulation of an effective classifica-tion system
for these disorders has been elusive but isneeded to introduce
order while providing a conceptualframework for diagnosis.
Data sources.This review discusses the evolution, be-ginning in
the 19th century, of postulates regarding thepathogenesis of cystic
and developmental renal diseases.Selected classification systems
proffered during this periodare discussed in pursuit of an ideal
classification schemathat would account for morphologic features
and theirclinical importance, with logical links to pathogenesis
andtreatment. Although this remains an elusive target, its gen-
eral outline is becoming clearer. A classification
approachfavored by the author is presented, which incorporatesmany
of the strengths contained in several previous
clas-sifications.
Conclusions.Genetic- and molecular-based postulatesregarding the
pathogenesis of the renal cystic and devel-opmental diseases have
implicated mutated master genesand the modification of genes that
are crucial in renal de-velopment and genes that are central to the
sensory effectsof the renal tubular primary cilium on cell
physiology.These scientific advances provide pathogenetic links
be-tween morphologically and genetically distinct entities
andcertain cystic and neoplastic entities, associations thatseemed
implausible not long ago. These advances mayeventually provide the
basis for future classification sys-tems while suggesting targets
for therapeutic approachesin the prevention and treatment of these
diseases.
(Arch Pathol Lab Med. 2010;134:554568)
Renal cystic diseases (RCDs) and congenital abnormal-ities of
the kidney and urinary tract (CAKUT) com-prise a group of
metanephric and ampullary bud misad-ventures and acquired lesions
that have captured the in-terest and challenged the imagination of
physicians forcenturies. There are several reasons for this medical
infat-uation, including the frequency of these disorders
(abnor-malities in urinary tract development occur in
approxi-mately 10% of the population); their astonishing
variety,which results in an impressive menu of gross
abnormali-ties; and most important, their clinical importance
(Figure1).112 Although most patients with some of the more com-mon
forms of maldevelopment, such as bifid ureter andhorseshoe kidney,
may have few significant complications,collectively, RCD/CAKUT
represent the most common
Accepted for publication February 26, 2009.From the Department
of Pathology, Louisiana State University Health
Sciences Center, Shreveport.The author has no relevant financial
interest in the products or com-
panies described in this article.Presented in part at the 4th
Annual Renal Pathology Society/Kidney
and Urology Foundation of America satellite meeting held in
associa-tion with the 21st European Congress of Pathology,
Istanbul, Turkey,September 13, 2007.
Reprints: Stephen M. Bonsib, MD, Department of Pathology,
LSUHealth Sciences Center, 1541 Kings Hwy, Shreveport, LA
71130-3932(e-mail: [email protected]).
cause of end-stage renal disease in children, accountingfor 40%
to 50% of cases, and includes autosomal dominantpolycystic kidney
disease, the most common type of RCDand the fourth leading cause of
end-stage renal disease inadults.15 Furthermore, renal hypoplasia
in the form of in-sufficient nephron endowment has been implicated
in asubstantial fraction of individuals with essential
hyper-tension.1315
The formulation of an effective classification system
forRCD/CAKUT has been an elusive goal driven by the needto
introduce order into this complex arena, and thereby,provide a
conceptual framework as attempts to unravel itspathogenesis were
pursued. Long before abnormalities ofthe kidney could be defined,
however, was the challengeof defining the anatomic features and
function of the nor-mal kidney and urinary tract so that deviations
from thisblueprint could be recognized. Some of the first and
mostprimitive assumptions of urinary tract structure and func-tion
were proffered a millennia ago, when Aristotle taughtthat urine was
formed by the bladder and that kidneyswere present not of actual
necessity, but as matters ofgreater finish and perfection. 16
Details of the normal gross renal and lower urinarytract (LUT)
anatomy were first unveiled in the 16th cen-tury by Leonardo de
Vinci and Vesalius, who generateddrawings of the female and male
genitourinary tracts,thus laying the foundation for the modern day
disciplines
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
Cystic Diseases and MalformationsBonsib 555
Figure 1. Composite photograph of domi-nant and recessive
polycystic kidney disease,multicystic dysplasia, renal aplasia, and
dys-plasia associated with lower urinary tract ob-struction.
of nephrology, urology, and nephropathology (Figure2).1618
Centuries later, the invention of the first micro-scopes by Hans
and Zacharias Janssen in the 1590s al-lowed the 17th century
masters of microscopic anatomy,such as William Bowman and Marcello
Malpighi, toglimpse the complexity of the renal microscopic
anatomy(Figure 3).1921 Later, Huber and Brodel in the early
20thcentury illustrated, in meticulous 3-dimensional serial
re-constructions and captured in elegant drawings, respec-tively,
its embryologic basis (Figures 4 and 5).22,23
THEORIES ON PATHOGENESIS OF RCD/CAKUT
Historically, the authors of most classifications used
pre-vailing concepts of pathogenesis to frame
classificationsystems. If this is a prerequisite for a useful
classificationscheme, then it would appear that the ideal
classificationmust await a thorough understanding of
RCD/CAKUTpathogenesis, an elusive goal, but one in which
muchprogress has occurred in the past decade. Interestingly,some of
the earliest theories of pathogenesis appearingduring the 19th
century are similar to those that persistedthroughout most of the
20th century.
Two of the earliest reported theories on renal cystogen-esis
were those of Virchow24 and of Rokitanky.25 Virchow,24in 1869,
proposed that obstruction by uric acid crystals orpapillary duct
atresia was operative in the pathogenesisof renal cysts.
Conversely, Rokitansky,25 in his 1885 textManual of Pathological
Anatomy, indicated that the consen-sus among German pathologists
was that renal cystsformed within the malpighian corpuscle when
tumifiedand gorged with the inflammatory product of these dis-eases
upon the surrounding strata. An obstructive etiol-ogy was also
favored by Danforth26 who wrote in 1888that the evolution of cysts
involved the unrolling or un-folding of the renal structure as it
slowly yields to thepressure of the fluid accumulating in the
cysts. The no-tion that renal cysts were neoplastic surfaced as
early asthe late 1800s when Sturm,27 in 1875, and Brigidi and
Sev-eri,28 in 1880, argued that cysts resulted from epithelial
proliferations or inclusion of mesonephric elements in thekidney
that subsequently proliferate.
Bunting29 summarized in detail, in a 1906 publication,the
prevailing theories on cystogenesis. The postulates invogue
included tubular obstruction attributable to externalcompression of
tubules by infection-related fibrosis, con-genital maldevelopment
or a neoplasm related to abnor-mal cell growth, and finally,
nonunion of primitive col-lecting ducts and secretory tubules. The
latter postulatefollowed the delineation by Kupffer,30 Huber,22 and
Bro-del23 of the dual role of the ampullary bud and renal blas-tema
in renal nephrogenesis. In the 1920s to 1930s, afterthe dual origin
of ampullary bud and nephrogenic blas-tema in nephrogenesis was
more widely recognized, cystformation, resulting from failure of
the 2 tissues to unite,emerged as the most popular theory.
Bunting,29 in his review of cytogenesis, made the in-sightful
comment that his 2 cases of cystic kidney diseasediffered
morphologically and clinically from many previ-ous reportedly
cases. Bunting29 noted that the attemptsto explain pathogenesis of
the congenital cystic kidneyhave been so numerous and so varied
that one is inclinedto question whether pathologists have been
dealingthroughout with a single pathological process. Becausethe
personal experience of these early investigators waslimited to
small numbers of cases, with no individual hav-ing access to the
full spectrum of RCD/CAKUT diseases,his concerns were appropriately
insightful. Regardless,even if these early investigators were
fortunate enough tohave exposure to the complete palate of
RCD/CAKUTpossibilities, they would not have been able to solve
thepuzzle of pathogenesis, which required advances in sci-entific
knowledge and technology only recently achieved.
Kampmeier,31 in 1923, published beautifully
illustrated,histologic pictures of fetal kidney in early gestation
andnoted the common occurrence of occasional ectatic
(cystic)tubules as a normal event in embryogenesis. This led himto
offer one of the earliest insights into the possibility ofa
molecular basis for many RCDs. He suggested that ec-
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556 Arch Pathol Lab MedVol 134, April 2010 Classification of
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Figure 2. Genitourinary tract, a diagram by Andreas Vesalius,
published in 1541 (Organs of Nutrition and Generation. Marburg,
Germany:Johannes Oporinus, printer. De humani corporis fabrica and
libri septum [On the fabric of the human body]; book 5).122
Figure 3. William Bowmans 1842 illustration of the vascular
supply to glomeruli, based on a dye injection study (from Bowman W.
On thestructure and use of the malpighian bodies of the kidney,
with observations on the circulation through that gland. Philos
Trans R Soc Lond Biol.1842;132:5780).19
tatic abnormal tubules could possibly persist and enlargeto form
the grossly visible, simple renal cysts of adults.He further
postulated that factors control the degenera-tion or suppression of
abnormal growth, in effect, impli-cating master genes that regulate
and orchestrate normalembryogenesis or that fail to do so in
abnormal embryo-genesis. He further noted that these factors could
alsoexplain coexistent lesions in other organ whose embryo-genesis
was similarly dysregulated.3133
Anatomic investigations into the site of cyst formationwithin
the nephron emerged in the mid-20th century, con-tributing further
to our understanding of cystic diseases.Lambert,34 in 1947,
employed serial section reconstruc-tions of cystic kidneys from 6
adults and 2 children andshowed that cystic dilations could develop
in any segmentof the nephron. In the 1950s and 1960s, Potter and
Osa-thanondh and others,3544 using the newly developed tech-nique
of microdissection, studied normal and congenitallycystic kidneys.
The exhaustive work Potter and Osatha-nondh4146 was particularly
noteworthy because it formedthe basis of a classification schema
known as the Potter
Classification, which was predicated on the anatomic
dis-tribution of cysts within the nephron.
In the mid to late 1900s, the obstructive theory of
path-ogenesis for renal dysplasia was popularized. Bern-stein47,48
noted that more than 90% of dysplastic kidneysare associated with
urinary tract abnormalities that areinvariably obstructive. The
renal lesions seem to parallelthe LUT abnormality, whether
unilateral versus bilateralor segmental in a duplex kidney, and
that the severity alsoappears proportional (Figure 6, A and B).
Bernstein47,48 ac-knowledged, however, that not all dysplastic
kidneys areassociated with obstruction because the many
familialmultiple malformation syndromes argue for a genetic
eti-ology. Appreciation that these disorders can affect
severalmembers of the same family implicated genetic causation.
Experimental studies, intended to implicate
obstructiveetiologies in metanephric dysgenesis, were initiated in
the1970s to 1990s. Extreme experimental maneuvers wereemployed,
where not only LUT obstruction, urethral orureteral obstruction was
induced early in embryogenesisbut also unilateral nephrectomy was
sometimes per-
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
Cystic Diseases and MalformationsBonsib 557
Figure 4. G. Carl Hubers 1905 illustration of his wax model
serial reconstructions of nephron differentiation (from Huber GC.
On the developmentand shape of uriniferous tubules of certain of
the higher mammals. Am J Anat. 1905;4(4)(suppl):198).22
Figure 5. Max Brodels 1907 illustration of the sequence of
nephron induction (from Kelly HA, Burnan CF. Diseases of Kidneys,
Ureter, andBladder: With Special Reference to the Diseases in
Woman. vol 2. New York, NY: D Appleton and Company; 1914).23
formed to further stress to the remaining, developing
kid-ney.4953 In most species examined, including pigs, chick-ens,
and rabbits, investigators failed to induce changestypical of
cystic dysplasia, instead severe hydronephrosiswas mostly
observed.4953 However, in the fetal lamb mod-el, convincing cystic
dysplasia was produced in some an-imals, although others developed
only severe hydrone-phrosis.54,55
Experiments of nature indicate that obstruction andmetanephric
maldevelopment are not inevitably linked be-cause a neonate can be
born with complete LUT obstruc-tion and resultant massive
hydroureteronephrosis, yetnephrogenesis can be preserved (Figure
7).5658 Anotherargument against simplistic anatomic causation is
the il-logic of implicating sequential injury, obstruction
followedby metanephric dysgenesis, for a synchronous activity
ofureteral and renal development. This creates a
physiologicconundrum: How can a nonfunctional, disordered
meta-nephric mass produce an ultrafiltrate of sufficient toxic-ity
or pressure to perturb the development of subsequentnephron
formation. Especially relevant to this concern arecases of cystic
dysplasia identified in the first trimester.5860McKenna and
Kampmeier,33 in their 1933 article entitledA Consideration of the
Development of the PolycysticKidney, captured the state of
understanding that existedthen, and which persisted until the end
of the 20th century
when they wrote: There are many theories which beginas logical
deduction, and later without foundation of ob-servation are handed
down from textbook to textbook andfrom paper to paper as facts.
Such is the hypothesis of theorigin of cystic kidney. 3 Bernstein
elaborated further, in1968, about the challenge investigators faced
in this fieldwhen he wrote: A classification in a strict
taxonomicsense cannot be devised because pathogenesis
remainsunknown and because considerable overlap exists
bothclinically and morphologically. 46
Although by the latter decades of the 20th century, theetiology
or etiologies for RCD/CAKUT remained un-known, implication of an
anatomic causation, especiallyurinary tract obstruction in severe
metanephric maldevel-opment, remained popular because of the
ubiquitous as-sociation. Knowledge of the embryologic development
ofthe kidney would appear to provide a logical basis forexplaining
departures from normal renal developmentand was especially popular
for many CAKUT lesions.However, because of the enormous diversity
of malformedurinary tracts, the limitless combinations of
abnormalitiesaffecting kidney and LUT, and the asymmetry of
renallesions, the delayed onset of some genetic cystic diseasesin
kidneys that were initially normal in form and the ac-quired nature
of others cannot be easily accommodatedby any simplistic
anatomic-based approach.312,6166 To
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558 Arch Pathol Lab MedVol 134, April 2010 Classification of
Renal Cystic Diseases and MalformationsBonsib
Figure 6. Two examples of bilateral dysplasia with extreme
degrees of (A) ureteral atresia and (B) ureteral dilation.
quote the time traveler in H. G. Wells 67 The Time Machine ,Very
simple was my explanation, and plausible enoughas most wrong
theories are!
Limitation in the understanding of pathogenesis, as not-ed by
Bernstein,47,48 has plagued the classification process,but has been
alleviated in recent years as the molecularcontributions to
RCD/CAKUT have been identified.68100The list of mutated genes
expressed during renal devel-opment is rapidly growing. These genes
code for a varietyof transcription and growth factors required for
the reg-ulation and orchestration of interactions between the
ure-teric bud and the metanephric blastema and its predeces-sors
tissues, the mesonephric and pronephric ducts. Oneof the most
common mutated genes in CAKUT is PAX2,a gene that serves a central
role in renal development.PAX2 is one of 9 paired-box transcription
factors, a masterorganizer gene expressed in the nephric duct,
metanephricmesenchyme, ureteric bud, and S-shaped body.6569
PAX2performs many functions at early stages of renal devel-opment.
It organizes caudal descent of the nephric ductwith PAX8 and GATA3,
emergence of the ureteric bud, andinduces WT1 in metanephric
blastema. PAX2 is also in-volved with branching morphogenesis and
the sustainedarborization of the collecting duct. With such
extensiveinvolvement in the early stages of metanephric kidney
in-duction, it is easy to envision how mutations of this
crucialgene, or other similarly critically located genes, could
re-sult in a vast array of maldevelopment.
Table 1 lists several of the most commonly mutated mas-
ter genes, displays the various malformations observed,and
reports associated clinical syndromes. It is clear thatthe renal
consequences of the mutation of a single mastergene can be diverse,
dependent upon the specific type ofmutation, missense, nonsense,
deletion, and so forth, andthe resultant functionality of the
mutated protein pro-duced. Modifying genes also influence the final
phenotypeadding an additional layer of complexity.
Furthermore,based on cDNA microarray analysis comparing the
RNAsignature of normal and dysplastic kidneys, the expres-sion
profiles of entire families of genes are affected inmany cases of
RCD/CAKUT.
A second major advance in understanding RCD/CAK-UT pathogenesis
has been the explosion in understandingof the molecular composition
and function of the renaltubule primary cilium.101110 Cilia are
eukaryotic organellesthat project from the cell surface; they can
exhibit motileor sensory functions. The basic structure of
nonmotile, pri-mary cilia of the renal tubular cells consists of 9
peripheralmicrotubular doublets that form the axoneme, surroundedby
a lipid bilayer that is continuous with the cell mem-brane. By
contrast, motile cilia of other organs have a cen-tral doublet of
microtubules in addition to the 9 peripheralmicrotubular doublets,
and the latter are linked by dyneinarms and other structural
components. All cilia are an-chored in the cytosol by the basal
body, a microtubularorganizer derived from the older of the 2
centrioles (Fig-ure 8). Assembly and maintenance of cilia is
provided bya bidirectional microtubular transport system.
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
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Figure 7. Complete urinary tract obstruction secondary to
ureteralatresia with a severely hydronephrotic, but otherwise
normal kidney.
Table 1. Selected Examples of Genes in Which Mutations can
Result in Various Congenital Abnormalities of the Kidneyand Urinary
Tract (CAKUT) Lesions
CAKUT PAX2 TCF2 EYA1 SIX1 SALL1 GATA3
Dysplasia Agenesis Hypoplasia UPJ obst VU reflux GCKD Syndrome
Renal-coloboma MODY5 BOR BOR Townes-Brock HDR
Abbreviations: BOR, branchial-oto-renal syndrome; GCKD,
glomerulocystic kidney disease; HDR, hypoparathyroidism, deafness
and renal dyspla-sia; MODY, maturity onset diabetes type 5; UPJ
obst, ureteropelvic junction obstruction; VU, vesicoureteral.
The proteins of the primary cilia are ancient and havebeen
highly conserved evolutionarily; in fact, some cys-toproteins have
been conserved for more than 1.5 billionyears from unicellular
organisms to vertebrates. Althoughprimary cilia have been
recognized for decades, they hadpreviously been regarded as
evolutionary vestiges. How-ever, more recently, it has been
recognized that primarycilia serve important functions in cellular
physiology, suchas cell cycle regulation, cell signaling,
apoptosis, and ep-ithelial cell polarization. The list of signaling
pathways in-fluenced by ciliary function is growing and includes
plate-let-derived growth factor receptor signaling,
hedgehogsignaling, epidermal growth factor signaling, and
5-HT6serotonin signaling.
Mutation of more than 20 molecules that are localized
to primary cilia, basal bodies, and centrosomes, and whichalso
reside in cell adhesions, have been identified in abroad range of
morphologically and clinically dissimilardisorders (Table 2). Most
of the cytoproteins identified in-teract with other cystoproteins
(Figure 9). Thus, mutationsof these physiologically interactive
proteins provide path-ophysiologic links between RCDs previously
regarded asunrelated because they differ in type of transmission,
ageof onset, extrarenal manifestations, and risk of and rate
ofprogression to end-stage renal disease. Mutated genes ofthe
primary cilium could provide an approach to the clas-sification of
at least an important subset of RCDs and,more significant, may
allow targeted therapies to be de-veloped in the future.
NOMENCLATURE AND TERMINOLOGYBefore proceeding with a review of
the classification
systems for RCD/CAKUT, it would be prudent to list
thenomenclature and terminology employed in the remainderof this
article and included in the most recent classifica-tions cited
later. The RCD/CAKUT diseases are compli-cated enough without
introducing communication obsta-cles. Although laxity in
terminology is understandable forthe pioneers in this field, this
is not acceptable today, andit risks creating confusion about
important entities, withresultant inappropriate clinical responses.
For purposes ofthis article, the terms used and their definitions
are pro-vided in Table 3. They represent a synthesis of
definitionsobtained from several reputable sources: The Committeeon
Terminology, Nomenclature, and Classification, Sectionon Urology,
American Academy of Pediatrics,112 and 2 ar-ticles published by
individuals of stature in this field ofinvestigation.111113
CLASSIFICATION SYSTEMSAlthough there have been numerous
classifications pro-
posed, those that strive to be all-inclusive employ
similargeneral strategies, strategies that continue today.
Prevail-ing notions of pathogenesis and obvious clinical
associa-tions have been closely linked to classification
strategiesfrom the beginning. Most classification systems
distin-guish entities with intrinsic abnormalities, presumed
toresult from developmental miscues that occurred early inthe
embryologic formation of the kidney and urinary tract,placing them
in a congenital category. The remaining cat-egories contain
acquired lesions that affect a kidney thatpreviously developed
normally. In these categories, cystformation as a consequence of
external forces, injuries, andneoplastic events are often
included.
One of the earliest forays into the daunting arena of
theclassification of cystic kidney disease was by I. N. Dan-
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560 Arch Pathol Lab MedVol 134, April 2010 Classification of
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Figure 8. Diagram of a primary cilium with location of
cystoproteins identified (reprinted with permission from the
American Society of Ne-phrology, Hildebrandt F, Zhou W.
Nephronophthisis-associated ciliopathies. J Am Soc Nephrol.
2007;18(6):18551871).108 PC-1, polycystin-1;PC-2, polycystin-2;
OFD1, oral facial digital syndrome 1; BBS, Bardet-Biedl syndrome;
BB, basal body; Cem, centriole; ER, endoplasmic reticulum;TJ, tight
junction; Des, desmosome; AJ, adherens junction; FAP, focal
adhesion plaque.
Table 2. Ciliopathies: Molecular, Genetic, and Pathologic
Features
Ciliopathy Protein Inheritance Lesion
Autosomal dominant PKD Polycystin 1 AD Cysts within the entire
nephronAutosomal dominant PKD Polycystin 2 AD Cysts within the
entire nephronAutosomal recessive PKD Fibrocystin AR Collecting
duct cystsMeckel-Gruber syndrome MKS proteins 1, 3 AR Cystic
dysplasiaOral-facial-digital syndrome OFD protein X linked
Glomerulocystic kidney diseaseBardet-Beidl syndrome BBS proteins
1-8 Digenic Tubulointerstitial nephritisVon HippelLindau VHL
protein AR Clear cell cysts and cancer
Abbreviations: PKD, polycystic kidney disease; AD, autosomal
dominant; AR, autosomal recessive.
forth26 and was published in 1888. The Danforth classifi-cation
contained 5 categories separating congenital formsfrom those with
clinical associations, such as obstruction,infection, and trauma
(Table 4). Danforth26 acknowledgedthe rudimentary nature of the
current understanding ofthese diseases, which handicapped formation
of a satis-factory classification, at the conclusion of his
article, whenhe wrote, I have to express my regret that so much
re-mains to be learned about cystic disease. . . . [I] hope thatin
the near future our knowledge will be more definiteand accurate. .
. . Although 120 years has elapsed sincehis review, regrettably,
our understanding remains incom-
plete and, therefore, so does a completely satisfactory
clas-sification.
As the field of pathology evolved, and more disease en-tities
were identified, classifications became lengthier butnot
necessarily crafted more effectively. In 1954, Whiteand
Braunstein114 formulated a classification of renal cys-tology,
based on etiologic groupings not too dissimilar tomany more modern
formulations (Table 5). The authorsconceded, in the first paragraph
of the article, that theyfaced challenges, stating The pathogenesis
and embryo-logic development of these cystic formations are quite
fan-tastic and appear to the authors as a constant urological
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
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Figure 9. A through D, the Potter and Osathanondh
microdissections of congenital cystic kidneys showing the examples
of their 4 types basedon cyst location (reprinted with permission
from Osathanondh V, Potter EL. Arch Pathol. 1964;77:466473, 474484,
484501, 502509). 4144
imponderable and The majority of cysts still defy un-derstanding
and therefore accurate grouping. 114 Whiteand Braunstein114 focused
on etiologic factors, as under-stood at the time, as the common
denominator for theirclassification. They were some of the first to
discuss ge-netic causes because of the heredofamilial nature of
thepolycystic kidney diseases, which can present at any age butare
usually bilateral and are associated with lesions in oth-er organs.
The authors114 also commented that the simplecortical cyst can be
associated with renal neoplasms. Al-though this association is
likely simply a reflection of theincreasing incidence of both
lesions with age, the conceptof dysregulated growth for both cyst
formation and neo-plasia in some cystic diseases now has an
established sci-entific basis, although not for the simple cortical
cyst.
White and Braunstein114 proclaim in their conclusionconcerning
the subject of renal cystology, that embryonicorigin has been
thoroughly modernized with advancedembryologic knowledge and a
clearer and more compre-hensive classification has been suggested.
Unfortunately,
their classification failed this claim. The pathologic fea-tures
of many of the RCDs that had become clearer bythat time permitted
morphologic separation of major cat-egories, such as renal
dysplasias versus the hereditarypolycystic diseases. However, these
authors114 lumpedthose entities into a single category: 1A
polycystic disease.Conversely, other primary categories contained
entitiesthat are not actually cystic diseases, such as their
categoryII, obstructive; category IV, vascular; and category V,
in-flammatory and infections. Inclusion of noncystic diseasesin
cystic disease classifications is a persistent problem
thatcontinues to plague many classification schema.
Failure to employ the known morphologic differencesthat exist
between several of the major RCDs, such asdominant and recessive
polycystic kidney disease and re-nal dysplasia, was prevalent in
the early RCD classifica-tion literature. Another example is
provided by the clas-sification of Stubitz et al.115 In their 1963
study,115 restrictedto pediatric cases, they proposed a
classification that em-ployed age of onset and laterality while
excluding major
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562 Arch Pathol Lab MedVol 134, April 2010 Classification of
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Table 3. Renal Cystic Disease (RCD) Nomenclature and
Terminology
Acquired renal cystic disease The spontaneous, idiopathic,
bilateral development of multiple cysts in previously noncystic
kidneysCystic kidney A kidney containing 3 or more cystsCystogen An
agent capable of inducing renal cyst formation or RCDDysmorphic
kidney A misshapen kidney and calyceal system; implies a congenital
lesion without any histologic or etiologic
implicationsGlomerulocystic kidney Glomerular cysts as a
dominant finding; glomerulocystic kidney disease is a primary
disease; glomerulo-
cystic kidney is a kidney with glomerular cysts but of diverse
etiologiesHeritable renal cystic disease Renal cystic disease in a
kindred, in a pattern predicted by Mendelian theoryInduced renal
cystic disease Renal cystic disease produced by exposure to drugs
or chemicalsMedullary sponge kidney A usually sporadic, medullary
cystic abnormality that is commonly diagnosed by
radiologyMulticystic kidney Multiple cystic lesions, most
frequently sporadic; they can be small, segmental, unilateral, or
bilateralPolycystic kidney A genetically determined cystic lesion
of either the autosomal-dominant form or autosomal-recessive
formRenal adysplasia Where findings of either combined renal
agenesis and renal dysplasia or a hereditary syndrome occurRenal
agenesis Absent kidneyRenal aplasia An extreme form of dysplasia,
in which a nubbin of dysplastic kidney caps a normal or an
abnormal
ureterRenal cyst An enclosed or communicating segment of nephron
or duct that is dilated to a diameter of 200 molRenal cystic
disease Morbidity attributable to the presence of renal cystsRenal
dysgenesis Abnormal development of the kidney in size, shape, or
structure; forms of renal dysgenesis include dys-
plasia, hypoplasia, aplasia, agenesis, and dysmorphismRenal
dysplasia Abnormal metanephric differentiation diagnosed
histologically; it can be diffuse, segmental, or focalRenal
hypoplasia A small kidney or segment with less than a reference
range number of nephrons; dysplastic elements are
not present
Table 4. The Danforth26 (1888) Classification ofRenal Cystic
Diseases
Diathetic causesCongenital causesMechanical obstruction,
consequent upon disease of the pel-
vic organsTraumatic causesPathogenic cysts
Table 5. The White and Braunstein114 (1954)Classification of
Renal Cystology
I. Congenital or developmentalA. Polycystic diseaseB. Serous
cystsC. Lymphatic cysts
II. ObstructiveA. DiverticulaB. ParapelvicC. Hydrocalycosis
III. NeoplasticA. CystadenomaB. CystadenocarcinomaC. AngiomaD.
Dermoid
IV. VascularA. HemangiomaB. AneurysmC. EmbolismD. Infarction
V. Inflammatory and infectiousA. PyogenicB. TuberculousC.
Chronic nephritis
VI. ParasiticA. EchinococcusB. TineaC. Trichina
Reprinted with permission from 114White EW, Braunstein L. Renal
cysticdisease. J Urol. 1954;71(1):1727. Copyright Elsevier
1954.
secondary causes, such as infectious causes, neoplasticcauses,
and chronic glomerulonephritis (Table 6). Al-though they
proclaimed, There is widespread confusionamong both clinicians and
pathologists concerning theclassification of cystic disease, and
stated, It is only re-cently that the true etiology and
significance of the uni-lateral multicystic disease and polycystic
kidney may havebeen understood; they grouped obvious cases of
reces-sive polycystic kidney disease and multicystic renal
dys-plasias associated with LUT anomalies into congenitalpolycystic
kidney diseases in the newborn.
The first influential classification of RCDs, embraced bymany
for several decades, was formulated by Potter andOsanthanondh in
the 1964.4145 Their classification was thefirst formulation
predicated on data derived from a sys-tematic, anatomic analysis
(Table 7). Potter and Osatha-nondh4145 performed a series of
elegant microdissectionstudies of the normal developing kidney and
on congen-itally cystic kidneys in which the entire nephron was
dis-sected (Figure 9, A through D). They identified 4 patternsof
cyst localization within the nephron that formed thebasis for the
Potter Classification of 4 types of RCD.
Although, in subsequent years, pathologists and clini-cians
attempted to place all cystic kidneys into one of the4 Potter
types, Potter46 states in her book Normal and Ab-normal Development
of the Kidney: The majority of cystsfound in children and infants
beyond the newborn periodfall outside of the four major categories
that result fromabnormalities during the formative years. Thus,
theirclassification was not intended to be all-encompassing in
its application. In a practical sense, it would difficult
orimpossible to know where nephron cysts reside withinany
individual cystic kidney without actually performinga
microdissection on each case, an impossible task.
Theirclassification had an eventual lethal failinglack of clini-cal
utilitybecause of the heterogeneity of some catego-ries. For
instance, their type III cystic kidney combinescases of dominant
polycystic kidney disease with renaldysplasias, a similar flaw
afflicting previous classifica-tions.
Two classifications, both comprehensive and clinically
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
Cystic Diseases and MalformationsBonsib 563
Table 6. The Staubutz, Jewett, and Pletman115
(1963)Classification of Pediatric Cystic Diseases
Group 1: Congenital polycystic kidney diseaseIn the newbornIn
the adult
Group 2: Congenital polycystic kidney in infants and
chil-dren
Group 3: Congenital unilateral multicystic kidneyGroup 4: Simple
or solitary cysts
Data derived from Staubitz WJ, Jewett TC Jr, Pletman RJ. Renal
cysticdisease in childhood. J Urol. 1963;90:812.
Table 8. Kissane116 (1966) Classification ofCongenital
Malformations of the Kidney
I. Abnormalities in amount of renal tissueA. Deficient
definitive renal parenchyma
a. Bilateral renal agenesisb. Unilateral renal agenesisc. Renal
hypoplasia
B. Excess renal tissue (supernumerary kidney)II. Anomalies of
position, form and orientation
A. Renal ectopiaa. Simpleb. Crossed
B. Renal fusionC. Anomalies of rotation
III. Anomalies of differentiationA. Renal dysplasia
a. Totalb. Segmentalc. Focald. Associated with congenital
obstruction
B. Polycystic kidney diseasea. Adult typeb. Infantile type
C. Medullary cystic diseasea. The sponge kidneyb. Uremic
medullary cystic disease
D. Simple renal cystE. Multilocular renal cystF. Miscellaneous
cysts of renal origin
a. Retroperitoneal cysts of nephric originb. Dysontogenic cysts
of nephric origin
i. Renal teratodermoidsii. Endometrial cysts of the kidney
G. Cysts in renal fossa of other nephric origina. Pyelocalyceal
cystsb. Pericalyceal lymphangiectasisc. Perinephric pseudocysts
Reprinted with permission from 116Kissane JM. Congenital
malforma-tion. In: Heptinstall RH, ed. Pathology of the Kidney. 1st
ed. Boston,MA: Little, Brown & Co; 1966:63117.
Table 7. The Potter46 (1964) Classification of RenalCystic
Diseases of the Newborn
Type I kidney Enlargement of the cortical- and
medullary-collecting ducts of both kidneys; usuallycauses death
soon after birth.
Type II kidney The ampullae of the collecting ducts
areprofoundly altered and incapable of pro-ducing functioning
nephrons; death resultsif bilateral.
Type III kidney Cysts are located in collecting duct or
anysegment of the nephron; is almost alwaysbilateral and
principally affects adults.
Type IV kidney Cysts are present at birth and produced dur-ing
distention of the terminal portion ofthe S-stage nephron because of
urethralobstruction.
Data derived from 46Potter EL. Cystic kidneys: age distribution
and re-sume of pathogenesis. In: Normal and Abnormal Development of
theKidney. Chicago, IL: Year Book Medical Publishers, Inc;
1972:289295.
relevant, were formulated by Kissane,116 in 1966, in the
firstedition of Heptinstalls Pathology of the Kidney and by
Elkinand Bernstein118 in 1969 (Tables 8 and 9). Both the
Kis-sane116 and the Elkin and Bernstein118 classification
providethe basic framework employed in classification scheme
oftoday. They include expanded categories of the 2 majorgenetic
polycystic diseases, dominant and recessive poly-cystic kidney
disease and the renal dysplasias, accom-modating the expanding
spectrum of those diseases. Kis-sane116 also included other CAKUT
abnormalities, such asabnormalities of position, form, and
orientation, whereasElkin and Bernstein118 added categories of
other geneticdisorders complicated by renal cysts, such as the
trisomysyndromes and the tuberous sclerosis complex.
Another example of a comprehensive classification ofRCD/CAKUT,
which is so large that it resembles more ofa tabulation of entities
than a classification system, wasrecently been published by
Bisceglia et al113 in their ex-cellent 2006 review of RCD (Table
10). This classificationrepresents an expansion on the strategy of
Kissane116 andElkin and Bernstein,118 employing key groupings of
ge-netic disorders, such as the 2 polycystic kidney diseases,and
entities with similar morphologic findings, such asmetanephric
dysgenesis of renal dysplasias, without mix-ing pathogenetically
unrelated entities, such a medullarysponge kidney with the genetic
medullary cystic diseasesand nephronophthisis
Unfortunately, the Elkin and Bernstein,118 and the Bri-sceglia
et al113 formulations suffer from unnecessary ad-ditional
complexity by inclusion of diseases that lack truecyst formation or
maldevelopment as defined in the glos-sary of terms in Table 3.
These include the Elikin and
Bernstein118 medullary necrosis, inflammatory and trau-matic
categories, and cystic degeneration of carcinomas,and the
Brisceglia et al113 renal tumors with cystic necrosisand some
pseudocystic diseases, such as pyelocalycealcysts and lymphocele.
The justification for inclusion ofnoncystic entities in a
classification of cystic diseases isthat some noncystic lesions
produce a space-occupying le-sion that, when imaged, elicit a
cystic disease in the dif-ferential diagnosis. However, the list of
truly cystic dis-eases is long enough that including noncystic and
non-maldevelopment diseases clutter the process unnecessari-ly.
As evident in Kissane,116 Elkin and Bernstein,118 andBrisceglia
et al113 classifications, our recognition and cat-aloguing of
RCD/CAKUT lesions has evolved so thatcomprehensive classification
systems are becoming daunt-ingly large. There are approaches,
however, that can makethis problem more manageable. One approach is
to dealmore selectively with subsets of entities as exemplified bya
series of classifications published by Bernstein and
col-leagues118120 through the years. These more focused
clas-sifications (not shown for economy of space) are usefulwhen
interest is limited to a certain key pathologic vari-ables or
clinical aspects. Examples would include their1968 classification
of renal hypoplasias and dysplasias,48their 1989 classification of
glomerulocystic kidney diseas-
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564 Arch Pathol Lab MedVol 134, April 2010 Classification of
Renal Cystic Diseases and MalformationsBonsib
Table 9. The Elkin and Bernstein117 (1969)Classification of
Renal Cystic Diseases
I. Renal dysplasiaA. Multicystic kidneyB. Focal and segmental
cystic dysplasiaC. Multiple cysts associated with lower urinary
tract ob-
structionII. Polycystic kidney disease
A. Infantile polycystic disease1. Polycystic disease of the
newborn2. Polycystic disease of childhood
a. Congenital hepatic fibrosisb. Medullary tubular ectasia
B. Adult polycystic diseaseIII. Cortical cysts
A. Trisomy syndromesB. Tuberous sclerosis complexC. Simple
cysts
a. Solitaryb. Multiple
IV. Medullary cystsA. Medullary spongeB. Medullary cystic
diseasesC. Medullary necrosisD. Pyelogenic cyst
V. Miscellaneous intrarenal cystsA. Inflammatory
a. Tuberculosisb. Calculus diseasec. Echinococcus disease
B. Neoplasticcystic degeneration of carcinomaC.
Traumaticintrarenal hematoma
VI. Extraparenchymal cystsA. ParapelvicB. Perinephric
Reprinted with permission from 117Elkin M, Bernstein J. Cystic
diseasesof the kidneyradiological and pathological considerations.
Clin Ra-diol. 1969;20(1):6582.
Table 11. The Liapis and Winyard121 (2006)Classification of
Renal Cystic Disease
A. Polycystic kidney disease1. Autosomal-dominant polycystic
kidney disease
Classic ADPKDEarly onset ADPKD in children
2. Autosomal-recessive polycystic kidney diseaseClassic ARPKD in
neonates and infantsMedullary duct ectasia in older children with
hepatic
fibrosis3. Glomerulocystic kidney disease
Familial GCKDRenal hypoplasia and UROM mutationAssociated with
HNFB1 mutationsHereditary GCKDAssociated with
ADPKD/ARPKD/TSCSyndromic nonhereditary GCKDSporadic GCKDAcquired
GCKD
B. Renal medullary cysts1. Nephronophthisis
Nephronophthisis, autosomal recessiveJuvenile
nephronophthisisNPH1, NPH4NPH1, NPH5 associated with Senior-Loken
syndromeInfantile NPH2
2. Medullary cystic diseasesAutosomal dominant MCKDMCKD
associated with hyperuricemia
3. Medullary sponge kidneyC. Cysts in hereditary cancer
syndromes
1. von Hippel-Lindau disease2. Tuberous sclerosis
D. Multilocular renal cystE. Localized cystic diseaseF. Simple
cortical cystsG. Acquired (dialysis-induced) cystsH.
Miscellaneous
1. Pyelocaliceal diverticula2. Perinephric pseudocysts3. Hygroma
renalis
Abbreviations: ADPKD, autosomal dominant polycystic kidney
disease;ARPKD, autosomal recessive polycystic kidney disease; GCKD,
glom-erulocystic kidney disease; MCKD, medullary cystic kidney
disease;NPH, nephronophthisis; TSC, tuberous sclerosis complex.
Reproduced with permission from 121Liapis H. Winyard P. Cystic
dis-eases and developmental kidney defects. In: Jennette JC, Olson
JL,Schwartz MM, Silva FG, eds. Heptinstalls Pathology of the
Kidney, 6thed. New York NY; Lippincott Williams & Wilkins;
2007.
Table 10. The Brisceglia, Galliani, Senger, Stallone,and Sessa
(2006) Classification of Renal Cystic
DiseaseAbridged
1. Autosomal-dominant polycystic kidney disease2.
Autosomal-recessive polycystic kidney disease3. Unilateral,
localized, segmental cystic disease4. Solitary and multiple, simple
renal cysts5. Dysplastic kidney6. Pluricystic kidney of multiple
malformation syndromes7. Juvenile nephronophthisis and medullary
cystic disease8. Medullary sponge kidney9. Glomerulocystic kidney
disease
10. Multilocular renal cystscystic nephroma and congeners11.
Renal cysts in hereditary syndromes12. Renal
lymphangioma/peripelvic-peripcalyceal lymphanges-
tasia13. Pyelocalyceal cyst, parapelvic cyst, perinephric
pseudocyst,
lymphocele14. Acquired renal cystic disease15. Renal cell
carcinomas with cystic change
Reprinted with permission from 113Brisceglia M, Galliani CA,
Senger C,Stallone C, Sessa A. Renal cystic disease: a review. Adv
Anat Pathol.2006;13(1):2656.
es,118 and their 1993 classification of congenital
nephrop-athies.120
A second divide and conquer approach, especiallysuited to
discussions of RCD/CAKUT, uses the textbookchapter format. An
excellent example of this is the chapterby Liapis and Winyard,121
appearing in the sixth and most
recent edition of Heptinstalls Pathology of the Kidney
(Table11). This beautifully written and illustrated chapter
pro-vides a classification of RCD (see Table 16.1 in Liapisand
Winyard121) and offers additional tables that displayentities
within the differential diagnosis of glomerulocys-tic kidney
disease and the developmental defects withinthe CAKUT spectrum and
a lengthy tabulation of manygenetic syndromes complicated by CAKUT
(see Table26.4, Table 26.5, and Table 26.6 in Liapis and
Win-yard121). In their classification of RCDs, Liapis and
Win-yard121 introduce additional genetic information in
theglomerulocystic disease category and the renal medullarycyst
categories, an approach that will likely expand in fu-ture
formulations by them and others.
The classification I would propose combines the land-mark
strategies of Kissane116 and Elkin and Bernstein,117and the more
detailed formulation of Brisceglia et al113 andLiapis and
Winyard,121 into 4 major categories, with a fifthmiscellaneous
category that could include other rare en-
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Arch Pathol Lab MedVol 134, April 2010 Classification of Renal
Cystic Diseases and MalformationsBonsib 565
Table 12. Bonsib (2009) Classification of RenalCystic Diseases
and Congenital Anomalies of the
Kidney and Urinary Tract
I. Polycystic renal diseasesA. Autosomal-recessive polycystic
kidney disease
Classic in neonates and infantsChildhood with hepatic
fibrosis
B. Autosomal-dominant polycystic kidney diseaseClassic adult
formEarly onset childhood form
C. Acquired renal cystic diseaseD. Glomerulocystic kidney
diseasesA. Familial GCKD
Renal hypoplasia and UROM mutationAssociated with HNFB1
mutations
B. Hereditary GCKDAssociated with ADPKD/ARPKD/TSC
C. Syndromic nonhereditary GCKDD. Sporadic GCKDE. Acquired
GCKD
II. Congenital anomalies of the kidney and urinary tractA. Renal
agenesis and dysplasia
AgenesisSporadic: unilateral or bilateralSyndromicNonsyndromic,
multiple malformation syndromesRenal dysplasiasSporadic: unilateral
or bilateralSyndromicNonsyndromic, multiple malformation
syndromesHereditary adysplasia
B. Renal hypoplasiasSimple hypoplasia: unilateral or
bilateralOligomeganephronic hypoplasiaReduced nephron generations
(cortical hypoplasia)Reduced nephron numbers (premature and low
birth
weight risk of hypertension)C. Abnormalities in form, position,
and number
Rotation anomalyRenal ectopiasRenal fusionsSupernumerary
kidneyIn combination with A, B, or D
D. Ureteral and urethral abnormalitiesUreteropelvic junction
obstructionUreteral duplication/bifid ureterVesicoureteral
refluxPrimary megaureterUreteral ectopiaPosterior urethral valvesIn
combination with A, B, or C
III. Tubulointerstitial syndromes cystsA. Renal tubular
dysgenesis
Autosomal recessiveSecondary twin-twin transfusionACE
inhibitor
B. Nephronophthisis: types 16C. Medullary cystic diseases:
Type 1Type 2/familial juvenile hyperuricemic nephropathy
D. Bardet-Biedel syndromes, types 112IV. Cystic neoplasms and
neoplastic cysts
A. Cystic nephromaB. Cystic partially differentiated
nephroblastomaC. Mixed epithelial and stromal tumorD. Multilocular
cystic renal cell carcinomaE. Tubulocystic renal cell carcinomaF.
Von HippelLindau diseaseG. Lymphangioma/hygroma renalis
V. Miscellaneous cystsA. Simple cortical cysts
Table 12. Continued
B. Medullary sponge kidneyC. Localized renal cystic disease
Abbreviations: ACE, angiotensin converting enzyme; ADPKD,
autoso-mal dominant polycystic kidney disease; ARPKD, autosomal
recessivepolycystic kidney disease; GCKD, glomerulocystic kidney
disease; TSC,tuberous sclerosis complex.
tities not listed. The first category groups the major
clinicalforms of the genetic polycystic kidney diseases and
glom-erulocystic kidney diseases with acquired RCD into apolycystic
renal disease category (Table 12). Although ge-netic and nongenetic
diseases are grouped in this category,these entities have in common
the initial normal nephronformation complicated by diffuse cystic
alterations whenfully expressed.
The diverse entities characterized by the metanephricdysgenesis
and LUT abnormalities of CAKUT are clus-tered together into the
second category that accommo-dates their occurrence in sporadic,
syndromic, and mul-tiple malformation syndromes, while allowing for
combi-nations of renal and LUT defects that can affect the
samekidney. This grouping accounts for the major possibilitiesbut
does not attempt to list the numerous syndromic en-tities that it
includes because of their large number andbecause many syndromes
would fall in multiple categoriesof this grouping.
The third category includes entities that are predomi-nately
interstitial diseases; some of the entities may havecoexistent
cysts with renal tubular dysgenesis, the majorexception. The
various forms of nephronophthisis andmedullary cystic diseases are
clustered together, but med-ullary sponge kidney is kept separate
in a final miscella-neous category. The fourth major category is
cystic renalneoplasms and neoplastic cysts. Only intrinsically
cysticrenal neoplasms are listed. Their number has expandedgreatly
in the past few years. Neoplasms with cystic de-generation and
necrosis are not included in this groupingbecause this finding is
not only common in renal neo-plasms but also occurs in nearly every
type of renal tumor.The many noncystic diseases that clutter
previously men-tioned formulations are excluded.
CONCLUSIONIn the 21st century, the genetic/molecular-based
pos-
tulates in the pathogenesis of the complex RCD/CAKUTfamily
implicate mutated master genes and modifyinggenes crucial in renal
development and in cell physiology.This insight has minimized the
importance of anatomic-based postulates that relate urinary tract
obstruction todevelopmental misadventures by placing them within
alarger paradigm of sequential intrinsic genetic and molec-ular
defects that culminate in the malformed kidney andLUT and in
progressive lesions developing in normallyformed kidneys. With the
burst of information on mole-cules that reside in the primary
cilium of renal tubules,there are now pathogenetic links among
morphologicallyand genetically distinct entities and among select
mixedcystic and neoplastic entities; such exciting
associationswould have seemed implausible not too many years
ago.
These advances may ultimately explain not only thepathogenesis
of most cystic renal diseases, whether con-genital, acquired, or
neoplastic, but also may, when fully
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566 Arch Pathol Lab MedVol 134, April 2010 Classification of
Renal Cystic Diseases and MalformationsBonsib
delineated, provide a molecular basis for targeted thera-pies to
prevent or ameliorate some diseases. Despite im-pressive scientific
advances, it remains difficult to developa completely satisfactory
classification of the diverse arrayof anomalies that affect the
urinary tract. Although clas-sifications incorporating genetic and
molecular data arenow emerging, there are complicating factors that
are dif-ficult to accommodate. These include the polygenetic
na-ture of some disorders, the accumulation of multiple ge-netic
defects that can affect susceptibility and influence thenature of
the malformation expressed, and different typesof mutations in a
single master gene that can clearly alterthe phenotypic
expression.
Contributing to this challenge is that a classificationsuitable
for one discipline, such as pathology, may not beoptimized to serve
the interests of another discipline.When pathologists encounter an
anatomic abnormality, westrive to place it within a diagnostic
category that willsatisfy and initiate the proper clinical
responses. Con-versely, formulating a purely molecular-based or
mecha-nistic classification can serve the interests of a basic
re-searcher striving to develop targeted therapies, for in-stance,
to affect the function of a mutated ciliary protein,but can fail to
meet the diagnostic needs of the patholo-gist.
The ideal classification scheme would account for mor-phologic
features and their clinical importance, with log-ical links to
pathogenesis, while providing a basis for ther-apeutic
interventions. Although such a comprehensiveclassification remains
an elusive target, its general outlineis becoming clearer but
remains a lofty goal yet to beachieved. The classification listed
in Table 12 strives tomeet the first 2 objectives cited above, but
likely falls shortin some respects, and with the pace of discovery
in RCD/CAKUT, it will soon be obsolete. In the final analysis,
ourinfatuation with these diseases derives from the impossi-ble
challenge their complexity creates. This is nicely cap-tured in the
quote by Potter when she stated in 1972, Themore complicated an
organ in its development, the moresubject it is to maldevelopment,
and in this respect thekidney outranks most other organs. 46
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