Professional Documents
Culture Documents
Context.Renal cystic diseases and congenital abnormalities of the kidney and urinary tract comprise a heterogeneous group of lesions whose pathogenesis has eluded
physicians for centuries. Recent advances in molecular and
genetic understanding of these diseases may provide the
solution to this riddle.
Objective.The formulation of an effective classification system for these disorders has been elusive but is
needed to introduce order while providing a conceptual
framework for diagnosis.
Data sources.This review discusses the evolution, beginning in the 19th century, of postulates regarding the
pathogenesis of cystic and developmental renal diseases.
Selected classification systems proffered during this period
are discussed in pursuit of an ideal classification schema
that would account for morphologic features and their
clinical importance, with logical links to pathogenesis and
treatment. Although this remains an elusive target, its gen-
enal cystic diseases (RCDs) and congenital abnormalities of the kidney and urinary tract (CAKUT) comprise a group of metanephric and ampullary bud misadventures and acquired lesions that have captured the interest and challenged the imagination of physicians for
centuries. There are several reasons for this medical infatuation, including the frequency of these disorders (abnormalities in urinary tract development occur in approximately 10% of the population); their astonishing variety,
which results in an impressive menu of gross abnormalities; and most important, their clinical importance (Figure
1).112 Although most patients with some of the more common forms of maldevelopment, such as bifid ureter and
horseshoe kidney, may have few significant complications,
collectively, RCD/CAKUT represent the most common
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 the
structure 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
Classification, which was predicated on the anatomic distribution of cysts within the nephron.
In the mid to late 1900s, the obstructive theory of pathogenesis for renal dysplasia was popularized. Bernstein47,48 noted that more than 90% of dysplastic kidneys
are associated with urinary tract abnormalities that are
invariably obstructive. The renal lesions seem to parallel
the LUT abnormality, whether unilateral versus bilateral
or segmental in a duplex kidney, and that the severity also
appears proportional (Figure 6, A and B). Bernstein47,48 acknowledged, however, that not all dysplastic kidneys are
associated with obstruction because the many familial
multiple malformation syndromes argue for a genetic etiology. Appreciation that these disorders can affect several
members of the same family implicated genetic causation.
Experimental studies, intended to implicate obstructive
etiologies in metanephric dysgenesis, were initiated in the
1970s to 1990s. Extreme experimental maneuvers were
employed, where not only LUT obstruction, urethral or
ureteral obstruction was induced early in embryogenesis
but also unilateral nephrectomy was sometimes perClassification of Renal Cystic Diseases and MalformationsBonsib
Figure 4. G. Carl Hubers 1905 illustration of his wax model serial reconstructions of nephron differentiation (from Huber GC. On the development
and 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, and
Bladder: 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 kidney.4953 In most species examined, including pigs, chickens, and rabbits, investigators failed to induce changes
typical of cystic dysplasia, instead severe hydronephrosis
was mostly observed.4953 However, in the fetal lamb model, convincing cystic dysplasia was produced in some animals, although others developed only severe hydronephrosis.54,55
Experiments of nature indicate that obstruction and
metanephric maldevelopment are not inevitably linked because a neonate can be born with complete LUT obstruction and resultant massive hydroureteronephrosis, yet
nephrogenesis can be preserved (Figure 7).5658 Another
argument against simplistic anatomic causation is the illogic of implicating sequential injury, obstruction followed
by metanephric dysgenesis, for a synchronous activity of
ureteral and renal development. This creates a physiologic
conundrum: How can a nonfunctional, disordered metanephric mass produce an ultrafiltrate of sufficient toxicity or pressure to perturb the development of subsequent
nephron formation. Especially relevant to this concern are
cases of cystic dysplasia identified in the first trimester.5860
McKenna and Kampmeier,33 in their 1933 article entitled
A Consideration of the Development of the Polycystic
Kidney, captured the state of understanding that existed
then, and which persisted until the end of the 20th century
Arch Pathol Lab MedVol 134, April 2010
Figure 6. Two examples of bilateral dysplasia with extreme degrees of (A) ureteral atresia and (B) ureteral dilation.
Table 1.
CAKUT
Selected Examples of Genes in Which Mutations can Result in Various Congenital Abnormalities of the Kidney
and Urinary Tract (CAKUT) Lesions
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 dysplasia; MODY, maturity onset diabetes type 5; UPJ obst, ureteropelvic junction obstruction; VU, vesicoureteral.
Arch Pathol Lab MedVol 134, April 2010
Figure 8. Diagram of a primary cilium with location of cystoproteins identified (reprinted with permission from the American Society of Nephrology, 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.
forth26 and was published in 1888. The Danforth classification contained 5 categories separating congenital forms
from those with clinical associations, such as obstruction,
infection, and trauma (Table 4). Danforth26 acknowledged
the rudimentary nature of the current understanding of
these diseases, which handicapped formation of a satisfactory classification, at the conclusion of his article, when
he wrote, I have to express my regret that so much remains to be learned about cystic disease. . . . [I] hope that
in the near future our knowledge will be more definite
and accurate. . . . Although 120 years has elapsed since
his review, regrettably, our understanding remains incom-
Table 2.
Ciliopathy
Protein
Inheritance
Polycystin 1
AD
Polycystin 2
AD
Fibrocystin
AR
MKS proteins 1, 3
AR
OFD protein
X linked
BBS proteins 1-8
Digenic
VHL protein
AR
AD, autosomal dominant; AR, autosomal recessive.
Lesion
Figure 9. A through D, the Potter and Osathanondh microdissections of congenital cystic kidneys showing the examples of their 4 types based
on 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 understanding and therefore accurate grouping. 114 White
and Braunstein114 focused on etiologic factors, as understood at the time, as the common denominator for their
classification. They were some of the first to discuss genetic causes because of the heredofamilial nature of the
polycystic kidney diseases, which can present at any age but
are usually bilateral and are associated with lesions in other organs. The authors114 also commented that the simple
cortical cyst can be associated with renal neoplasms. Although this association is likely simply a reflection of the
increasing incidence of both lesions with age, the concept
of dysregulated growth for both cyst formation and neoplasia in some cystic diseases now has an established scientific basis, although not for the simple cortical cyst.
White and Braunstein114 proclaim in their conclusion
concerning the subject of renal cystology, that embryonic
origin has been thoroughly modernized with advanced
embryologic knowledge and a clearer and more comprehensive classification has been suggested. Unfortunately,
Arch Pathol Lab MedVol 134, April 2010
their classification failed this claim. The pathologic features of many of the RCDs that had become clearer by
that time permitted morphologic separation of major categories, such as renal dysplasias versus the hereditary
polycystic diseases. However, these authors114 lumped
those entities into a single category: 1A polycystic disease.
Conversely, other primary categories contained entities
that are not actually cystic diseases, such as their category
II, obstructive; category IV, vascular; and category V, inflammatory and infections. Inclusion of noncystic diseases
in cystic disease classifications is a persistent problem that
continues to plague many classification schema.
Failure to employ the known morphologic differences
that exist between several of the major RCDs, such as
dominant and recessive polycystic kidney disease and renal dysplasia, was prevalent in the early RCD classification literature. Another example is provided by the classification of Stubitz et al.115 In their 1963 study,115 restricted
to pediatric cases, they proposed a classification that employed age of onset and laterality while excluding major
Classification of Renal Cystic Diseases and MalformationsBonsib 561
Table 3.
Acquired renal cystic disease
Cystic kidney
Cystogen
Dysmorphic kidney
Glomerulocystic kidney
Heritable renal cystic disease
Induced renal cystic disease
Medullary sponge kidney
Multicystic kidney
Polycystic kidney
Renal adysplasia
Renal agenesis
Renal aplasia
Renal cyst
Renal cystic disease
Renal dysgenesis
Renal dysplasia
Renal hypoplasia
The spontaneous, idiopathic, bilateral development of multiple cysts in previously noncystic kidneys
A kidney containing 3 or more cysts
An agent capable of inducing renal cyst formation or RCD
A misshapen kidney and calyceal system; implies a congenital lesion without any histologic or etiologic
implications
Glomerular cysts as a dominant finding; glomerulocystic kidney disease is a primary disease; glomerulocystic kidney is a kidney with glomerular cysts but of diverse etiologies
Renal cystic disease in a kindred, in a pattern predicted by Mendelian theory
Renal cystic disease produced by exposure to drugs or chemicals
A usually sporadic, medullary cystic abnormality that is commonly diagnosed by radiology
Multiple cystic lesions, most frequently sporadic; they can be small, segmental, unilateral, or bilateral
A genetically determined cystic lesion of either the autosomal-dominant form or autosomal-recessive
form
Where findings of either combined renal agenesis and renal dysplasia or a hereditary syndrome occur
Absent kidney
An extreme form of dysplasia, in which a nubbin of dysplastic kidney caps a normal or an abnormal
ureter
An enclosed or communicating segment of nephron or duct that is dilated to a diameter of 200 mol
Morbidity attributable to the presence of renal cysts
Abnormal development of the kidney in size, shape, or structure; forms of renal dysgenesis include dysplasia, hypoplasia, aplasia, agenesis, and dysmorphism
Abnormal metanephric differentiation diagnosed histologically; it can be diffuse, segmental, or focal
A small kidney or segment with less than a reference range number of nephrons; dysplastic elements are
not present
Diathetic causes
Congenital causes
Mechanical obstruction, consequent upon disease of the pelvic organs
Traumatic causes
Pathogenic cysts
562 Arch Pathol Lab MedVol 134, April 2010
Table 7.
Type I kidney
Bernstein118 medullary necrosis, inflammatory and traumatic categories, and cystic degeneration of carcinomas,
and the Brisceglia et al113 renal tumors with cystic necrosis
and some pseudocystic diseases, such as pyelocalyceal
cysts and lymphocele. The justification for inclusion of
noncystic entities in a classification of cystic diseases is
that some noncystic lesions produce a space-occupying lesion that, when imaged, elicit a cystic disease in the differential diagnosis. However, the list of truly cystic diseases is long enough that including noncystic and nonmaldevelopment diseases clutter the process unnecessarily.
As evident in Kissane,116 Elkin and Bernstein,118 and
Brisceglia et al113 classifications, our recognition and cataloguing of RCD/CAKUT lesions has evolved so that
comprehensive classification systems are becoming dauntingly large. There are approaches, however, that can make
this problem more manageable. One approach is to deal
more selectively with subsets of entities as exemplified by
a series of classifications published by Bernstein and colleagues118120 through the years. These more focused classifications (not shown for economy of space) are useful
when interest is limited to a certain key pathologic variables or clinical aspects. Examples would include their
1968 classification of renal hypoplasias and dysplasias,48
their 1989 classification of glomerulocystic kidney diseasClassification of Renal Cystic Diseases and MalformationsBonsib 563
I. Renal dysplasia
A. Multicystic kidney
B. Focal and segmental cystic dysplasia
C. Multiple cysts associated with lower urinary tract obstruction
II. Polycystic kidney disease
A. Infantile polycystic disease
1. Polycystic disease of the newborn
2. Polycystic disease of childhood
a. Congenital hepatic fibrosis
b. Medullary tubular ectasia
B. Adult polycystic disease
III. Cortical cysts
A. Trisomy syndromes
B. Tuberous sclerosis complex
C. Simple cysts
a. Solitary
b. Multiple
IV. Medullary cysts
A. Medullary sponge
B. Medullary cystic diseases
C. Medullary necrosis
D. Pyelogenic cyst
V. Miscellaneous intrarenal cysts
A. Inflammatory
a. Tuberculosis
b. Calculus disease
c. Echinococcus disease
B. Neoplasticcystic degeneration of carcinoma
C. Traumaticintrarenal hematoma
VI. Extraparenchymal cysts
A. Parapelvic
B. Perinephric
Reprinted with permission from 117Elkin M, Bernstein J. Cystic diseases
of the kidneyradiological and pathological considerations. Clin Radiol. 1969;20(1):6582.
Table 12.
Continued
tities not listed. The first category groups the major clinical
forms of the genetic polycystic kidney diseases and glomerulocystic kidney diseases with acquired RCD into a
polycystic renal disease category (Table 12). Although genetic and nongenetic diseases are grouped in this category,
these entities have in common the initial normal nephron
formation complicated by diffuse cystic alterations when
fully expressed.
The diverse entities characterized by the metanephric
dysgenesis and LUT abnormalities of CAKUT are clustered together into the second category that accommodates their occurrence in sporadic, syndromic, and multiple malformation syndromes, while allowing for combinations of renal and LUT defects that can affect the same
kidney. This grouping accounts for the major possibilities
but does not attempt to list the numerous syndromic entities that it includes because of their large number and
because many syndromes would fall in multiple categories
of this grouping.
The third category includes entities that are predominately interstitial diseases; some of the entities may have
coexistent cysts with renal tubular dysgenesis, the major
exception. The various forms of nephronophthisis and
medullary cystic diseases are clustered together, but medullary sponge kidney is kept separate in a final miscellaneous category. The fourth major category is cystic renal
neoplasms and neoplastic cysts. Only intrinsically cystic
renal neoplasms are listed. Their number has expanded
greatly in the past few years. Neoplasms with cystic degeneration and necrosis are not included in this grouping
because this finding is not only common in renal neoplasms but also occurs in nearly every type of renal tumor.
The many noncystic diseases that clutter previously mentioned formulations are excluded.
CONCLUSION
In the 21st century, the genetic/molecular-based postulates in the pathogenesis of the complex RCD/CAKUT
family implicate mutated master genes and modifying
genes crucial in renal development and in cell physiology.
This insight has minimized the importance of anatomicbased postulates that relate urinary tract obstruction to
developmental misadventures by placing them within a
larger paradigm of sequential intrinsic genetic and molecular defects that culminate in the malformed kidney and
LUT and in progressive lesions developing in normally
formed kidneys. With the burst of information on molecules that reside in the primary cilium of renal tubules,
there are now pathogenetic links among morphologically
and genetically distinct entities and among select mixed
cystic and neoplastic entities; such exciting associations
would have seemed implausible not too many years ago.
These advances may ultimately explain not only the
pathogenesis of most cystic renal diseases, whether congenital, acquired, or neoplastic, but also may, when fully
Classification of Renal Cystic Diseases and MalformationsBonsib 565
delineated, provide a molecular basis for targeted therapies to prevent or ameliorate some diseases. Despite impressive scientific advances, it remains difficult to develop
a completely satisfactory classification of the diverse array
of anomalies that affect the urinary tract. Although classifications incorporating genetic and molecular data are
now emerging, there are complicating factors that are difficult to accommodate. These include the polygenetic nature of some disorders, the accumulation of multiple genetic defects that can affect susceptibility and influence the
nature of the malformation expressed, and different types
of mutations in a single master gene that can clearly alter
the phenotypic expression.
Contributing to this challenge is that a classification
suitable for one discipline, such as pathology, may not be
optimized to serve the interests of another discipline.
When pathologists encounter an anatomic abnormality, we
strive to place it within a diagnostic category that will
satisfy and initiate the proper clinical responses. Conversely, formulating a purely molecular-based or mechanistic classification can serve the interests of a basic researcher striving to develop targeted therapies, for instance, to affect the function of a mutated ciliary protein,
but can fail to meet the diagnostic needs of the pathologist.
The ideal classification scheme would account for morphologic features and their clinical importance, with logical links to pathogenesis, while providing a basis for therapeutic interventions. Although such a comprehensive
classification remains an elusive target, its general outline
is becoming clearer but remains a lofty goal yet to be
achieved. The classification listed in Table 12 strives to
meet the first 2 objectives cited above, but likely falls short
in some respects, and with the pace of discovery in RCD/
CAKUT, it will soon be obsolete. In the final analysis, our
infatuation with these diseases derives from the impossible challenge their complexity creates. This is nicely captured in the quote by Potter when she stated in 1972, The
more complicated an organ in its development, the more
subject it is to maldevelopment, and in this respect the
kidney outranks most other organs. 46
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