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The classification of renal cystic diseases and other congenital malformations of the kidney and urinary tract.

Renal 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). (1-12) 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 cause of end-stage renal disease in children, accounting for 40% to 50% of cases, and includes autosomal dominant polycystic kidney disease, the most common type of RCD and the fourth leading cause of end-stage renal disease in adults. (1-5) Furthermore, renal hypoplasia in the form of insufficient nephron endowment has been implicated in a substantial fraction of individuals with essential hypertension. (13-15)

The formulation of an effective classification system for RCD/CAKUT has been an elusive goal driven by the need to introduce order into this complex arena, and thereby, provide a conceptual framework as attempts to unravel its pathogenesis were pursued. Long before abnormalities of the kidney could be defined, however, was the challenge of defining the anatomic features and function of the normal kidney and urinary tract so that deviations from this blueprint could be recognized. Some of the first and most primitive assumptions of urinary tract structure and function were proffered a millennia ago, when Aristotle taught that urine was formed by the bladder and that kidneys were present "not of actual necessity, but as matters of greater finish and perfection." (16)

Details of the normal gross renal and lower urinary tract (LUT) anatomy were first unveiled in the 16th century by Leonardo de Vinci and Vesalius, who generated drawings of the female and male genitourinary tracts, thus laying the foundation for the modern day disciplines of nephrology, urology, and nephropathology (Figure 2). (16-18) Centuries later, the invention of the first microscopes by Hans and Zacharias Janssen in the 1590s allowed the 17th century masters of microscopic anatomy, such as William Bowman and Marcello Malpighi, to glimpse the complexity of the renal microscopic anatomy (Figure 3). (19-21) Later, Huber and Brodel in the early 20th century illustrated, in meticulous 3-dimensional serial reconstructions and captured in elegant drawings, respectively, its embryologic basis (Figures 4 and 5). (22,23)

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THEORIES ON PATHOGENESIS OF RCD/CAKUT

Historically, the authors of most classifications used prevailing concepts of pathogenesis to frame classification systems. If this is a prerequisite for a useful classification scheme, then it would appear that the ideal classification must await a thorough understanding of RCD/CAKUT pathogenesis, an elusive goal, but one in which much progress has occurred in the past decade. Interestingly, some of the earliest theories of pathogenesis appearing during the 19th century are similar to those that persisted throughout most of the 20th century.

Two of the earliest reported theories on renal cystogenesis were those of Virchow (24) and of Rokitanky. (25) Virchow, (24) in 1869, proposed that obstruction by uric acid crystals or papillary duct atresia was operative in the pathogenesis of renal cysts. Conversely, Rokitansky, (25) in his 1885 text Manual of Pathological Anatomy, indicated that the consensus among German pathologists was that renal cysts formed within the malpighian corpuscle "when tumified and gorged with the inflammatory product of these diseases upon the surrounding strata." An obstructive etiology was also favored by Danforth (26) who wrote in 1888 that the evolution of cysts involved the "unrolling or unfolding of the renal structure as it slowly yields to the pressure of the fluid accumulating in the cysts." The notion that renal cysts were neoplastic surfaced as early as the late 1800s when Sturm, (27) in 1875, and Brigidi and Severi, (28) in 1880, argued that cysts resulted from epithelial proliferations or inclusion of mesonephric elements in the kidney that subsequently proliferate.

Bunting (29) summarized in detail, in a 1906 publication, the prevailing theories on cystogenesis. The postulates in vogue included tubular obstruction attributable to external compression of tubules by infection-related fibrosis, congenital maldevelopment or a neoplasm related to abnormal cell growth, and finally, nonunion of primitive collecting ducts and secretory tubules. The latter postulate followed the delineation by Kupffer, (30) Huber, (22) and Brodel (23) of the dual role of the ampullary bud and renal blastema in renal nephrogenesis. In the 1920s to 1930s, after the dual origin of ampullary bud and nephrogenic blastema in nephrogenesis was more widely recognized, cyst formation, resulting from failure of the 2 tissues to unite, emerged as the most popular theory.

Bunting, (29) in his review of cytogenesis, made the insightful comment that his 2 cases of cystic kidney disease differed morphologically and clinically from many previous reportedly cases. Bunting (29) noted that "the attempts to explain pathogenesis of the congenital cystic kidney have been so numerous and so varied that one is inclined to question whether pathologists have been dealing throughout with a single pathological process." Because the personal experience of these early investigators was limited to small numbers of cases, with no individual having access to the full spectrum of RCD/CAKUT diseases, his concerns were appropriately insightful. Regardless, even if these early investigators were fortunate enough to have exposure to the complete palate of RCD/CAKUT possibilities, they would not have been able to solve the puzzle of pathogenesis, which required advances in scientific knowledge and technology only recently achieved.

Kampmeier, (31) in 1923, published beautifully illustrated, histologic pictures of fetal kidney in early gestation and noted the common occurrence of occasional ectatic (cystic) tubules as a normal event in embryogenesis. This led him to offer one of the earliest insights into the possibility of a molecular basis for many RCDs. He suggested that ectatic abnormal tubules could possibly persist and enlarge to form the grossly visible, simple renal cysts of adults. He further postulated that "factors control the degeneration or suppression of abnormal growth," in effect, implicating master genes that regulate and orchestrate normal embryogenesis or that fail to do so in abnormal embryogenesis. He further noted that these "factors" could also explain coexistent lesions in other organ whose embryogenesis was similarly dysregulated. (31-33)

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Anatomic investigations into the site of cyst formation within the nephron emerged in the mid-20th century, contributing further to our understanding of cystic diseases. Lambert, (34) in 1947, employed serial section reconstructions of cystic kidneys from 6 adults and 2 children and showed that cystic dilations could develop in any segment of the nephron. In the 1950s and 1960s, Potter and Osathanondh and others, (35-44) using the newly developed technique of microdissection, studied normal and congenitally cystic kidneys. The exhaustive work Potter and Osathanondh (41-46) was particularly noteworthy because it formed the basis of a classification schema known as the Potter 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. Bernstein (47,48) 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). Bernstein (47,48) 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 performed to further stress to the remaining, developing kidney. (49-53) In most species examined, including pigs, chickens, and rabbits, investigators failed to induce changes typical of cystic dysplasia, instead severe hydronephrosis was mostly observed. (49-53) However, in the fetal lamb model, convincing cystic dysplasia was produced in some animals, although others developed only severe hydronephrosis. (54,55)

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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). (56-58) 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. (58-60) 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 when they wrote: "There are many theories which begin as logical deduction, and later without foundation of observation are handed down from textbook to textbook and from paper to paper as facts. Such is the hypothesis of the origin of cystic kidney." (3) Bernstein elaborated further, in 1968, about the challenge investigators faced in this field when he wrote: "A classification in a strict taxonomic sense cannot be devised because pathogenesis remains unknown and because considerable overlap exists both clinically and morphologically." (46)

Although by the latter decades of the 20th century, the etiology or etiologies for RCD/CAKUT remained unknown, implication of an anatomic causation, especially urinary tract obstruction in severe metanephric maldevelopment, remained popular because of the ubiquitous association. Knowledge of the embryologic development of the kidney would appear to provide a logical basis for explaining departures from normal renal development and was especially popular for many CAKUT lesions. However, because of the enormous diversity of malformed urinary tracts, the limitless combinations of abnormalities affecting kidney and LUT, and the asymmetry of renal lesions, the delayed onset of some genetic cystic diseases in kidneys that were initially normal in form and the acquired nature of others cannot be easily accommodated by any simplistic anatomic-based approach. (3-12,61-66) To quote the time traveler in H. G. Wells' (67) The Time Machine, "Very simple was my explanation, and plausible enough--as most wrong theories are!"

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Limitation in the understanding of pathogenesis, as noted by Bernstein, (47,48) has plagued the classification process, but has been alleviated in recent years as the molecular contributions to RCD/CAKUT have been identified. (68-100) The list of mutated genes expressed during renal development is rapidly growing. These genes code for a variety of transcription and growth factors required for the regulation and orchestration of interactions between the ureteric bud and the metanephric blastema and its predecessor's tissues, the mesonephric and pronephric ducts. One of 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 master organizer gene expressed in the nephric duct, metanephric mesenchyme, ureteric bud, and S-shaped body. (65-69) PAX2 performs many functions at early stages of renal development. It organizes caudal descent of the nephric duct with PAX8 and GATA3, emergence of the ureteric bud, and induces WT1 in metanephric blastema. PAX2 is also involved with branching morphogenesis and the sustained arborization of the collecting duct. With such extensive involvement in the early stages of metanephric kidney induction, it is easy to envision how mutations of this crucial gene, or other similarly critically located genes, could result in a vast array of maldevelopment.

Table 1 lists several of the most commonly mutated master genes, displays the various malformations observed, and reports associated clinical syndromes. It is clear that the renal consequences of the mutation of a single master gene can be diverse, dependent upon the specific type of mutation, missense, nonsense, deletion, and so forth, and the resultant functionality of the mutated protein produced. Modifying genes also influence the final phenotype adding an additional layer of complexity. Furthermore, based on cDNA microarray analysis comparing the RNA signature of normal and dysplastic kidneys, the expression profiles of entire families of genes are affected in many cases of RCD/CAKUT.

A second major advance in understanding RCD/CAKUT pathogenesis has been the explosion in understanding of the molecular composition and function of the renal tubule primary cilium. (101-110) Cilia are eukaryotic organelles that project from the cell surface; they can exhibit motile or sensory functions. The basic structure of nonmotile, primary cilia of the renal tubular cells consists of 9 peripheral microtubular doublets that form the axoneme, surrounded by a lipid bilayer that is continuous with the cell membrane. By contrast, motile cilia of other organs have a central doublet of microtubules in addition to the 9 peripheral microtubular doublets, and the latter are linked by dynein arms and other structural components. All cilia are anchored in the cytosol by the basal body, a microtubular organizer derived from the older of the 2 centrioles (Figure 8). Assembly and maintenance of cilia is provided by a bidirectional microtubular transport system.

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The proteins of the primary cilia are ancient and have been highly conserved evolutionarily; in fact, some cystoproteins have been conserved for more than 1.5 billion years from unicellular organisms to vertebrates. Although primary cilia have been recognized for decades, they had previously been regarded as evolutionary vestiges. However, more recently, it has been recognized that primary cilia serve important functions in cellular physiology, such as cell cycle regulation, cell signaling, apoptosis, and epithelial cell polarization. The list of signaling pathways influenced by ciliary function is growing and includes platelet-derived growth factor receptor a signaling, hedgehog signaling, epidermal growth factor signaling, and 5-HT6 serotonin signaling.

Mutation of more than 20 molecules that are localized to primary cilia, basal bodies, and centrosomes, and which also reside in cell adhesions, have been identified in a broad range of morphologically and clinically dissimilar disorders (Table 2). Most of the cytoproteins identified interact with other cystoproteins (Figure 9). Thus, mutations of these physiologically interactive proteins provide pathophysiologic links between RCDs previously regarded as unrelated because they differ in type of transmission, age of onset, extrarenal manifestations, and risk of and rate of progression to end-stage renal disease. Mutated genes of the primary cilium could provide an approach to the classification of at least an important subset of RCDs and, more significant, may allow targeted therapies to be developed in the future.

NOMENCLATURE AND TERMINOLOGY

Before proceeding with a review of the classification systems for RCD/CAKUT, it would be prudent to list the nomenclature and terminology employed in the remainder of this article and included in the most recent classifications cited later. The RCD/CAKUT diseases are complicated enough without introducing communication obstacles. Although laxity in terminology is understandable for the pioneers in this field, this is not acceptable today, and it risks creating confusion about important entities, with resultant inappropriate clinical responses. For purposes of this article, the terms used and their definitions are provided in Table 3. They represent a synthesis of definitions obtained from several reputable sources: The Committee on Terminology, Nomenclature, and Classification, Section on Urology, American Academy of Pediatrics, (112) and 2 articles published by individuals of stature in this field of investigation. (111-113)

CLASSIFICATION SYSTEMS

Although there have been numerous classifications proposed, those that strive to be all-inclusive employ similar general strategies, strategies that continue today. Prevailing notions of pathogenesis and obvious clinical associations have been closely linked to classification strategies from the beginning. Most classification systems distinguish entities with intrinsic abnormalities, presumed to result from developmental miscues that occurred early in the embryologic formation of the kidney and urinary tract, placing them in a congenital category. The remaining categories contain acquired lesions that affect a kidney that previously developed normally. In these categories, cyst formation as a consequence of external forces, injuries, and neoplastic events are often included.

One of the earliest forays into the daunting arena of the classification of cystic kidney disease was by I. N. Dan forth (26) 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 incomplete and, therefore, so does a completely satisfactory classification.

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As the field of pathology evolved, and more disease entities were identified, classifications became lengthier but not necessarily crafted more effectively. In 1954, White and Braunstein (114) formulated a classification of renal cystology, based on etiologic groupings not too dissimilar to many more modern formulations (Table 5). The authors conceded, in the first paragraph of the article, that they faced challenges, stating The pathogenesis and embryologic development of these cystic formations are quite fantastic and appear to the authors as a constant urological imponderable" and The majority of cysts still defy understanding and therefore accurate grouping." (114) White and Braunstein (114) 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 authors (114) 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.

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White and Braunstein (114) 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, 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 authors (114) 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 secondary causes, such as infectious causes, neoplastic causes, and chronic glomerulonephritis (Table 6). Although they proclaimed, There is widespread confusion among both clinicians and pathologists concerning the classification of cystic disease," and stated, "It is only recently that the true etiology and significance of the unilateral multicystic disease and polycystic kidney may have been understood"; they grouped obvious cases of recessive polycystic kidney disease and multicystic renal dysplasias associated with LUT anomalies into congenital polycystic kidney diseases in the newborn.

The first influential classification of RCDs, embraced by many for several decades, was formulated by Potter and Osanthanondh in the 1964. (41-45) Their classification was the first formulation predicated on data derived from a systematic, anatomic analysis (Table 7). Potter and Osathanondh (41-45) performed a series of elegant microdissection studies of the normal developing kidney and on congenitally cystic kidneys in which the entire nephron was dissected (Figure 9, A through D). They identified 4 patterns of cyst localization within the nephron that formed the basis for the Potter Classification of 4 types of RCD.

Although, in subsequent years, pathologists and clinicians attempted to place all cystic kidneys into one of the 4 Potter types, Potter (46) states in her book Normal and Abnormal Development of the Kidney: "The majority of cysts found in children and infants beyond the newborn period fall outside of the four major categories that result from abnormalities during the formative years." Thus, their classification was not intended to be all-encompassing in its application. In a practical sense, it would difficult or impossible to know where nephron cysts reside within any individual cystic kidney without actually performing a microdissection on each case, an impossible task. Their classification had an eventual lethal failing-lack of clinical utility-because of the heterogeneity of some categories. For instance, their type III cystic kidney combines cases of dominant polycystic kidney disease with renal dysplasias, a similar flaw afflicting previous classifications.

Two classifications, both comprehensive and clinically relevant, were formulated by Kissane, (116) in 1966, in the first edition of Heptinstall's Pathology of the Kidney and by Elkin and Bernstein (118) in 1969 (Tables 8 and 9). Both the Kissane (116) and the Elkin and Bernstein (118) classification provide the basic framework employed in classification scheme of today. They include expanded categories of the 2 major genetic polycystic diseases, dominant and recessive polycystic kidney disease and the renal dysplasias, accommodating the expanding spectrum of those diseases. Kissane (116) also included other CAKUT abnormalities, such as abnormalities of position, form, and orientation, whereas Elkin and Bernstein118 added categories of other genetic disorders complicated by renal cysts, such as the trisomy syndromes and the tuberous sclerosis complex.

Another example of a comprehensive classification of RCD/CAKUT, which is so large that it resembles more of a tabulation of entities than a classification system, was recently been published by Bisceglia et al (113) in their excellent 2006 review of RCD (Table 10). This classification represents an expansion on the strategy of Kissane116 and Elkin and Bernstein,118 employing key groupings of genetic disorders, such as the 2 polycystic kidney diseases, and entities with similar morphologic findings, such as metanephric dysgenesis of renal dysplasias, without mixing pathogenetically unrelated entities, such a medullary sponge kidney with the genetic medullary cystic diseases and nephronophthisis

Unfortunately, the Elkin and Bernstein,118 and the Brisceglia et al (113) formulations suffer from unnecessary additional complexity by inclusion of diseases that lack true cyst formation or maldevelopment as defined in the glossary of terms in Table 3. These include the Elikin and Bernstein118 medullary necrosis, inflammatory and traumatic categories, and cystic degeneration of carcinomas, and the Brisceglia et al (113) 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 al (113) 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 colleagues (118-120) 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 diseases, (118) and their 1993 classification of congenital nephropathies. (120)

A second divide and conquer" approach, especially suited to discussions of RCD/CAKUT, uses the textbook chapter format. An excellent example of this is the chapter by Liapis and Winyard, (121) appearing in the sixth and most recent edition of Heptinstall's Pathology of the Kidney (Table 11). This beautifully written and illustrated chapter provides a classification of RCD (see "Table 16.1" in Liapis and Winyard (121)) and offers additional tables that display entities within the differential diagnosis of glomerulocystic kidney disease and the developmental defects within the CAKUT spectrum and a lengthy tabulation of many genetic syndromes complicated by CAKUT (see Table 26.4," Table 26.5," and Table 26.6" in Liapis and Winyard121). In their classification of RCDs, Liapis and Winyard121 introduce additional genetic information in the glomerulocystic disease category and the renal medullary cyst categories, an approach that will likely expand in future formulations by them and others.

The classification I would propose combines the landmark strategies of Kissane116 and Elkin and Bernstein, (117) and the more detailed formulation of Brisceglia et al (113) and Liapis and Winyard, (121) into 4 major categories, with a fifth miscellaneous category that could include other rare entities 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 anatomic-based 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 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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Stephen M. Bonsib, MD

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 companies described in this article.

Presented in part at the 4th Annual Renal Pathology Society/Kidney and Urology Foundation of America satellite meeting held in association with the 21st European Congress of Pathology, Istanbul, Turkey, September 13, 2007.

Reprints: Stephen M. Bonsib, MD, Department of Pathology, LSU Health Sciences Center, 1541 Kings Hwy, Shreveport, LA 71 130-3932 (e-mail: sbonsi@lsuhsc.edu).
Table 1. Selected Examples of Genes in Which Mutations can Result in
Various Congenital Abnormalities of the Kidney and Urinary Tract
(CAKUT) Lesions

CAKUT             PAX2        TCF2    EYA1   SIX1      SALL1

Dysplasia          X           XX             XX
Agenesis                               X      X
Hypoplasia         X            X                        X
UPJ obst           X            X                        X
VU reflux                                                X
GCKD                            X
Syndrome     Renal-coloboma   MODY5   BOR    BOR    Townes-Brock

CAKUT        GATA3

Dysplasia      X
Agenesis       X
Hypoplasia
UPJ obst
VU reflux      X
GCKD
Syndrome      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.

Table 2. Ciliopathies: Molecular, Genetic, and Pathologic Features

Ciliopathy                          Protein        Inheritance

Autosomal dominant PKD         Polycystin 1        AD
Autosomal dominant PKD         Polycystin 2        AD
Autosomal recessive PKD        Fibrocystin         AR
Meckel-Gruber syndrome         MKS proteins 1, 3   AR
Oral-facial-digital syndrome   OFD protein         X linked
Bardet-Beidl syndrome          BBS proteins 1-8    Digenic
Von Hippel-Lindau              VHL protein         AR

Ciliopathy                                  Lesion

Autosomal dominant PKD         Cysts within the entire nephron
Autosomal dominant PKD         Cysts within the entire nephron
Autosomal recessive PKD        Collecting duct cysts
Meckel-Gruber syndrome         Cystic dysplasia
Oral-facial-digital syndrome   Glomerulocystic kidney disease
Bardet-Beidl syndrome          Tubulointerstitial nephritis
Von Hippel-Lindau              Clear cell cysts and cancer

Abbreviations: PKD, polycystic kidney disease; AD, autosomal dominant;
AR, autosomal recessive.

Table 3. Renal Cystic Disease (RCD) Nomenclature and Terminology

Acquired renal cystic disease    The spontaneous, idiopathic,
                                   bilateral development of multiple
                                   cysts in previously noncystic
                                   kidneys
Cystic kidney                    A kidney containing 3 or more cysts
Cystogen                         An agent capable of inducing renal
                                   cyst formation or RCD
Dysmorphic kidney                A misshapen kidney and calyceal
                                   system; implies a congenital lesion
                                   without any histologic or etiologic
                                   implications
Glomerulocystic 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 etiologies
Heritable renal cystic disease   Renal cystic disease in a kindred,
                                   in a pattern predicted by Mendelian
                                   theory
Induced renal cystic disease     Renal cystic disease produced by
                                   exposure to drugs or chemicals
Medullary sponge kidney          A usually sporadic, medullary cystic
                                   abnormality that is commonly
                                   diagnosed by radiology
Multicystic kidney               Multiple cystic lesions, most
                                   frequently sporadic; they can be
                                   small, segmental, unilateral, or
                                   bilateral
Polycystic kidney                A genetically determined cystic
                                   lesion of either the
                                   autosomal-dominant form or
                                   autosomal-recessive form
Renal adysplasia                 Where findings of either combined
                                   renal agenesis and renal dysplasia
                                   or a hereditary syndrome occur
Renal agenesis                   Absent kidney
Renal aplasia                    An extreme form of dysplasia, in
                                   which a nubbin of dysplastic kidney
                                   caps a normal or an abnormal ureter
Renal cyst                       An enclosed or communicating segment
                                   of nephron or duct that is dilated
                                   to a diameter of [greater than or
                                   equal to] 200 [micro]mol
Renal cystic disease             Morbidity attributable to the
                                   presence of renal cysts
Renal dysgenesis                 Abnormal development of the kidney
                                   in size, shape, or structure; forms
                                   of renal dysgenesis include dys-
                                   plasia, hypoplasia, aplasia,
                                   agenesis, and dysmorphism
Renal dysplasia                  Abnormal metanephric differentiation
                                   diagnosed histologically; it can be
                                   diffuse, segmental, or focal
Renal hypoplasia                 A small kidney or segment with less
                                   than a reference range number of
                                   nephrons; dysplastic elements are
                                   not present

Table 4. The Danforth (26) (1888) Classification of
Renal Cystic Diseases

Diathetic causes
Congenital causes
Mechanical obstruction, consequent upon disease of the pelvic
  organs
Traumatic causes
Pathogenic cysts

Table 5. The White and Braunstein (114) (1954)
Classification of Renal Cystology

  I. Congenital or developmental
     A. Polycystic disease
     B. Serous cysts
     C. Lymphatic cysts
 II. Obstructive
     A. Diverticula
     B. Parapelvic
     C. Hydrocalycosis
III. Neoplastic
     A. Cystadenoma
     B. Cystadenocarcinoma
     C. Angioma
     D. Dermoid
 IV. Vascular
     A. Hemangioma
     B. Aneurysm
     C. Embolism
     D. Infarction
  V. Inflammatory and infectious
     A. Pyogenic
     B. Tuberculous
     C. Chronic nephritis
 VI. Parasitic
     A. Echinococcus
     B. Tinea
     C. Trichina

Reprinted with permission from 114White EW, Braunstein L. Renal cystic
disease. J Urol. 1954;71(1):17-2 7. Copyright Elsevier 1954.

Table 6. The Staubutz, Jewett, and Pletman (115) (1963)
Classification of Pediatric Cystic Diseases

Group 1:   Congenital polycystic kidney disease
             In the newborn
             In the adult
Group 2:   Congenital polycystic kidney in infants and chil-
             dren
Group 3:   Congenital unilateral multicystic kidney
Group 4:   Simple or solitary cysts

Data derived from Staubitz WJ, Jewett TC Jr, Pletman RJ. Renal cystic
disease in childhood. J Urol. 1963;90:8-12.

Table 7. The Potter (46) (1964) Classification of Renal
Cystic Diseases of the Newborn

Type  I kidney     Enlargement of the cortical- and medullary-
                     collecting ducts of both kidneys; usually
                     causes death soon after birth.
Type  II kidney    The ampullae of the collecting ducts are
                     profoundly altered and incapable of pro-
                     ducing functioning nephrons; death results
                     if bilateral.
Type  III kidney   Cysts are located in collecting duct or any
                     segment of the nephron; is almost always
                     bilateral and principally affects adults.
Type  IV kidney    Cysts are present at birth and produced dur-
                     ing distention of the terminal portion of
                     the S-stage nephron because of urethral
                     obstruction.

Data derived from (46) Potter EL. Cystic kidneys: age distribution
and resume of pathogenesis. In: Normal and Abnormal Development of the
Kidney. Chicago, IL: Year Book Medical Publishers, Inc; 1972:289-295.

Table 8. Kissane (116) (1966) Classification of
Congenital Malformations of the Kidney

  I. Abnormalities in amount of renal tissue
     A. Deficient definitive renal parenchyma
        a. Bilateral renal agenesis
        b. Unilateral renal agenesis
        c. Renal hypoplasia
     B. Excess renal tissue (supernumerary kidney)
 II. Anomalies of position, form and orientation
     A. Renal ectopia
        a. Simple
        b. Crossed
     B. Renal fusion
     C. Anomalies of rotation
III. Anomalies of differentiation
     A. Renal dysplasia
        a. Total
        b. Segmental
        c. Focal
        d. Associated with congenital obstruction
     B. Polycystic kidney disease
        a. Adult type
        b. Infantile type
     C. Medullary cystic disease
        a. The sponge kidney
        b. Uremic medullary cystic disease
     D. Simple renal cyst
     E. Multilocular renal cyst
     F. Miscellaneous cysts of renal origin
        a. Retroperitoneal cysts of nephric origin
        b. Dysontogenic cysts of nephric origin
           i. Renal teratodermoids
           ii. Endometrial cysts ofthe kidney
     G. Cysts in renal fossa of other nephric origin
        a. Pyelocalyceal cysts
        b. Pericalyceal lymphangiectasis
        c. Perinephric pseudocysts

Reprinted with permission from 116Kissane JM. Congenital malformation.
In: Heptinstall RH, ed. Pathology of the Kidney. 1st ed. Boston,
MA: Little, Brown & Co; 1966:63-1 17.

Table 9. The Elkin and Bernstein (117) (1969)
Classification of Renal Cystic Diseases

  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. Neoplastic-cystic degeneration of carcinoma
     C. Traumatic-intrarenal hematoma
 VI. Extraparenchymal cysts
     A. Parapelvic
     B. Perinephric

Reprinted with permission from 117Elkin M, Bernstein J. Cystic diseases
of the kidney-radiological and pathological considerations. Clin
Radiol. 1969;20(1):65-82.

Table 10. The Brisceglia, Galliani, Senger, Stallone,
and Sessa (2006) Classification of Renal Cystic
Disease-Abridged

1. Autosomal-dominant polycystic kidney disease
2. Autosomal-recessive polycystic kidney disease
3. Unilateral, localized, segmental cystic disease
4. Solitary and multiple, simple renal cysts
5. Dysplastic kidney
6. Pluricystic kidney of multiple malformation syndromes
7. Juvenile nephronophthisis and medullary cystic disease
8. Medullary sponge kidney
9. Glomerulocystic kidney disease
10. Multilocular renal cysts-cystic nephroma and congeners
11. Renal cysts in hereditary syndromes
12. Renal lymphangioma/peripelvic-peripcalyceal lymphangestasia
13. Pyelocalyceal cyst, parapelvic cyst, perinephric pseudocyst,
    lymphocele
14. Acquired renal cystic disease
15. 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):26-56.

Table 11. The Liapis and Winyard121 (2006)
Classification of Renal Cystic Disease

A. Polycystic kidney disease
   1. Autosomal-dominant polycystic kidney disease
      Classic ADPKD
      Early onset ADPKD in children
   2. Autosomal-recessive polycystic kidney disease
      Classic ARPKD in neonates and infants
      Medullary duct ectasia in older children with hepatic fibrosis
   3. Glomerulocystic kidney disease
      Familial GCKD
      Renal hypoplasia and UROM mutation
      Associated with HNFB1 mutations
      Hereditary GCKD
      Associated with ADPKD/ARPKD/TSC
      Syndromic nonhereditary GCKD
      Sporadic GCKD
      Acquired GCKD
B. Renal medullary cysts
   1. Nephronophthisis
      Nephronophthisis, autosomal recessive
      Juvenile nephronophthisis
      NPH1, NPH4
      NPH1, NPH5 associated with Senior-Loken syndrome
      Infantile NPH2
   2. Medullary cystic diseases
      Autosomal dominant MCKD
      MCKD associated with hyperuricemia
   3. Medullary sponge kidney

C. Cysts in hereditary cancer syndromes
   1. von Hippel-Lindau disease
   2. Tuberous sclerosis
D. Multilocular renal cyst
E. Localized cystic disease
F. Simple cortical cysts
G. Acquired (dialysis-induced) cysts
H. Miscellaneous
   1. Pyelocaliceal diverticula
   2. Perinephric pseudocysts
   3. Hygroma renalis

Abbreviations: ADPKD, autosomal dominant polycystic kidney disease;
ARPKD, autosomal recessive polycystic kidney disease; GCKD,
glomerulocystic kidney disease; MCKD, medullary cystic kidney
disease; NPH, nephronophthisis; TSC, tuberous sclerosis complex.

Reproduced with permission from (121) Liapis H. Winyard P. Cystic
diseases and developmental kidney defects. In: Jennette JC, Olson JL,
Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney,
6th ed. New York NY; Lippincott Williams & Wilkins; 2007.

Table 12. Bonsib (2009) Classification of Renal
Cystic Diseases and Congenital Anomalies of the
Kidney and Urinary Tract

  I. Polycystic renal diseases
     A. Autosomal-recessive polycystic kidney disease
        Classic in neonates and infants
        Childhood with hepatic fibrosis
     B. Autosomal-dominant polycystic kidney disease
        Classic adult form
        Early onset childhood form
     C. Acquired renal cystic disease
     D. Glomerulocystic kidney diseases
     A. Familial GCKD
        Renal hypoplasia and UROM mutation
        Associated with HNFB1 mutations
     B. Hereditary GCKD
        Associated with ADPKD/ARPKD/TSC
     C. Syndromic nonhereditary GCKD
     D. Sporadic GCKD
     E. Acquired GCKD
 II. Congenital anomalies of the kidney and urinary tract
     A. Renal agenesis and dysplasia
        Agenesis
        Sporadic: unilateral or bilateral
        Syndromic
        Nonsyndromic, multiple malformation syndromes
        Renal dysplasias
        Sporadic: unilateral or bilateral
        Syndromic
        Nonsyndromic, multiple malformation syndromes
        Hereditary adysplasia
     B. Renal hypoplasias
        Simple hypoplasia: unilateral or bilateral
        Oligomeganephronic hypoplasia
        Reduced nephron generations ("cortical hypoplasia")
        Reduced nephron numbers (premature and low birth
          weight risk of hypertension)
     C. Abnormalities in form, position, and number
        Rotation anomaly
        Renal ectopias
        Renal fusions
        Supernumerary kidney
        In combination with A, B, or D
     D. Ureteral and urethral abnormalities
        Ureteropelvic junction obstruction
        Ureteral duplication/bifid ureter
        Vesicoureteral reflux
        Primary megaureter
        Ureteral ectopia
        Posterior urethral valves
        In combination with A, B, or C
III. Tubulointerstitial syndromes cysts
     A. Renal tubular dysgenesis
        Autosomal recessive
        Secondary twin-twin transfusion
        ACE inhibitor
     B. Nephronophthisis: types 1-6
     C. Medullary cystic diseases:
        Type 1
        Type 2/familial juvenile hyperuricemic nephropathy
     D. Bardet-Biedel syndromes, types 1-12
 IV. Cystic neoplasms and neoplastic cysts
     A. Cystic nephroma
     B. Cystic partially differentiated nephroblastoma
     C. Mixed epithelial and stromal tumor
     D. Multilocular cystic renal cell carcinoma
     E. Tubulocystic renal cell carcinoma
     F. Von Hippel-Lindau disease
     G. Lymphangioma/hygroma renalis
  V. Miscellaneous cysts
     A. Simple cortical cysts
     B. Medullary sponge kidney
     C. Localized renal cystic disease

Abbreviations: ACE, angiotensin converting enzyme; ADPKD, autosomal
dominant polycystic kidney disease; ARPKD, autosomal recessive
polycystic kidney disease; GCKD, glomerulocystic kidney disease; TSC,
tuberous sclerosis complex.
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Author:Bonsib, Stephen M.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:7TURK
Date:Apr 1, 2010
Words:9869
Previous Article:Jay Bernstein, MD, 1927-2009.
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