The Classification of Renal Cystic Diseases and Other Congenital Malformations of the Kidney and Urinary Tract Stephen M. Bonsib, MD

● 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-

eral outline is becoming clearer. A classification approach favored by the author is presented, which incorporates many of the strengths contained in several previous classifications. Conclusions.—Genetic- and molecular-based postulates regarding the pathogenesis of the renal cystic and developmental diseases have implicated mutated master genes and the modification of genes that are crucial in renal development and genes that are central to the sensory effects of the renal tubular primary cilium on cell physiology. These scientific advances provide pathogenetic links between morphologically and genetically distinct entities and certain cystic and neoplastic entities, associations that seemed implausible not long ago. These advances may eventually provide the basis for future classification systems while suggesting targets for therapeutic approaches in the prevention and treatment of these diseases. (Arch Pathol Lab Med. 2010;134:554–568)

R

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

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).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

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 71130-3932 (e-mail: [email protected]). 554 Arch Pathol Lab Med—Vol 134, April 2010

Classification of Renal Cystic Diseases and Malformations—Bonsib

Figure 1. Composite photograph of dominant and recessive polycystic kidney disease, multicystic dysplasia, renal aplasia, and dysplasia associated with lower urinary tract obstruction.

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 Bro¨del 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 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 Virchow24 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 Danforth26 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 Arch Pathol Lab Med—Vol 134, April 2010

proliferations or inclusion of mesonephric elements in the kidney that subsequently proliferate. Bunting29 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 Bro¨del23 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. Bunting29 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 ecClassification of Renal Cystic Diseases and Malformations—Bonsib 555

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 Bowman’s 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;132:57–80). 19

tatic 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 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 Osathanondh41–46 was particularly noteworthy because it formed the basis of a classification schema known as the Potter 556 Arch Pathol Lab Med—Vol 134, April 2010

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 Malformations—Bonsib

Figure 4. G. Carl Huber’s 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):1–98). 22 Figure 5. Max Bro¨del’s 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.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 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 Arch Pathol Lab Med—Vol 134, April 2010

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 Classification of Renal Cystic Diseases and Malformations—Bonsib 557

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 enough— as most wrong theories are!’’ 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 mas558 Arch Pathol Lab Med—Vol 134, April 2010

ter 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. Classification of Renal Cystic Diseases and Malformations—Bonsib

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.

Figure 7. Complete urinary tract obstruction secondary to ureteral atresia with a severely hydronephrotic, but otherwise normal kidney.

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 ␣ signaling, hedgehog signaling, epidermal growth factor signaling, and 5-HT6 serotonin signaling. Mutation of more than 20 molecules that are localized

Table 1. CAKUT

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-

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 Med—Vol 134, April 2010

Classification of Renal Cystic Diseases and Malformations—Bonsib 559

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):1855–1871). 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.

plete and, therefore, so does a completely satisfactory classification. 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 Braunstein114 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

Ciliopathies: Molecular, Genetic, and Pathologic Features

Ciliopathy

Autosomal dominant PKD Autosomal dominant PKD Autosomal recessive PKD Meckel-Gruber syndrome Oral-facial-digital syndrome Bardet-Beidl syndrome Von Hippel–Lindau Abbreviations: PKD, polycystic kidney disease;

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.

560 Arch Pathol Lab Med—Vol 134, April 2010

Lesion

Cysts within the entire nephron Cysts within the entire nephron Collecting duct cysts Cystic dysplasia Glomerulocystic kidney disease Tubulointerstitial nephritis Clear cell cysts and cancer

Classification of Renal Cystic Diseases and Malformations—Bonsib

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;77:466–473, 474–484, 484–501, 502–509). 41–44

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 Med—Vol 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 Malformations—Bonsib 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

Renal Cystic Disease (RCD) Nomenclature and Terminology

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 ⱖ200 ␮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

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 Osathanondh41–45 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, Potter46 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 Table 4.

The Danforth26 (1888) Classification of Renal Cystic Diseases

Diathetic causes Congenital causes Mechanical obstruction, consequent upon disease of the pelvic organs Traumatic causes Pathogenic cysts 562 Arch Pathol Lab Med—Vol 134, April 2010

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

Table 5. The White and Braunstein114 (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):17–27. Copyright Elsevier 1954. Classification of Renal Cystic Diseases and Malformations—Bonsib

Table 6. The Staubutz, Jewett, and Pletman115 (1963) Classification of Pediatric Cystic Diseases

Table 8. Kissane116 (1966) Classification of Congenital Malformations of the Kidney

Group 1: Congenital polycystic kidney disease In the newborn In the adult Group 2: Congenital polycystic kidney in infants and children 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.

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 of the 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; 1966:63–117.

relevant, were formulated by Kissane,116 in 1966, in the first edition of Heptinstall’s Pathology of the Kidney and by Elkin and Bernstein118 in 1969 (Tables 8 and 9). Both the Kissane116 and the Elkin and Bernstein118 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. Kissane116 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 al113 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 al113 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

Table 7.

The Potter46 (1964) Classification of Renal Cystic Diseases of the Newborn

Type I kidney

Enlargement of the cortical- and medullarycollecting 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 producing 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 during distention of the terminal portion of the S-stage nephron because of urethral obstruction. Data derived from 46Potter EL. Cystic kidneys: age distribution and re´sume´ of pathogenesis. In: Normal and Abnormal Development of the Kidney. Chicago, IL: Year Book Medical Publishers, Inc; 1972:289–295. Arch Pathol Lab Med—Vol 134, April 2010

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 colleagues118–120 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 diseasClassification of Renal Cystic Diseases and Malformations—Bonsib 563

Table 9. The Elkin and Bernstein117 (1969) Classification of Renal Cystic Diseases

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

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.

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 121Liapis 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.

es,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 Table 10. The Brisceglia, Galliani, Senger, Stallone, and Sessa (2006) Classification of Renal Cystic Disease—Abridged 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Autosomal-dominant polycystic kidney disease Autosomal-recessive polycystic kidney disease Unilateral, localized, segmental cystic disease Solitary and multiple, simple renal cysts Dysplastic kidney Pluricystic kidney of multiple malformation syndromes Juvenile nephronophthisis and medullary cystic disease Medullary sponge kidney Glomerulocystic kidney disease Multilocular renal cysts—cystic nephroma and congeners Renal cysts in hereditary syndromes 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. 564 Arch Pathol Lab Med—Vol 134, April 2010

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 Winyard121) 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 al113 and Liapis and Winyard,121 into 4 major categories, with a fifth miscellaneous category that could include other rare enClassification of Renal Cystic Diseases and Malformations—Bonsib

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 Arch Pathol Lab Med—Vol 134, April 2010

Table 12.

Continued

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.

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 Malformations—Bonsib 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 References 1. Lewis MA, Shaw J. Report from the paediatric renal registry. In: Ansell D, Feest T, ed. The UK Renal Registry: The Fifth Annual Report. Bristol, England: The Renal Association; 2002:253–273. 2. Potter EL. Normal and Abnormal Development of the Kidney. Chicago, IL: Year Book Medical Publishers, Inc; 1972. 3. Guay-Woodford LM, Sedor JR. Developmental disorders of the kidney and urinary tract. Nephrol Self Assess Program. 2007;6:27–31. 4. Guay-Woodford LM, Torres VE. Congenital malformations of the urinary tract. Nephrol Self Assess Program. 2005;4:170–175. 5. Torres VE, Scheinman S. Congenital malformations of the kidney and urinary tract. Nephrol Self Assess Program. 2004;3:8–11. 6. Woolf AS, Price KL, Scambler PJ, Winyard PJD. Evolving concepts in human renal dysplasia. J Am Soc Nephrol. 2004;15(4):998–1007. 7. Murer L, Benetti E, Artifoni L. Embryology and genetics of primary vesicoureteral reflux and associated renal dysplasia. Pediatr Nephrol. 2007;22(6):788– 797. 8. Kanwar YS, Carone FA, Kumar A, Wada J, Ota K, Wallner EI. Role of extracellular matrix, growth factors and proto-oncogenes in metanephric development. Kidney Int. 1997;52(3):589–606. 9. Pope JC IV, Brock JW III, Adams MC, Stephens FD, Ichikawa I. How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol. 1999;10(9):2018–2028. 10. Ichikawa I, Kuwayama F, Pope JC IV, Stephens FD, Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int. 2002;61(3):889–898. 11. Woolf AS, Winyard PJD. Advances in the cell biology and genetics of human kidney malformations. J Am Soc Nephrol. 1998;9(6):1114–1125.

566 Arch Pathol Lab Med—Vol 134, April 2010

12. Winyard P, Chitty L. Dysplastic and polycystic kidneys: diagnosis, associations and management. Prenat Diagn. 2001;21(11):924–935. 13. Ingelfinger JR. Disparities in renal endowment: causes and consequences. Adv Chronic Kidney Dis. 2008;15(2):107–114. 14. Hoy WE, Bertram JF, Denton RD, Zimanyi M, Samuel T, Hughson MD. Nephron number, glomerular volume, renal disease and hypertension. Curr Opin Nephrol Hyperten. 2008;17(3):258–265. 15. Houghson MD, Douglas-Denton R, Bertram JF, Hoy WE. Hypertension, glomerular volume, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int. 2006;69(4):671–678. 16. Bonsib SM. Non-neoplastic diseases of the kidney. In: Bostwich DG and Cheng L, eds. Urologic Surgical Pathology. 2nd ed. St. Louis, MO: Mosby; 2008: 1–81. 17. Clark K, Pedretti C. The Drawings of Leonardo da Vinci in the Collection of Her Majesty the Queen at Windsor Castle. Vol 1–3. London, England: Phaidon Press Limited; 1968. 18. Murphy LJT, ed. The History of Urology. Springfield, IL: Charles C Thomas; 1972. 19. 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;132:57–80. 20. Fine LG. William Bowman’s description of the glomerulus. Am J Nephrol. 1985;5(6):433–440. 21. Hayman JM Jr. Malpighi’s ‘‘concerning the structure of the kidneys’’: a translation and introduction. Ann Med Hist. 1925;7(2):242–263. 22. Huber GC. On the development and shape of uriniferous tubules of certain of the higher mammals. Am J Anat. 1905;4(4 suppl):1–98. 23. 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. 24. Virchow R. Ueber hydrops renum cysticus congenitus. Virchow Arch Pathol Anat Physiol Klin Med. 1869;46(4):506–511. 25. Rokitansky C. A Manual of Pathological Anatomy. Vol 1. Swaine AE, Sieveking E, Moore CH, Day GE, trans. Philadelphia, PA: Blanchard & Lea; 1855. 26. Danforth IN. The evolution of the cystic kidney. JAMA. 1888;11(16):541– 545. 27. Sturm P. Ueber das adenom der niere und u¨ber die beziehung desselben zu einigen andern neubildungen der niere. Arch Heilk. 1875;16:193–197. 28. Brigidi DV, Severi A. Contributo alla patogenesi della cisti renali. Sperimentale. 1880;46:1–9. 29. Bunting CH. Congenital cystic kidney and liver with family tendency. J Exp Med. 1906;8(2):271–288. 30. Kupffer C. Untersuchungen u¨ber die entwicklung des harn- und geschlechtssystems. Arch Mikrobiol Anat. 186;51:233–239. 31. Kampmeier OF. A hitherto unrecognized mode of origin of congenital renal cysts. Surg Gynecol Obstet. 1923;36:208–216. 32. Kampmeier OF. The metanephros or so-called permanent kidney in part provisional and vestigial. Anat Rec. 1926;33(2):115–120. 33. McKenna CM, Kampmeier OF. A consideration of the polycystic kidney. Trans Am Assoc Genitourin Surg. 1933;26:377–383. 34. Lambert PP. Polycystic disease of the kidney: a review. Arch Pathol. 1947; 44:34. 35. Bialestock D. The morphogenesis of renal cysts in the stillborn studied by micro-dissection technique. J Pathol Bacteriol. 1956;71(1):51–59. 36. Baxter TJ. Cysts arising in the renal corpuscle: a microdissection study. Arch Dis Child. 1965;40(213):455–463. 37. Osathanondh V, Potter EL. Development of the human kidney as shown by microdissection, II: renal pelvis, calyces and papillae. Arch Pathol. 1963;76: 276–289. 38. Osathanondh V, Potter EL. Development of the human kidney as shown by microdissection, III: formation and interrelationship of collecting tubules and nephrons. Arch Pathol. 1963;76:290–302. 39. Osathanondh V, Potter EL. Development of the human kidney as shown by microdissection, IV: development of tubular portions of nephrons. Arch Pathol. 1966;82(5):391–402. 40. Osathanondh V, Potter EL. Development of the human kidney as shown by microdissection, V: development of vascular pattern of glomeruli. Arch Pathol. 1966;82(5):403–411. 41. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys type 1 due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol. 1964;77: 466–473. 42. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys type 2 due to inhibition of ampullary activity. Arch Pathol. 1964;77:474–484. 43. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys type 3 due to multiple abnormalities of development. Arch Pathol. 1964;77:484–501. 44. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys type 4 due to urethral obstruction. Arch Pathol. 1964;77:502–509. 45. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys: historical survey. Arch Pathol. 1964;77:459–465. 46. Potter EL. Cystic kidneys: age distribution and re´sume´ of pathogenesis. In: Normal and Abnormal Development of the Kidney. Chicago, IL: Year Book Medical Publishers, Inc; 1972:289–295. 47. Bernstein J. The morphogenesis of renal parenchymal maldevelopment (renal dysplasia). Pediatr Clin North Am. 1971;18(2):395–407.

Classification of Renal Cystic Diseases and Malformations—Bonsib

48. Bernstein J. Developmental abnormalities of the renal parenchyma—renal hypoplasia and dysplasia. Pathol Annu. 1968;2:213–247. 49. Taxy JB. Renal dysplasia: a review. Pathol Annu. 1985;2(pt 2):139–159. 50. Beck AD. The effect of intra-uterine urinary obstruction upon the development of the fetal kidney. J Urol. 1971;105(6):784–788. 51. Berman DJ, Maizels M. The role of urinary obstruction in the genesis of renal dysplasia: a model in the chick embryo. J Urol. 1982;128(5):1091–1096. 52. Fetterman GH, Ravitch MM, Herman FE. Cystic changes in fetal kidneys following ureteral ligation: studies by microdissection. Kidney Int. 1974;5(2):111– 118. 53. McVary KT, Maizels M. Urinary obstruction reduces glomerulogenesis in the developing kidney: a model in the rabbit. J Urol. 1989;142(2, pt 2):646–651. 54. Peters CA, Carr MC, Lais A, Retik AB, Mandell J. The response of the fetal kidney to obstruction. J Urol. 1992;148(2, pt 2):503–509. 55. Pringle KC, Bonsib SM. Development of fetal lamb lung and kidney in obstructive uropathy: a preliminary report. Fetal Ther. 1988;3(1–2):118–128. 56. Bonsib SM. Fetal obstructive uropathy without renal dysplasia: a study of the renal findings in 13 cases presenting with megacystis. J Urol. 1998;160(6, pt 1):2166–2170. 57. Daı¨kha-Dahmane F, Dommesmrgues M, Muller F, et al. Development of human kidney in obstructive uropathy: correlations with ultrasonography and urine biochemistry. Kidney Int. 1997;52(1):21–32. 58. Bonsib SM, Koontz P. Renal maldevelopment: a pediatric renal biopsy study. Mod Pathol. 1997;10(12):1233–1238. 59. Kirillova IA, Kulazhenko VP, Kulazhenko LG, Novikova IV. Cystic kidney in an 8-week embryo. Acta Anat (Basel). 1982;114(1):68–73. 60. Matsell DG, Bennett T, Goodyer P, Goodyer C, Han VK. The pathogenesis of multicystic dysplastic kidney disease: insights from the study of fetal kidneys. Lab Invest. 1996;74(5):883–893. 61. Zerres K, Vo¨lpel MC, Weiss H. Cystic kidneys: genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum Genet. 1984;68(2):104–135. 62. Matsell DG. Renal dysplasia: new approaches to an old problem. Am J Kidney Dis. 1998;32(4):535–543. 63. Orellana SA, Avner ED. Cystic maldevelopment of the kidney. Semin Nephrol. 1995;15(4):341–352. 64. Kravtzova GI, Lazjuk GI, Lurie IW. The malformations of the urinary system in autosomal disorders. Virchows Arch A Path Anat and Histol. 1975;368(2):167– 178. 65. Becker N, Avner ED. Congenital nephropathies and uropathies. Pediatr Clin North Am. 1995;42(6):1319–1341. 66. Brenner BM. Determinants of epithelial differentiation during early nephrogenesis. J Am Soc Nephrol. 1990;1(2):127–139. 67. Wells HG. The Time Machine. London, England: William Heinemann; 1895. Serialized in: New Rev. 1894–1895. 68. Bellanne´-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1␤ mutations. Ann Intern Med. 2004; 140(7):510–517. 69. Edghill EL, Bingham C, Ellard S, Hattersley AT. Mutations in hepatocyte nuclear factor-1␤ and their related phenotypes. J Med Genet. 2006;43(1):84–90. 70. Ulinski T, Lescure S, Beaufils S, et al. Renal phenotypes related to hepatocyte nuclear factor-1␤ (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol. 2006;17(2):497–503. 71. Bingham C, Bulman MP, Ellard S, et al. Mutations in the hepatocyte nuclear factor-1␤ gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet. 2001;68(1):219–224. 72. Decramer S, Parant O, Beaufils S, et al. Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys. J Am Soc Nephrol. 2007;18(3):923–933. 73. Bingham C, Ellard S, Allen L, et al. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1␤. Kidney Int. 2000;57(3):898–907. 74. Weber S, Moriniere V, Knu¨ppel T, et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol. 2006;17(10):2864–2870. 75. Woolf AS. Renal hypoplasia and dysplasia: starting to put the puzzle together. J Am Soc Nephrol. 2006;17(10):2647–2649. 76. Fletcher J, Hu M, Berman Y, et al. Multicystic dysplastic kidney and variable phenotype in a family with a novel deletion mutation of PAX2. J Am Soc Nephrol. 2005;16(9):2754–2761. 77. Sanyanusin P, McNoe LA, Sullivan MJ, et al. Mutation of PAX2 in two siblings with renal-coloboma syndrome. Hum Mol Genet. 1995;4(11):2183– 2184. 78. Dressler GR. Transcription factors in renal development: the WT1 and Pax2 story. Semin Nephrol. 1995;15(4):263–271. 79. Cheong HI, Cho HY, Kim JH, Yu YS, Ha IS, Choi Y. A clinico-genetic study of renal coloboma syndrome in children. Pediatr Nephrol. 2007;22(9):1283– 1289. 80. Dziarmaga A, Quinlan J, Goodyer P. Renal hypoplasia: lessons from Pax2. Pediatr Nephrol. 2006;21(1):26–31. 81. Salomon R, Tellier AL, Attie-Bitach T, et al. PAX2 mutations in oligomeganephronia. Kidney Int. 2001;59(2):457–462. 82. Eccles MR, Schimmenti LA. Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations. Clin Genet. 1999;56(1):1–9. 83. Quinlan J, Lemire M, Hudson T, et al. A common variant of the PAX2 gene

Arch Pathol Lab Med—Vol 134, April 2010

is associated with reduced newborn kidney size. J Am Soc Nephrol. 2007;18(6): 1915–1921. 84. Pohl M, Bhatnagar V, Mendoza SA, Nigam SK. Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney Int. 2002;61(1):10–19. 85. McMahon AP, Aronow BJ, Davidson DR, et al. GUDMAP: the genitourinary developmental molecular anatomy project. J Am Soc Nephrol. 2008;19(4): 667–671. 86. Williams G, Fletcher JT, Alexander SI, Craig JC. Vesicoureteral reflux. J Am Soc Nephrol. 2008;19(5):847–862. 87. Murawski IJ, Gupta IR. Vesicoureteric reflux and renal malformations: a developmental problem. Clin Genet. 2006;69(2):105–117. 88. Jain S, Suarez AA, McGuire J, Liapis H. Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease. Pediatr Nephrol. 2007;22(7):962–974. 89. Scho¨nfelder EM, Knu¨ppel T, Tasic V, et al. Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans. Am J Kidney Dis. 2006;47(6): 1004–1012. 90. Jenkins D, Bitner-Glindzicz M, Malcolm S, et al. De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure. J Am Soc Nephrol. 2005;16(7):2141–2149. 91. Kumar S. Mechanism of injury in uromodulin-associated kidney disease. J Am Soc Nephrol. 2007;18(1):10–12. 92. Schumacher K, Strehl R, De Vries U, Groene HJ, Minuth WW. SBA-positive fibers between the CD ampulla, mesenchyme, and renal capsule. J Am Soc Nephrol. 2002;13(10):2446–2453. 93. Ko¨mhoff M, Wang JL, Cheng HF, et al. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int. 2000; 57(2):414–422. 94. Hildebrandt F, Strahm B, Nothwang H-G, et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. Kidney Int. 1997;51(1):261–269. 95. Orman H, Fernandez C, Jung M, et al. Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet. 2000;66(1):118–127. 96. Christodoulou K, Tsingis M, Stavrou C, et al. Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease (ADMCKD). Hum Mol Genet. 1998;7(5):905–911. 97. Scolari F, Puzzer D, Amoroso A, et al. Identification of a new locus for medullary cystic disease on chromosome 16p12. Am J Hum Genet. 1999;64(6): 1655–1660. 98. Torra R, Badenas C, Darnell A, et al. Facilitated diagnosis of the contiguous gene syndrome: tuberous sclerosis and polycystic kidneys by means of haplotype studies. Am J Kidney Dis. 1998;31(6):1038–1043. 99. Martignoni G, Bonetti F, Pea M, Tardanico R, Brunelli M, Eble JN. Renal disease in adults with TSC2/PKD1 contiguous gene syndrome. Am J Surg Pathol. 2002;26(2):198–205. 100. Bingham C, Bulman MP, Ellard S, et al. Mutations in the hepatocyte nuclear factor-1␤ gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet. 2001;68(1):219–224. 101. Pohl M, Bhatnagar V, Mendoza SA, Nigam SK. Towards an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney Int. 2002;61(1):10–19. 102. Guay-Woodford LM. Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome complex. Pediatr Nephrol. 2006;21(10):1369–1376. 103. Benzing T, Walz G. Cilium-generated signaling: a cellular GPS? Curr Opin Nephrol-Hypertens. 2006;15(3):245–249. 104. Marshall WF, Nonaka S. Cilia: turning in to the cell’s antenna. Curr Biol. 2006;16(15):R604–R614. 105. Torres VE, Harris PC. Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol. 2006;2(1):40–55. 106. Singla V, Reiter JF. The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science. 2006;313(5787):629–633. 107. Schermer B, Ghenoiu C, Bartram M, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol. 2006;175(4):547–554. 108. Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol. 2007;18(6):1855–1871. 109. Tobin JL, Beales PL. Bardet-Biedl syndrome: beyond the cilium. Pediatr Nephrol. 2007;22(7):926–936. 110. Oliver J. The von Hippel-Lindau protein controls ciliogenesis. Kidney Int. 2007;71:382–383. 111. Gardner KD Jr. Cystic kidneys. Kidney Int. 1988;33:610–621. 112. Glassberg KI, Stephens FD, Lebowitz RL, et al. Renal dysgenesis and cystic disease of the kidney: a report of the Committee on Terminology, Nomenclature, and Classification, Section on Urology. J Urol. 1987;138(4, pt 2):1085– 1092. 113. Brisceglia M, Galliani CA, Senger C, Stallone C, Sessa A. Renal cystic disease: a review. Adv Anat Pathol. 2006;13(1):26–56. 114. White EW, Braunstein L. Renal cystic disease. J Urol. 1954;71(1):17–27. 115. Staubitz WJ, Jewett TC Jr, Pletman RJ. Renal cystic disease in childhood. J Urol. 1963;90:8–12. 116. Kissane JM. Congenital malformation. In: Heptinstall RH, ed. Pathology of the Kidney. 1st ed. Boston, MA: Little, Brown & Co; 1966:63–117.

Classification of Renal Cystic Diseases and Malformations—Bonsib 567

117. Elkin M, Bernstein J. Cystic diseases of the kidney—radiological and pathological considerations. Clin Radiol. 1969;20(1):65–82. 118. Bernstein J. Hereditary renal disease. In: Churg J, Spargo B, Mostofi FK, Abell MR, eds. Kidney Disease: Present Status. Baltimore, MD: Williams & Wilkins Co; 1979:295–326. Information Age Publishing (IAP); Monograph 20. 119. Bernstein J. Landing BH: Glomerulocystic kidney diseases. In: Bartsocas CS, ed. Genetics of Kidney Disorders. New York, NY: Alan R Liss Inc; 1989:27– 43.

568 Arch Pathol Lab Med—Vol 134, April 2010

120. Bernstein J. Glomerulocystic kidney disease—nosological considerations. Pediatr Nephrol. 1993;7(4):464–470. 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. Philadelphia, PA; Lippincott Williams & Wilkins; 2007:1257–1306. 122. Vesalius A. Organs of Nutrition and Generation. Marburg, Germany: Johannes Oporinus, printer; 1541. De humani corporis fabrica and libri septum [On the fabric of the human body]; book 5.

Classification of Renal Cystic Diseases and Malformations—Bonsib