klasifikasi renal cyst disease

554 Arch Pathol Lab MedVol 134, April 2010 Classification of Renal Cystic Diseases and MalformationsBonsib

The Classification of Renal Cystic Diseases and OtherCongenital Malformations of the Kidney and

Urinary TractStephen M. Bonsib, MD

Context.Renal cystic diseases and congenital abnor-malities of the kidney and urinary tract comprise a hetero-geneous group of lesions whose pathogenesis has eludedphysicians for centuries. Recent advances in molecular andgenetic understanding of these diseases may provide thesolution to this riddle.

Objective.The formulation of an effective classifica-tion system for these disorders has been elusive but isneeded to introduce order while providing a conceptualframework for diagnosis.

Data sources.This review discusses the evolution, be-ginning in the 19th century, of postulates regarding thepathogenesis of cystic and developmental renal diseases.Selected classification systems proffered during this periodare discussed in pursuit of an ideal classification schemathat would account for morphologic features and theirclinical importance, with logical links to pathogenesis andtreatment. Although this remains an elusive target, its gen-

eral outline is becoming clearer. A classification approachfavored by the author is presented, which incorporatesmany of the strengths contained in several previous clas-sifications.

Conclusions.Genetic- and molecular-based postulatesregarding the pathogenesis of the renal cystic and devel-opmental diseases have implicated mutated master genesand the modification of genes that are crucial in renal de-velopment and genes that are central to the sensory effectsof the renal tubular primary cilium on cell physiology.These scientific advances provide pathogenetic links be-tween morphologically and genetically distinct entities andcertain cystic and neoplastic entities, associations thatseemed implausible not long ago. These advances mayeventually provide the basis for future classification sys-tems while suggesting targets for therapeutic approachesin the prevention and treatment of these diseases.

(Arch Pathol Lab Med. 2010;134:554568)

Renal cystic diseases (RCDs) and congenital abnormal-ities of the kidney and urinary tract (CAKUT) com-prise a group of metanephric and ampullary bud misad-ventures and acquired lesions that have captured the in-terest and challenged the imagination of physicians forcenturies. There are several reasons for this medical infat-uation, including the frequency of these disorders (abnor-malities in urinary tract development occur in approxi-mately 10% of the population); their astonishing variety,which results in an impressive menu of gross abnormali-ties; and most important, their clinical importance (Figure1).112 Although most patients with some of the more com-mon forms of maldevelopment, such as bifid ureter andhorseshoe kidney, may have few significant complications,collectively, RCD/CAKUT represent the most common

Accepted for publication February 26, 2009.From the Department of Pathology, Louisiana State University Health

Sciences Center, Shreveport.The author has no relevant financial interest in the products or com-

panies described in this article.Presented in part at the 4th Annual Renal Pathology Society/Kidney

and Urology Foundation of America satellite meeting held in associa-tion with the 21st European Congress of Pathology, Istanbul, Turkey,September 13, 2007.

Reprints: Stephen M. Bonsib, MD, Department of Pathology, LSUHealth Sciences Center, 1541 Kings Hwy, Shreveport, LA 71130-3932(e-mail: [email protected]).

cause of end-stage renal disease in children, accountingfor 40% to 50% of cases, and includes autosomal dominantpolycystic kidney disease, the most common type of RCDand the fourth leading cause of end-stage renal disease inadults.15 Furthermore, renal hypoplasia in the form of in-sufficient nephron endowment has been implicated in asubstantial fraction of individuals with essential hyper-tension.1315

The formulation of an effective classification system forRCD/CAKUT has been an elusive goal driven by the needto introduce order into this complex arena, and thereby,provide a conceptual framework as attempts to unravel itspathogenesis were pursued. Long before abnormalities ofthe kidney could be defined, however, was the challengeof defining the anatomic features and function of the nor-mal kidney and urinary tract so that deviations from thisblueprint could be recognized. Some of the first and mostprimitive assumptions of urinary tract structure and func-tion were proffered a millennia ago, when Aristotle taughtthat urine was formed by the bladder and that kidneyswere present not of actual necessity, but as matters ofgreater finish and perfection. 16

Details of the normal gross renal and lower urinarytract (LUT) anatomy were first unveiled in the 16th cen-tury by Leonardo de Vinci and Vesalius, who generateddrawings of the female and male genitourinary tracts,thus laying the foundation for the modern day disciplines

Arch Pathol Lab MedVol 134, April 2010 Classification of Renal Cystic Diseases and MalformationsBonsib 555

Figure 1. Composite photograph of domi-nant and recessive polycystic kidney disease,multicystic dysplasia, renal aplasia, and dys-plasia associated with lower urinary tract ob-struction.

of nephrology, urology, and nephropathology (Figure2).1618 Centuries later, the invention of the first micro-scopes by Hans and Zacharias Janssen in the 1590s al-lowed the 17th century masters of microscopic anatomy,such as William Bowman and Marcello Malpighi, toglimpse the complexity of the renal microscopic anatomy(Figure 3).1921 Later, Huber and Brodel in the early 20thcentury illustrated, in meticulous 3-dimensional serial re-constructions and captured in elegant drawings, respec-tively, its embryologic basis (Figures 4 and 5).22,23

THEORIES ON PATHOGENESIS OF RCD/CAKUT

Historically, the authors of most classifications used pre-vailing concepts of pathogenesis to frame classificationsystems. If this is a prerequisite for a useful classificationscheme, then it would appear that the ideal classificationmust await a thorough understanding of RCD/CAKUTpathogenesis, an elusive goal, but one in which muchprogress has occurred in the past decade. Interestingly,some of the earliest theories of pathogenesis appearingduring the 19th century are similar to those that persistedthroughout most of the 20th century.

Two of the earliest reported theories on renal cystogen-esis were those of Virchow24 and of Rokitanky.25 Virchow,24in 1869, proposed that obstruction by uric acid crystals orpapillary duct atresia was operative in the pathogenesisof renal cysts. Conversely, Rokitansky,25 in his 1885 textManual of Pathological Anatomy, indicated that the consen-sus among German pathologists was that renal cystsformed within the malpighian corpuscle when tumifiedand gorged with the inflammatory product of these dis-eases upon the surrounding strata. An obstructive etiol-ogy was also favored by Danforth26 who wrote in 1888that the evolution of cysts involved the unrolling or un-folding of the renal structure as it slowly yields to thepressure of the fluid accumulating in the cysts. The no-tion that renal cysts were neoplastic surfaced as early asthe late 1800s when Sturm,27 in 1875, and Brigidi and Sev-eri,28 in 1880, argued that cysts resulted from epithelial

proliferations or inclusion of mesonephric elements in thekidney that subsequently proliferate.

Bunting29 summarized in detail, in a 1906 publication,the prevailing theories on cystogenesis. The postulates invogue included tubular obstruction attributable to externalcompression of tubules by infection-related fibrosis, con-genital maldevelopment or a neoplasm related to abnor-mal cell growth, and finally, nonunion of primitive col-lecting ducts and secretory tubules. The latter postulatefollowed the delineation by Kupffer,30 Huber,22 and Bro-del23 of the dual role of the ampullary bud and renal blas-tema in renal nephrogenesis. In the 1920s to 1930s, afterthe dual origin of ampullary bud and nephrogenic blas-tema in nephrogenesis was more widely recognized, cystformation, resulting from failure of the 2 tissues to unite,emerged as the most popular theory.

Bunting,29 in his review of cytogenesis, made the in-sightful comment that his 2 cases of cystic kidney diseasediffered morphologically and clinically from many previ-ous reportedly cases. Bunting29 noted that the attemptsto explain pathogenesis of the congenital cystic kidneyhave been so numerous and so varied that one is inclinedto question whether pathologists have been dealingthroughout with a single pathological process. Becausethe personal experience of these early investigators waslimited to small numbers of cases, with no individual hav-ing access to the full spectrum of RCD/CAKUT diseases,his concerns were appropriately insightful. Regardless,even if these early investigators were fortunate enough tohave exposure to the complete palate of RCD/CAKUTpossibilities, they would not have been able to solve thepuzzle of pathogenesis, which required advances in sci-entific knowledge and technology only recently achieved.

Kampmeier,31 in 1923, published beautifully illustrated,histologic pictures of fetal kidney in early gestation andnoted the common occurrence of occasional ectatic (cystic)tubules as a normal event in embryogenesis. This led himto offer one of the earliest insights into the possibility ofa molecular basis for many RCDs. He suggested that ec-


Figure 2. Genitourinary tract, a diagram by Andreas Vesalius, published in 1541 (Organs of Nutrition and Generation. Marburg, Germany:Johannes Oporinus, printer. De humani corporis fabrica and libri septum [On the fabric of the human body]; book 5).122

Figure 3. William Bowmans 1842 illustration of the vascular supply to glomeruli, based on a dye injection study (from Bowman W. On thestructure and use of the malpighian bodies of the kidney, with observations on the circulation through that gland. Philos Trans R Soc Lond Biol.1842;132:5780).19

tatic abnormal tubules could possibly persist and enlargeto form the grossly visible, simple renal cysts of adults.He further postulated that factors control the degenera-tion or suppression of abnormal growth, in effect, impli-cating master genes that regulate and orchestrate normalembryogenesis or that fail to do so in abnormal embryo-genesis. He further noted that these factors could alsoexplain coexistent lesions in other organ whose embryo-genesis was similarly dysregulated.3133

Anatomic investigations into the site of cyst formationwithin the nephron emerged in the mid-20th century, con-tributing further to our understanding of cystic diseases.Lambert,34 in 1947, employed serial section reconstruc-tions of cystic kidneys from 6 adults and 2 children andshowed that cystic dilations could develop in any segmentof the nephron. In the 1950s and 1960s, Potter and Osa-thanondh and others,3544 using the newly developed tech-nique of microdissection, studied normal and congenitallycystic kidneys. The exhaustive work Potter and Osatha-nondh4146 was particularly noteworthy because it formedthe basis of a classification schema known as the Potter

Classification, which was predicated on the anatomic dis-tribution of cysts within the nephron.

In the mid to late 1900s, the obstructive theory of path-ogenesis for renal dysplasia was popularized. Bern-stein47,48 noted that more than 90% of dysplastic kidneysare associated with urinary tract abnormalities that areinvariably obstructive. The renal lesions seem to parallelthe LUT abnormality, whether unilateral versus bilateralor segmental in a duplex kidney, and that the severity alsoappears proportional (Figure 6, A and B). Bernstein47,48 ac-knowledged, however, that not all dysplastic kidneys areassociated with obstruction because the many familialmultiple malformation syndromes argue for a genetic eti-ology. Appreciation that these disorders can affect severalmembers of the same family implicated genetic causation.

Experimental studies, intended to implicate obstructiveetiologies in metanephric dysgenesis, were initiated in the1970s to 1990s. Extreme experimental maneuvers wereemployed, where not only LUT obstruction, urethral orureteral obstruction was induced early in embryogenesisbut also unilateral nephrectomy was sometimes per-


Figure 4. G. Carl Hubers 1905 illustration of his wax model serial reconstructions of nephron differentiation (from Huber GC. On the developmentand shape of uriniferous tubules of certain of the higher mammals. Am J Anat. 1905;4(4)(suppl):198).22

Figure 5. Max Brodels 1907 illustration of the sequence of nephron induction (from Kelly HA, Burnan CF. Diseases of Kidneys, Ureter, andBladder: With Special Reference to the Diseases in Woman. vol 2. New York, NY: D Appleton and Company; 1914).23

formed to further stress to the remaining, developing kid-ney.4953 In most species examined, including pigs, chick-ens, and rabbits, investigators failed to induce changestypical of cystic dysplasia, instead severe hydronephrosiswas mostly observed.4953 However, in the fetal lamb mod-el, convincing cystic dysplasia was produced in some an-imals, although others developed only severe hydrone-phrosis.54,55

Experiments of nature indicate that obstruction andmetanephric maldevelopment are not inevitably linked be-cause a neonate can be born with complete LUT obstruc-tion and resultant massive hydroureteronephrosis, yetnephrogenesis can be preserved (Figure 7).5658 Anotherargument against simplistic anatomic causation is the il-logic of implicating sequential injury, obstruction followedby metanephric dysgenesis, for a synchronous activity ofureteral and renal development. This creates a physiologicconundrum: How can a nonfunctional, disordered meta-nephric mass produce an ultrafiltrate of sufficient toxic-ity or pressure to perturb the development of subsequentnephron formation. Especially relevant to this concern arecases of cystic dysplasia identified in the first trimester.5860McKenna and Kampmeier,33 in their 1933 article entitledA Consideration of the Development of the PolycysticKidney, captured the state of understanding that existedthen, and which persisted until the end of the 20th century

when they wrote: There are many theories which beginas logical deduction, and later without foundation of ob-servation are handed down from textbook to textbook andfrom paper to paper as facts. Such is the hypothesis of theorigin of cystic kidney. 3 Bernstein elaborated further, in1968, about the challenge investigators faced in this fieldwhen he wrote: A classification in a strict taxonomicsense cannot be devised because pathogenesis remainsunknown and because considerable overlap exists bothclinically and morphologically. 46

Although by the latter decades of the 20th century, theetiology or etiologies for RCD/CAKUT remained un-known, implication of an anatomic causation, especiallyurinary tract obstruction in severe metanephric maldevel-opment, remained popular because of the ubiquitous as-sociation. Knowledge of the embryologic development ofthe kidney would appear to provide a logical basis forexplaining departures from normal renal developmentand was especially popular for many CAKUT lesions.However, because of the enormous diversity of malformedurinary tracts, the limitless combinations of abnormalitiesaffecting kidney and LUT, and the asymmetry of renallesions, the delayed onset of some genetic cystic diseasesin kidneys that were initially normal in form and the ac-quired nature of others cannot be easily accommodatedby any simplistic anatomic-based approach.312,6166 To


Figure 6. Two examples of bilateral dysplasia with extreme degrees of (A) ureteral atresia and (B) ureteral dilation.

quote the time traveler in H. G. Wells 67 The Time Machine ,Very simple was my explanation, and plausible enoughas most wrong theories are!

Limitation in the understanding of pathogenesis, as not-ed by Bernstein,47,48 has plagued the classification process,but has been alleviated in recent years as the molecularcontributions to RCD/CAKUT have been identified.68100The list of mutated genes expressed during renal devel-opment is rapidly growing. These genes code for a varietyof transcription and growth factors required for the reg-ulation and orchestration of interactions between the ure-teric bud and the metanephric blastema and its predeces-sors tissues, the mesonephric and pronephric ducts. Oneof the most common mutated genes in CAKUT is PAX2,a gene that serves a central role in renal development.PAX2 is one of 9 paired-box transcription factors, a masterorganizer gene expressed in the nephric duct, metanephricmesenchyme, ureteric bud, and S-shaped body.6569 PAX2performs many functions at early stages of renal devel-opment. It organizes caudal descent of the nephric ductwith PAX8 and GATA3, emergence of the ureteric bud, andinduces WT1 in metanephric blastema. PAX2 is also in-volved with branching morphogenesis and the sustainedarborization of the collecting duct. With such extensiveinvolvement in the early stages of metanephric kidney in-duction, it is easy to envision how mutations of this crucialgene, or other similarly critically located genes, could re-sult in a vast array of maldevelopment.

Table 1 lists several of the most commonly mutated mas-

ter genes, displays the various malformations observed,and reports associated clinical syndromes. It is clear thatthe renal consequences of the mutation of a single mastergene can be diverse, dependent upon the specific type ofmutation, missense, nonsense, deletion, and so forth, andthe resultant functionality of the mutated protein pro-duced. Modifying genes also influence the final phenotypeadding an additional layer of complexity. Furthermore,based on cDNA microarray analysis comparing the RNAsignature of normal and dysplastic kidneys, the expres-sion profiles of entire families of genes are affected inmany cases of RCD/CAKUT.

A second major advance in understanding RCD/CAK-UT pathogenesis has been the explosion in understandingof the molecular composition and function of the renaltubule primary cilium.101110 Cilia are eukaryotic organellesthat project from the cell surface; they can exhibit motileor sensory functions. The basic structure of nonmotile, pri-mary cilia of the renal tubular cells consists of 9 peripheralmicrotubular doublets that form the axoneme, surroundedby a lipid bilayer that is continuous with the cell mem-brane. By contrast, motile cilia of other organs have a cen-tral doublet of microtubules in addition to the 9 peripheralmicrotubular doublets, and the latter are linked by dyneinarms and other structural components. All cilia are an-chored in the cytosol by the basal body, a microtubularorganizer derived from the older of the 2 centrioles (Fig-ure 8). Assembly and maintenance of cilia is provided bya bidirectional microtubular transport system.


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

Table 1. Selected Examples of Genes in Which Mutations can Result in Various Congenital Abnormalities of the Kidneyand Urinary Tract (CAKUT) Lesions

CAKUT PAX2 TCF2 EYA1 SIX1 SALL1 GATA3

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

Abbreviations: BOR, branchial-oto-renal syndrome; GCKD, glomerulocystic kidney disease; HDR, hypoparathyroidism, deafness and renal dyspla-sia; MODY, maturity onset diabetes type 5; UPJ obst, ureteropelvic junction obstruction; VU, vesicoureteral.

The proteins of the primary cilia are ancient and havebeen highly conserved evolutionarily; in fact, some cys-toproteins have been conserved for more than 1.5 billionyears from unicellular organisms to vertebrates. Althoughprimary cilia have been recognized for decades, they hadpreviously been regarded as evolutionary vestiges. How-ever, more recently, it has been recognized that primarycilia serve important functions in cellular physiology, suchas cell cycle regulation, cell signaling, apoptosis, and ep-ithelial cell polarization. The list of signaling pathways in-fluenced by ciliary function is growing and includes plate-let-derived growth factor receptor signaling, hedgehogsignaling, epidermal growth factor signaling, and 5-HT6serotonin signaling.

Mutation of more than 20 molecules that are localized

to primary cilia, basal bodies, and centrosomes, and whichalso reside in cell adhesions, have been identified in abroad range of morphologically and clinically dissimilardisorders (Table 2). Most of the cytoproteins identified in-teract with other cystoproteins (Figure 9). Thus, mutationsof these physiologically interactive proteins provide path-ophysiologic links between RCDs previously regarded asunrelated because they differ in type of transmission, ageof onset, extrarenal manifestations, and risk of and rate ofprogression to end-stage renal disease. Mutated genes ofthe primary cilium could provide an approach to the clas-sification of at least an important subset of RCDs and,more significant, may allow targeted therapies to be de-veloped in the future.

NOMENCLATURE AND TERMINOLOGYBefore proceeding with a review of the classification

systems for RCD/CAKUT, it would be prudent to list thenomenclature and terminology employed in the remainderof this article and included in the most recent classifica-tions cited later. The RCD/CAKUT diseases are compli-cated enough without introducing communication obsta-cles. Although laxity in terminology is understandable forthe pioneers in this field, this is not acceptable today, andit risks creating confusion about important entities, withresultant inappropriate clinical responses. For purposes ofthis article, the terms used and their definitions are pro-vided in Table 3. They represent a synthesis of definitionsobtained from several reputable sources: The Committeeon Terminology, Nomenclature, and Classification, Sectionon Urology, American Academy of Pediatrics,112 and 2 ar-ticles published by individuals of stature in this field ofinvestigation.111113

CLASSIFICATION SYSTEMSAlthough there have been numerous classifications pro-

posed, those that strive to be all-inclusive employ similargeneral strategies, strategies that continue today. Prevail-ing notions of pathogenesis and obvious clinical associa-tions have been closely linked to classification strategiesfrom the beginning. Most classification systems distin-guish entities with intrinsic abnormalities, presumed toresult from developmental miscues that occurred early inthe embryologic formation of the kidney and urinary tract,placing them in a congenital category. The remaining cat-egories contain acquired lesions that affect a kidney thatpreviously developed normally. In these categories, cystformation as a consequence of external forces, injuries, andneoplastic events are often included.

One of the earliest forays into the daunting arena of theclassification of cystic kidney disease was by I. N. Dan-


Figure 8. Diagram of a primary cilium with location of cystoproteins identified (reprinted with permission from the American Society of Ne-phrology, Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol. 2007;18(6):18551871).108 PC-1, polycystin-1;PC-2, polycystin-2; OFD1, oral facial digital syndrome 1; BBS, Bardet-Biedl syndrome; BB, basal body; Cem, centriole; ER, endoplasmic reticulum;TJ, tight junction; Des, desmosome; AJ, adherens junction; FAP, focal adhesion plaque.

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

Ciliopathy Protein Inheritance Lesion

Autosomal dominant PKD Polycystin 1 AD Cysts within the entire nephronAutosomal dominant PKD Polycystin 2 AD Cysts within the entire nephronAutosomal recessive PKD Fibrocystin AR Collecting duct cystsMeckel-Gruber syndrome MKS proteins 1, 3 AR Cystic dysplasiaOral-facial-digital syndrome OFD protein X linked Glomerulocystic kidney diseaseBardet-Beidl syndrome BBS proteins 1-8 Digenic Tubulointerstitial nephritisVon HippelLindau VHL protein AR Clear cell cysts and cancer

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

forth26 and was published in 1888. The Danforth classifi-cation contained 5 categories separating congenital formsfrom those with clinical associations, such as obstruction,infection, and trauma (Table 4). Danforth26 acknowledgedthe rudimentary nature of the current understanding ofthese diseases, which handicapped formation of a satis-factory classification, at the conclusion of his article, whenhe wrote, I have to express my regret that so much re-mains to be learned about cystic disease. . . . [I] hope thatin the near future our knowledge will be more definiteand accurate. . . . Although 120 years has elapsed sincehis review, regrettably, our understanding remains incom-

plete and, therefore, so does a completely satisfactory clas-sification.

As the field of pathology evolved, and more disease en-tities were identified, classifications became lengthier butnot necessarily crafted more effectively. In 1954, Whiteand Braunstein114 formulated a classification of renal cys-tology, based on etiologic groupings not too dissimilar tomany more modern formulations (Table 5). The authorsconceded, in the first paragraph of the article, that theyfaced challenges, stating The pathogenesis and embryo-logic development of these cystic formations are quite fan-tastic and appear to the authors as a constant urological


Figure 9. A through D, the Potter and Osathanondh microdissections of congenital cystic kidneys showing the examples of their 4 types basedon cyst location (reprinted with permission from Osathanondh V, Potter EL. Arch Pathol. 1964;77:466473, 474484, 484501, 502509). 4144

imponderable and The majority of cysts still defy un-derstanding and therefore accurate grouping. 114 Whiteand Braunstein114 focused on etiologic factors, as under-stood at the time, as the common denominator for theirclassification. They were some of the first to discuss ge-netic causes because of the heredofamilial nature of thepolycystic kidney diseases, which can present at any age butare usually bilateral and are associated with lesions in oth-er organs. The authors114 also commented that the simplecortical cyst can be associated with renal neoplasms. Al-though this association is likely simply a reflection of theincreasing incidence of both lesions with age, the conceptof dysregulated growth for both cyst formation and neo-plasia in some cystic diseases now has an established sci-entific basis, although not for the simple cortical cyst.

White and Braunstein114 proclaim in their conclusionconcerning the subject of renal cystology, that embryonicorigin has been thoroughly modernized with advancedembryologic knowledge and a clearer and more compre-hensive classification has been suggested. Unfortunately,

their classification failed this claim. The pathologic fea-tures of many of the RCDs that had become clearer bythat time permitted morphologic separation of major cat-egories, such as renal dysplasias versus the hereditarypolycystic diseases. However, these authors114 lumpedthose entities into a single category: 1A polycystic disease.Conversely, other primary categories contained entitiesthat are not actually cystic diseases, such as their categoryII, obstructive; category IV, vascular; and category V, in-flammatory and infections. Inclusion of noncystic diseasesin cystic disease classifications is a persistent problem thatcontinues to plague many classification schema.

Failure to employ the known morphologic differencesthat exist between several of the major RCDs, such asdominant and recessive polycystic kidney disease and re-nal dysplasia, was prevalent in the early RCD classifica-tion literature. Another example is provided by the clas-sification of Stubitz et al.115 In their 1963 study,115 restrictedto pediatric cases, they proposed a classification that em-ployed age of onset and laterality while excluding major


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

Acquired renal cystic disease The spontaneous, idiopathic, bilateral development of multiple cysts in previously noncystic kidneysCystic kidney A kidney containing 3 or more cystsCystogen An agent capable of inducing renal cyst formation or RCDDysmorphic kidney A misshapen kidney and calyceal system; implies a congenital lesion without any histologic or etiologic

implicationsGlomerulocystic kidney Glomerular cysts as a dominant finding; glomerulocystic kidney disease is a primary disease; glomerulo-

cystic kidney is a kidney with glomerular cysts but of diverse etiologiesHeritable renal cystic disease Renal cystic disease in a kindred, in a pattern predicted by Mendelian theoryInduced renal cystic disease Renal cystic disease produced by exposure to drugs or chemicalsMedullary sponge kidney A usually sporadic, medullary cystic abnormality that is commonly diagnosed by radiologyMulticystic kidney Multiple cystic lesions, most frequently sporadic; they can be small, segmental, unilateral, or bilateralPolycystic kidney A genetically determined cystic lesion of either the autosomal-dominant form or autosomal-recessive

formRenal adysplasia Where findings of either combined renal agenesis and renal dysplasia or a hereditary syndrome occurRenal agenesis Absent kidneyRenal aplasia An extreme form of dysplasia, in which a nubbin of dysplastic kidney caps a normal or an abnormal

ureterRenal cyst An enclosed or communicating segment of nephron or duct that is dilated to a diameter of 200 molRenal cystic disease Morbidity attributable to the presence of renal cystsRenal dysgenesis Abnormal development of the kidney in size, shape, or structure; forms of renal dysgenesis include dys-

plasia, hypoplasia, aplasia, agenesis, and dysmorphismRenal dysplasia Abnormal metanephric differentiation diagnosed histologically; it can be diffuse, segmental, or focalRenal hypoplasia A small kidney or segment with less than a reference range number of nephrons; dysplastic elements are

not present

Table 4. The Danforth26 (1888) Classification ofRenal Cystic Diseases

Diathetic causesCongenital causesMechanical obstruction, consequent upon disease of the pel-

vic organsTraumatic causesPathogenic cysts

Table 5. The White and Braunstein114 (1954)Classification of Renal Cystology

I. Congenital or developmentalA. Polycystic diseaseB. Serous cystsC. Lymphatic cysts

II. ObstructiveA. DiverticulaB. ParapelvicC. Hydrocalycosis

III. NeoplasticA. CystadenomaB. CystadenocarcinomaC. AngiomaD. Dermoid

IV. VascularA. HemangiomaB. AneurysmC. EmbolismD. Infarction

V. Inflammatory and infectiousA. PyogenicB. TuberculousC. Chronic nephritis

VI. ParasiticA. EchinococcusB. TineaC. Trichina

Reprinted with permission from 114White EW, Braunstein L. Renal cysticdisease. J Urol. 1954;71(1):1727. Copyright Elsevier 1954.

secondary causes, such as infectious causes, neoplasticcauses, and chronic glomerulonephritis (Table 6). Al-though they proclaimed, There is widespread confusionamong both clinicians and pathologists concerning theclassification of cystic disease, and stated, It is only re-cently that the true etiology and significance of the uni-lateral multicystic disease and polycystic kidney may havebeen understood; they grouped obvious cases of reces-sive polycystic kidney disease and multicystic renal dys-plasias associated with LUT anomalies into congenitalpolycystic kidney diseases in the newborn.

The first influential classification of RCDs, embraced bymany for several decades, was formulated by Potter andOsanthanondh in the 1964.4145 Their classification was thefirst formulation predicated on data derived from a sys-tematic, anatomic analysis (Table 7). Potter and Osatha-nondh4145 performed a series of elegant microdissectionstudies of the normal developing kidney and on congen-itally cystic kidneys in which the entire nephron was dis-sected (Figure 9, A through D). They identified 4 patternsof cyst localization within the nephron that formed thebasis for the Potter Classification of 4 types of RCD.

Although, in subsequent years, pathologists and clini-cians attempted to place all cystic kidneys into one of the4 Potter types, Potter46 states in her book Normal and Ab-normal Development of the Kidney: The majority of cystsfound in children and infants beyond the newborn periodfall outside of the four major categories that result fromabnormalities during the formative years. Thus, theirclassification was not intended to be all-encompassing in

its application. In a practical sense, it would difficult orimpossible to know where nephron cysts reside withinany individual cystic kidney without actually performinga microdissection on each case, an impossible task. Theirclassification had an eventual lethal failinglack of clini-cal utilitybecause of the heterogeneity of some catego-ries. For instance, their type III cystic kidney combinescases of dominant polycystic kidney disease with renaldysplasias, a similar flaw afflicting previous classifica-tions.

Two classifications, both comprehensive and clinically


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

Group 1: Congenital polycystic kidney diseaseIn the newbornIn the adult

Group 2: Congenital polycystic kidney in infants and chil-dren

Group 3: Congenital unilateral multicystic kidneyGroup 4: Simple or solitary cysts

Data derived from Staubitz WJ, Jewett TC Jr, Pletman RJ. Renal cysticdisease in childhood. J Urol. 1963;90:812.

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

I. Abnormalities in amount of renal tissueA. Deficient definitive renal parenchyma

a. Bilateral renal agenesisb. Unilateral renal agenesisc. Renal hypoplasia

B. Excess renal tissue (supernumerary kidney)II. Anomalies of position, form and orientation

A. Renal ectopiaa. Simpleb. Crossed

B. Renal fusionC. Anomalies of rotation

III. Anomalies of differentiationA. Renal dysplasia

a. Totalb. Segmentalc. Focald. Associated with congenital obstruction

B. Polycystic kidney diseasea. Adult typeb. Infantile type

C. Medullary cystic diseasea. The sponge kidneyb. Uremic medullary cystic disease

D. Simple renal cystE. Multilocular renal cystF. Miscellaneous cysts of renal origin

a. Retroperitoneal cysts of nephric originb. Dysontogenic cysts of nephric origin

i. Renal teratodermoidsii. Endometrial cysts of the kidney

G. Cysts in renal fossa of other nephric origina. Pyelocalyceal cystsb. Pericalyceal lymphangiectasisc. Perinephric pseudocysts

Reprinted with permission from 116Kissane JM. Congenital malforma-tion. In: Heptinstall RH, ed. Pathology of the Kidney. 1st ed. Boston,MA: Little, Brown & Co; 1966:63117.

Table 7. The Potter46 (1964) Classification of RenalCystic Diseases of the Newborn

Type I kidney Enlargement of the cortical- and medullary-collecting ducts of both kidneys; usuallycauses death soon after birth.

Type II kidney The ampullae of the collecting ducts areprofoundly altered and incapable of pro-ducing functioning nephrons; death resultsif bilateral.

Type III kidney Cysts are located in collecting duct or anysegment of the nephron; is almost alwaysbilateral and principally affects adults.

Type IV kidney Cysts are present at birth and produced dur-ing distention of the terminal portion ofthe S-stage nephron because of urethralobstruction.

Data derived from 46Potter EL. Cystic kidneys: age distribution and re-sume of pathogenesis. In: Normal and Abnormal Development of theKidney. Chicago, IL: Year Book Medical Publishers, Inc; 1972:289295.

relevant, were formulated by Kissane,116 in 1966, in the firstedition of Heptinstalls Pathology of the Kidney and by Elkinand Bernstein118 in 1969 (Tables 8 and 9). Both the Kis-sane116 and the Elkin and Bernstein118 classification providethe basic framework employed in classification scheme oftoday. They include expanded categories of the 2 majorgenetic polycystic diseases, dominant and recessive poly-cystic kidney disease and the renal dysplasias, accom-modating the expanding spectrum of those diseases. Kis-sane116 also included other CAKUT abnormalities, such asabnormalities of position, form, and orientation, whereasElkin and Bernstein118 added categories of other geneticdisorders complicated by renal cysts, such as the trisomysyndromes and the tuberous sclerosis complex.

Another example of a comprehensive classification ofRCD/CAKUT, which is so large that it resembles more ofa tabulation of entities than a classification system, wasrecently been published by Bisceglia et al113 in their ex-cellent 2006 review of RCD (Table 10). This classificationrepresents an expansion on the strategy of Kissane116 andElkin and Bernstein,118 employing key groupings of ge-netic disorders, such as the 2 polycystic kidney diseases,and entities with similar morphologic findings, such asmetanephric dysgenesis of renal dysplasias, without mix-ing pathogenetically unrelated entities, such a medullarysponge kidney with the genetic medullary cystic diseasesand nephronophthisis

Unfortunately, the Elkin and Bernstein,118 and the Bri-sceglia et al113 formulations suffer from unnecessary ad-ditional complexity by inclusion of diseases that lack truecyst formation or maldevelopment as defined in the glos-sary of terms in Table 3. These include the Elikin and

Bernstein118 medullary necrosis, inflammatory and trau-matic categories, and cystic degeneration of carcinomas,and the Brisceglia et al113 renal tumors with cystic necrosisand some pseudocystic diseases, such as pyelocalycealcysts and lymphocele. The justification for inclusion ofnoncystic entities in a classification of cystic diseases isthat some noncystic lesions produce a space-occupying le-sion that, when imaged, elicit a cystic disease in the dif-ferential diagnosis. However, the list of truly cystic dis-eases is long enough that including noncystic and non-maldevelopment diseases clutter the process unnecessari-ly.

As evident in Kissane,116 Elkin and Bernstein,118 andBrisceglia et al113 classifications, our recognition and cat-aloguing of RCD/CAKUT lesions has evolved so thatcomprehensive classification systems are becoming daunt-ingly large. There are approaches, however, that can makethis problem more manageable. One approach is to dealmore selectively with subsets of entities as exemplified bya series of classifications published by Bernstein and col-leagues118120 through the years. These more focused clas-sifications (not shown for economy of space) are usefulwhen interest is limited to a certain key pathologic vari-ables or clinical aspects. Examples would include their1968 classification of renal hypoplasias and dysplasias,48their 1989 classification of glomerulocystic kidney diseas-


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

I. Renal dysplasiaA. Multicystic kidneyB. Focal and segmental cystic dysplasiaC. Multiple cysts associated with lower urinary tract ob-

structionII. Polycystic kidney disease

A. Infantile polycystic disease1. Polycystic disease of the newborn2. Polycystic disease of childhood

a. Congenital hepatic fibrosisb. Medullary tubular ectasia

B. Adult polycystic diseaseIII. Cortical cysts

A. Trisomy syndromesB. Tuberous sclerosis complexC. Simple cysts

a. Solitaryb. Multiple

IV. Medullary cystsA. Medullary spongeB. Medullary cystic diseasesC. Medullary necrosisD. Pyelogenic cyst

V. Miscellaneous intrarenal cystsA. Inflammatory

a. Tuberculosisb. Calculus diseasec. Echinococcus disease

B. Neoplasticcystic degeneration of carcinomaC. Traumaticintrarenal hematoma

VI. Extraparenchymal cystsA. ParapelvicB. Perinephric

Reprinted with permission from 117Elkin M, Bernstein J. Cystic diseasesof the kidneyradiological and pathological considerations. Clin Ra-diol. 1969;20(1):6582.

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

A. Polycystic kidney disease1. Autosomal-dominant polycystic kidney disease

Classic ADPKDEarly onset ADPKD in children

2. Autosomal-recessive polycystic kidney diseaseClassic ARPKD in neonates and infantsMedullary duct ectasia in older children with hepatic

fibrosis3. Glomerulocystic kidney disease

Familial GCKDRenal hypoplasia and UROM mutationAssociated with HNFB1 mutationsHereditary GCKDAssociated with ADPKD/ARPKD/TSCSyndromic nonhereditary GCKDSporadic GCKDAcquired GCKD

B. Renal medullary cysts1. Nephronophthisis

Nephronophthisis, autosomal recessiveJuvenile nephronophthisisNPH1, NPH4NPH1, NPH5 associated with Senior-Loken syndromeInfantile NPH2

2. Medullary cystic diseasesAutosomal dominant MCKDMCKD associated with hyperuricemia

3. Medullary sponge kidneyC. Cysts in hereditary cancer syndromes

1. von Hippel-Lindau disease2. Tuberous sclerosis

D. Multilocular renal cystE. Localized cystic diseaseF. Simple cortical cystsG. Acquired (dialysis-induced) cystsH. Miscellaneous

1. Pyelocaliceal diverticula2. Perinephric pseudocysts3. Hygroma renalis

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

Reproduced with permission from 121Liapis H. Winyard P. Cystic dis-eases and developmental kidney defects. In: Jennette JC, Olson JL,Schwartz MM, Silva FG, eds. Heptinstalls Pathology of the Kidney, 6thed. New York NY; Lippincott Williams & Wilkins; 2007.

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

DiseaseAbridged

1. Autosomal-dominant polycystic kidney disease2. Autosomal-recessive polycystic kidney disease3. Unilateral, localized, segmental cystic disease4. Solitary and multiple, simple renal cysts5. Dysplastic kidney6. Pluricystic kidney of multiple malformation syndromes7. Juvenile nephronophthisis and medullary cystic disease8. Medullary sponge kidney9. Glomerulocystic kidney disease

10. Multilocular renal cystscystic nephroma and congeners11. Renal cysts in hereditary syndromes12. Renal lymphangioma/peripelvic-peripcalyceal lymphanges-

tasia13. Pyelocalyceal cyst, parapelvic cyst, perinephric pseudocyst,

lymphocele14. Acquired renal cystic disease15. Renal cell carcinomas with cystic change

Reprinted with permission from 113Brisceglia M, Galliani CA, Senger C,Stallone C, Sessa A. Renal cystic disease: a review. Adv Anat Pathol.2006;13(1):2656.

es,118 and their 1993 classification of congenital nephrop-athies.120

A second divide and conquer approach, especiallysuited to discussions of RCD/CAKUT, uses the textbookchapter format. An excellent example of this is the chapterby Liapis and Winyard,121 appearing in the sixth and most

recent edition of Heptinstalls Pathology of the Kidney (Table11). This beautifully written and illustrated chapter pro-vides a classification of RCD (see Table 16.1 in Liapisand Winyard121) and offers additional tables that displayentities within the differential diagnosis of glomerulocys-tic kidney disease and the developmental defects withinthe CAKUT spectrum and a lengthy tabulation of manygenetic syndromes complicated by CAKUT (see Table26.4, Table 26.5, and Table 26.6 in Liapis and Win-yard121). In their classification of RCDs, Liapis and Win-yard121 introduce additional genetic information in theglomerulocystic disease category and the renal medullarycyst categories, an approach that will likely expand in fu-ture formulations by them and others.

The classification I would propose combines the land-mark strategies of Kissane116 and Elkin and Bernstein,117and the more detailed formulation of Brisceglia et al113 andLiapis and Winyard,121 into 4 major categories, with a fifthmiscellaneous category that could include other rare en-


Table 12. Bonsib (2009) Classification of RenalCystic Diseases and Congenital Anomalies of the

Kidney and Urinary Tract

I. Polycystic renal diseasesA. Autosomal-recessive polycystic kidney disease

Classic in neonates and infantsChildhood with hepatic fibrosis

B. Autosomal-dominant polycystic kidney diseaseClassic adult formEarly onset childhood form

C. Acquired renal cystic diseaseD. Glomerulocystic kidney diseasesA. Familial GCKD

Renal hypoplasia and UROM mutationAssociated with HNFB1 mutations

B. Hereditary GCKDAssociated with ADPKD/ARPKD/TSC

C. Syndromic nonhereditary GCKDD. Sporadic GCKDE. Acquired GCKD

II. Congenital anomalies of the kidney and urinary tractA. Renal agenesis and dysplasia

AgenesisSporadic: unilateral or bilateralSyndromicNonsyndromic, multiple malformation syndromesRenal dysplasiasSporadic: unilateral or bilateralSyndromicNonsyndromic, multiple malformation syndromesHereditary adysplasia

B. Renal hypoplasiasSimple hypoplasia: unilateral or bilateralOligomeganephronic hypoplasiaReduced nephron generations (cortical hypoplasia)Reduced nephron numbers (premature and low birth

weight risk of hypertension)C. Abnormalities in form, position, and number

Rotation anomalyRenal ectopiasRenal fusionsSupernumerary kidneyIn combination with A, B, or D

D. Ureteral and urethral abnormalitiesUreteropelvic junction obstructionUreteral duplication/bifid ureterVesicoureteral refluxPrimary megaureterUreteral ectopiaPosterior urethral valvesIn combination with A, B, or C

III. Tubulointerstitial syndromes cystsA. Renal tubular dysgenesis

Autosomal recessiveSecondary twin-twin transfusionACE inhibitor

B. Nephronophthisis: types 16C. Medullary cystic diseases:

Type 1Type 2/familial juvenile hyperuricemic nephropathy

D. Bardet-Biedel syndromes, types 112IV. Cystic neoplasms and neoplastic cysts

A. Cystic nephromaB. Cystic partially differentiated nephroblastomaC. Mixed epithelial and stromal tumorD. Multilocular cystic renal cell carcinomaE. Tubulocystic renal cell carcinomaF. Von HippelLindau diseaseG. Lymphangioma/hygroma renalis

V. Miscellaneous cystsA. Simple cortical cysts

Table 12. Continued

B. Medullary sponge kidneyC. Localized renal cystic disease

Abbreviations: ACE, angiotensin converting enzyme; ADPKD, autoso-mal dominant polycystic kidney disease; ARPKD, autosomal recessivepolycystic kidney disease; GCKD, glomerulocystic kidney disease; TSC,tuberous sclerosis complex.

tities not listed. The first category groups the major clinicalforms of the genetic polycystic kidney diseases and glom-erulocystic kidney diseases with acquired RCD into apolycystic renal disease category (Table 12). Although ge-netic and nongenetic diseases are grouped in this category,these entities have in common the initial normal nephronformation complicated by diffuse cystic alterations whenfully expressed.

The diverse entities characterized by the metanephricdysgenesis and LUT abnormalities of CAKUT are clus-tered together into the second category that accommo-dates their occurrence in sporadic, syndromic, and mul-tiple malformation syndromes, while allowing for combi-nations of renal and LUT defects that can affect the samekidney. This grouping accounts for the major possibilitiesbut does not attempt to list the numerous syndromic en-tities that it includes because of their large number andbecause many syndromes would fall in multiple categoriesof this grouping.

The third category includes entities that are predomi-nately interstitial diseases; some of the entities may havecoexistent cysts with renal tubular dysgenesis, the majorexception. The various forms of nephronophthisis andmedullary cystic diseases are clustered together, but med-ullary sponge kidney is kept separate in a final miscella-neous category. The fourth major category is cystic renalneoplasms and neoplastic cysts. Only intrinsically cysticrenal neoplasms are listed. Their number has expandedgreatly in the past few years. Neoplasms with cystic de-generation and necrosis are not included in this groupingbecause this finding is not only common in renal neo-plasms but also occurs in nearly every type of renal tumor.The many noncystic diseases that clutter previously men-tioned formulations are excluded.

CONCLUSIONIn the 21st century, the genetic/molecular-based pos-

tulates in the pathogenesis of the complex RCD/CAKUTfamily implicate mutated master genes and modifyinggenes crucial in renal development and in cell physiology.This insight has minimized the importance of anatomic-based postulates that relate urinary tract obstruction todevelopmental misadventures by placing them within alarger paradigm of sequential intrinsic genetic and molec-ular defects that culminate in the malformed kidney andLUT and in progressive lesions developing in normallyformed kidneys. With the burst of information on mole-cules that reside in the primary cilium of renal tubules,there are now pathogenetic links among morphologicallyand genetically distinct entities and among select mixedcystic and neoplastic entities; such exciting associationswould have seemed implausible not too many years ago.

These advances may ultimately explain not only thepathogenesis of most cystic renal diseases, whether con-genital, acquired, or neoplastic, but also may, when fully


delineated, provide a molecular basis for targeted thera-pies to prevent or ameliorate some diseases. Despite im-pressive scientific advances, it remains difficult to developa completely satisfactory classification of the diverse arrayof anomalies that affect the urinary tract. Although clas-sifications incorporating genetic and molecular data arenow emerging, there are complicating factors that are dif-ficult to accommodate. These include the polygenetic na-ture of some disorders, the accumulation of multiple ge-netic defects that can affect susceptibility and influence thenature of the malformation expressed, and different typesof mutations in a single master gene that can clearly alterthe phenotypic expression.

Contributing to this challenge is that a classificationsuitable for one discipline, such as pathology, may not beoptimized to serve the interests of another discipline.When pathologists encounter an anatomic abnormality, westrive to place it within a diagnostic category that willsatisfy and initiate the proper clinical responses. Con-versely, formulating a purely molecular-based or mecha-nistic classification can serve the interests of a basic re-searcher striving to develop targeted therapies, for in-stance, to affect the function of a mutated ciliary protein,but can fail to meet the diagnostic needs of the patholo-gist.

The ideal classification scheme would account for mor-phologic features and their clinical importance, with log-ical links to pathogenesis, while providing a basis for ther-apeutic interventions. Although such a comprehensiveclassification remains an elusive target, its general outlineis becoming clearer but remains a lofty goal yet to beachieved. The classification listed in Table 12 strives tomeet the first 2 objectives cited above, but likely falls shortin some respects, and with the pace of discovery in RCD/CAKUT, it will soon be obsolete. In the final analysis, ourinfatuation with these diseases derives from the impossi-ble challenge their complexity creates. This is nicely cap-tured in the quote by Potter when she stated in 1972, Themore complicated an organ in its development, the moresubject it is to maldevelopment, and in this respect thekidney outranks most other organs. 46

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