Nonneoplastic Diseases of the Kidney

Rotation Anomaly

During ascent of the kidney to a lumbar location, the renal pelvis rotates 90 degrees from an anterior to a medial position ( Fig. 1.12 ). Failure of the pelvis to assume a medial orientation, reverse rotation, and overrotation to a posterior or even lateral location comprises a spectrum of orientation abnormalities known as rotation anomalies. Some degree of malrotation occurs in 1:400 to 1:1000 individuals. The most common rotation anomaly is nonrotation or incomplete medial rotation resulting in an anterior location of the pelvis and ureter ( Figs. 1.20 and 1.26 ). This may occur as an isolated abnormality in an otherwise normal kidney. It always accompanies renal ectopia or renal fusion. Ureteropelvic obstruction may on occasion result from a crossing vessel ( Fig. 1.26 ). Excess rotation and reverse rotation with the pelvis posterior or lateral are rare.

Renal Ectopia

Failure of the kidney to assume its proper location in the renal fossa is known as renal ectopia. The several varieties are named according to location ( Table 1.6 ). Renal ectopia should be distinguished from renal ptosis in which a normally situated kidney shifts to a lower position. The origin of the renal artery from a normal aortic location identifies a lower-situated kidney as ptotic rather than ectopic. The incidence of ectopia at autopsy ranges from 1:660 to 1:1200. Renal ectopia is bilateral in 10% of cases.

The three most common forms of renal ectopia are pelvic, iliac, and abdominal, all of which are inferiorly located. The kidney may be nonreniform in shape, its pelvis and ureter are anterior (nonrotated), and the ureter is short and usually placed in the bladder, but it may have a high insertion on the pelvis that leads to obstruction. The vascular supply is influenced by the final location of the kidney, arising from the aorta or from the common iliac, internal or external iliac, or inferior mesenteric arteries ( Fig. 1.27 ). The contralateral kidney may be normal or occasionally may be absent or even dysplastic. Other anomalies of urologic organs and cardiovascular, skeletal, and gastrointestinal systems are frequent in both sexes.

Cephaloid ectopia is usually associated with an omphalocele. The kidney appears to continue its ascent when the abdominal organs herniate into the omphalocele sac. The ureter and pelvis are typically normal. Thoracic ectopia is rare and usually involves the left kidney. The kidney resides in an extrapleural location in the posterior mediastinum. The diaphragm must be intact to distinguish this anomaly from herniation of the kidney and possibly other abdominal organs into the thorax secondary to diaphragmatic hernia. The lower lobe of the lung may be hypoplastic, but other anomalies are not present. Thoracic ectopia is usually asymptomatic, with a normal ureter and pelvis.

In crossed ectopia the kidney is situated opposite the side of insertion of its ureter in the trigone. Four combinations are possible ( Table 1.6 ). In 90% of cases there is also fusion to the other kidney. In crossed fused ectopia the kidneys may assume a variety of shapes and positions giving rise to six “types”: inferior, superior, lump, sigmoid, disk, and L-shaped. The kidneys function normally and their ureters are normally located within the bladder, but their pelves are nonrotated. Extrarenal anomalies (genital, skeletal, and anorectal) occur in 20% to 25% of patients.

Renal Fusion

Horseshoe kidney is the most common form of renal fusion. It is the midline fusion of two distinct renal masses, each with its own ureter and pelvis ( Figs. 1.28 and 1.29 ). Horseshoe kidney is relatively common (1:400 to 1:2000) with a 2:1 male predominance. Horseshoe kidney is commonly seen as part of other anomalies such as trisomy 18 (25%), caudal dysplasia syndrome, and Zellweger syndrome. The fusion is typically at the lower poles but can vary greatly in the quantity of fused parenchyma. A horseshoe kidney is ectopic and usually situated anterior to the aorta and vena cava. Occasionally the fusion is posterior to the vena cava or posterior to both the aorta and vena cava. The ureters and pelves are always anterior. This placement, coupled with commonly encountered high insertion of the ureter on the pelvis, can result in obstruction ( Fig. 1.28 ). Approximately 30% of patients also have other anomalies of the urinary tract, central nervous system, heart, gastrointestinal tract, or skeletal system.

Supernumerary Kidney

A supernumerary or duplicated kidney is one of the rarest disorders. It has been defined as “a free accessory organ that is a distinct, encapsulated, large or small parenchymatous mass topographically related to the usual kidney by a loose, cellular attachment at most and often by no attachment whatsoever.” It may be located below (most common), above, or adjacent to the kidney and is rarely bilateral. It is connected to the lower urinary tract by either a bifid ureter or its own separate ureter ( Fig. 1.30 ). In half of the reported cases, complications have developed related to obstruction and infection.

Hypoplasia

Hypoplasia refers to a small (< 50% of normal) but otherwise normally developed kidney. By definition, nephron formation is normal, albeit deficient, in quantity, and dysplastic elements (metanephric dysgenesis) are absent. There are four types of hypoplasia ( Table 1.7 ).

Simple Hypoplasia

Simple hypoplasia is a rare, usually bilateral, and often nonhereditary disease in which the small size of the kidney usually reflects a marked reduction in the number of renal lobes. Frequently only one to five lobes are present ( Fig. 1.31 ). Dysplastic elements, by definition, are absent. When the condition is unilateral, the contralateral kidney may be hypertrophied. When it is bilateral, the small kidneys may eventually fail to provide renal function with body growth, and renal failure and nephron sclerosis may develop, the onset of which is determined by the degree of hypoplasia.

Oligomeganephronia

Oligomeganephronia may be the most common form of renal hypoplasia. It is a bilateral, nonhereditary disorder. Most cases are sporadic; however, few associations have been described with mutations in transcription factors involved in renal development including PAX2, HNF1B, and SIX. The kidneys are small because of a reduction in the number of renal lobes and the number of nephrons within each lobe. Microscopically, the nephrons present are tremendously enlarged ( Fig. 1.32 ). Glomerular and tubular volumes have been measured to be 12 times and 17 times normal, respectively.

Children with oligomeganephronia present with a concentration defect causing polyuria, polydipsia, and salt wasting, resembling patients with nephronophthisis. Renal insufficiency and proteinuria gradually develop with body growth as progressive glomerular and tubulointerstitial scarring occur. The absence of a family history of renal disease, the presence of proteinuria, and imaging studies revealing symmetrically small noncystic kidneys usually permit separation from nephronophthisis.

Cortical Hypoplasia

Cortical hypoplasia is a type of hypoplasia not generally recognized; it does not appear in standard texts of urologic pathology. Examples of cortical hypoplasia, however, are amply demonstrated in the Atlas of Medical Renal Pathology by Bonsib. Cortical hypoplasia refers to a reduction in the number of nephron generations that results in cortical thinning, reduction in overall renal size, and, if severe, a clinically significant reduction in nephron endowment, a major risk factor for hypertension and renal insufficiency. The “normal” number of generations ranges from 10 to 14, although rarely are more than 9 to 10 generations evident even in a well-oriented section. Determination of nephron generations is best performed with a nephrectomy specimen with sections oriented along medullary rays. Nephron generation counting is admittedly imprecise. However, if there is a 50% reduction in nephron generations, that is, four to five generations in a properly oriented section, then the reliability of this assessment is reasonable ( Fig. 1.33 ). This form of hypoplasia may coexist with other forms of hypoplasia, especially Ask-Upmark segmental hypoplasia.

Segmental Hypoplasia (Ask-Upmark Kidney)

Segmental hypoplasia may manifest in neonates or adults and is often associated with hypertension. There is widespread agreement that vesicoureteral reflux is the fundamental injury. Some investigators regard it as an acquired lesion because its evolution over time has been radiographically documented in a few cases. Others agree with reflux-related injury but believe that most cases are developmental in origin secondary to in utero reflux that damages the developing renal lobe. That this condition often manifests in neonates and children supports a developmental basis. Furthermore, it is associated with renal vascular anomalies in 40% of cases and may be coexistent with lobes that show cortical hypoplasia. Segmental hypoplasia is defined as a small kidney with a deep cortical groove and dilatation of adjacent calyx ( Fig. 1.34A ). Microscopic features include sharply delineated cortical lesions ( Fig. 1.34B ). The cortex contains few tubules, with no or only rare glomeruli. There is little or no inflammation, nor is glomerulosclerosis or tubular atrophy present to indicate a regressive lesion. Finally, the kidney should have no evidence of metanephric dysgenesis. The medulla is characteristically absent. If present it may be rudimentary or flattened, with no loops of Henle, and may contain a distinctive cellular interstitial mesenchymal tissue not present in the normal renal pyramid.

Renal Agenesis

Absence of the kidney and its corresponding ureter is known as renal agenesis ( Table 1.8 ). The corresponding bladder hemitrigone is also absent because it represents the distal continuation of the ureteral smooth muscle ( Fig. 1.35 ). Failure to identify a kidney in a child or an adult does not prove congenital absence of the kidney because cystic dysplastic kidneys identified in newborns have been shown radiographically to regress further over time and may become undetectable.

Bilateral Renal Agenesis (Potter Syndrome)

Bilateral renal agenesis is a uniformly fatal disorder known as Potter syndrome ( Fig. 1.36 ). Both ureters are also absent, so the bladder has no ureteral orifices. Approximately 40% of affected fetuses are stillbirths, and those born alive die of pulmonary failure within 48 hours. Mothers present with severe oligohydramnios because fetal urine normally accounts for most of the amniotic fluid in the second half of gestation. Oligohydramnios impairs pulmonary development that results in pulmonary hypoplasia and produces a variety of distinctive gross features known as the Potter phenotype or oligohydramnios phenotype ( Table 1.9 ). Figs. 1.37 and 1.38 demonstrate some of the characteristic facial and placental findings. Some urologists refer to any fetus born with the oligohydramnios phenotype as having Potter syndrome, rather than reserving the term for the entity of bilateral renal-ureteral agenesis as initially described. This can be confusing because oligohydramnios has other causes ( Table 1.10 ).

Table 1.9

Oligohydramnios Phenotype

• Potter facies

• Increased interocular distance

• Broad, flattened nose

• Prominent inner canthic folds (sweeping downward and laterally)

• Receding chin

• Large, low-set ears with little cartilage

• Positional deformities (flexion of hips and knees, clubbed feet)

• Dry skin

• Hypoplastic lungs

• Small bladder with absent trigone

• Placenta: amnion nodosum

Table 1.10

Causes of Oligohydramnios

Major causes

• Potter syndrome (bilateral renal agenesis)

• Bilateral renal dysplasia

• Distal (complete) urinary tract obstruction

Rare causes

• Autosomal recessive polycystic kidney disease

• Glomerulocystic kidney disease

• Renal tubular dysgenesis

• Chronic amniotic fluid leak

• In utero acute renal failure

• Idiopathic conditions

Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney is a rare disorder that occurs in 1 in 20,000 to 50,000 births ( Table 1.14 ). In ARPKD, parents lack the disease and 25% of siblings are affected. It is associated with mutations of the polycystic kidney and hepatic disease 1 ( PKHD1 ) gene, on chromosome 6p12. The product of this gene, fibrocystin/polyductin, localizes to the primary cilium and centrosome of renal tubule epithelial cells. Organogenesis in ARPKD appears normal based on microdissection studies of severe neonatal forms. The primary lesion is fusiform ectasia of cortical and medullary collecting ducts, eventually leading to renal failure in severely affected cases. The renal lesion is accompanied by a bile duct plate malformation that develops into congenital hepatic fibrosis in surviving older patients.

Recessive polycystic kidney disease was originally believed to be an invariably lethal neonatal disorder. Observation of some patients who survived into childhood prompted Blyth and Ockenden to propose a classification of patients into perinatal, neonatal, infantile, and juvenile forms. These forms vary in the degree of cyst formation. Although conceptually useful, it is often difficult to place a patient into a given category. More than 100 mutations of the PKHD1 gene have been identified that account for the clinical spectrum. The most severe neonatal cases manifest with pulmonary hypoplasia secondary to the massive renal enlargement that compromises pulmonary development. It appears that as the extent of cyst formation decreases, the child has better pulmonary development and a greater likelihood of survival. Unfortunately, with increasing duration of survival there is worsening of the liver disease that may culminate in congenital hepatic fibrosis. If one examines the kidneys of children with congenital hepatic fibrosis, two-thirds have a concentrating defect and have some degree of medullary cyst formation, findings indicating that ARPKD and congenital hepatic fibrosis are different manifestations of a single entity.

Most cases of ARPKD result in stillbirth, early neonatal death, or end-stage kidney disease by age 20 years. Affected neonates have massively enlarged and diffusely cystic kidneys that produce abdominal distention and compress thoracic organs ( Fig. 1.48A ). The lungs cannot develop normally, and death results from pulmonary hypoplasia. Despite the impressive cyst formation, the kidneys may be functional. If they are nonfunctional, oligohydramnios and a Potter phenotype may develop.

In severe cases, the cysts extend throughout the cortex and medulla in a distinctive radiating pattern imparting a spongy quality ( Fig. 1.48B ). Histologically, the cysts consist of dilated collecting ducts lined with uniform cuboidal cells ( Figs. 1.49 and 1.50 ). The nephrons between the collecting ducts appear normal.

The liver in patients dying in the neonatal period shows portal bile duct proliferation that assumes a distinctive dilated and irregular branched pattern of anastomosing channels at the periphery of portal triads ( Fig. 1.51 ). There is an increase in the size of portal areas with increased fibrous tissue. In older patients, congenital hepatic fibrosis develops, resulting in portal hypertension and hepatosplenomegaly.

In less severely affected kidneys of older children the appearance is variable, and the diagnosis may be less obvious. The kidneys are smaller, and the cysts are fewer. Medullary cysts are always present and tend to be elongated. Cortical cysts if present are often rounded and variably distributed ( Fig. 1.52 ). The parenchyma adjacent to the cysts eventually develops atrophic changes with tubulointerstitial scarring and glomerulosclerosis. These features may create a resemblance to ADPKD. The presence of the liver lesion of congenital hepatic fibrosis therefore is a useful diagnostic feature. However, many diseases may be associated with renal cysts and liver disease, and awareness of additional anomalies is required for proper classification ( Table 1.15 ).

Autosomal Dominant Polycystic Kidney Disease

ADPKD is the most common cystic kidney disease and the most common genetically transmitted renal disease. It occurs with an estimated frequency of between 1:500 and 1:1000 ( Table 1.14 ). It is the fourth leading cause of end-stage renal disease, and affected patients comprise 5% to 10% of patients treated with dialysis. Although patients vary greatly in the age of onset of symptoms, most present in their third to fifth decade of life. Penetrance is nearly 100% if the individual survives to 80 years. Approximately 25% of affected patients lack a family history and presumably represent a new mutation. The disease results from mutations of PKD1 and PKD2 that localize to chromosome 16 in 90% of patients and to chromosome 4 in 10%, respectively. The gene product of PKD1 is polycystin-1, a transmembrane glycoprotein involved in cell signaling. PKD2 encodes for polycystin-2, a member of the transient receptor potential channel superfamily of nonselective cation channels.

Patients with ADPKD present with a variety of symptoms, most referable to the urinary tract. Chronic flank pain is the most common and correlates with renal weight and cyst size greater than 3 cm. Acute flank pain often reflects hemorrhage into a cyst. Hematuria is the second most common symptom. This may be gross, resulting in clot formation and urinary tract obstruction. Hypertension often develops early in the disease, and activation of the renin-angiotensin system secondary to intrarenal vascular occlusion by expanding cysts has been implicated. Urinary tract infection develops in 50% to 75% of patients and affects women more often than men. The infection may be confined to the collecting system or a cyst, or it may involve the parenchyma. Perinephric extension with abscess is a serious complication with a 60% mortality rate. Urate or calcium oxalate nephrolithiasis develops in 10% of patients. Extrarenal complications related to hypertension and berry aneurysms develop in 5% to 15%. Infection and cardiovascular disease represent the most common causes of death.

Early in the disease ( Fig. 1.53 ), the kidney may appear nearly normal with only scattered cysts in the cortex and medulla, and normal intervening parenchyma. The cysts initially are small and develop in only about 1% of nephrons. Microdissection studies have shown that the cysts develop in all segments of the nephron. Scanning electron microscopy and immunohistochemistry of cyst lining cells have confirmed these observations.

As the disease progresses, the cysts grow in size and number, with resulting massive renal enlargement ( Fig. 1.54 ). The cysts range in size from a few millimeters to several centimeters, and cyst contents vary from transparent to opaque to hemorrhagic fluid. Most cysts are lined with a single layer of flattened to cuboidal epithelium ( Fig. 1.55 ). Hyperplastic foci or polyp formation are detectable in some cysts ( Fig. 1.56 ). The cyst contents may be proteinaceous or include red cells or calcific deposits. The intervening parenchyma shows interstitial fibrosis with a lymphoid infiltrate, tubular atrophy, and glomerular and vascular sclerosis. Despite the cystic transformation, the kidneys retain a reniform shape and preserve their collecting systems.

Nephronophthisis

Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy in which cysts often develop. It inevitably leads to end-stage kidney disease. The first description of nephronophthisis was by Smith and Graham in 1945, who used the term medullary cystic disease to highlight the grossly visible medullary cysts. Fanconi, in 1951, coined the term juvenile familial nephronophthisis in reference to its histologic outcome; nephronophthisis is Greek for “disintegration of nephrons.” Most reports of nephronophthisis that appeared before the 1990s combined the two entities into the medullary cystic disease/juvenile nephronophthisis complex because of their morphologic similarities, a practice no longer appropriate considering differences in genetics and pathogenesis. Nephronophthisis is autosomal recessive and a ciliopathy, whereas medullary cystic kidney disease, now referred to as autosomal dominant tubulointerstitial disease (ADTID), is autosomal dominant and is not a ciliopathy as discussed later.

There are three clinical phenotypes of nephronophthisis that are distinguished by age of onset: infantile, juvenile, and adolescent forms. Affected individuals present with polyuria and polydipsia resulting from salt wasting, a concentration defect, anemia disproportionately severe for the level of renal insufficiency, and growth retardation. Although fundamentally a tubulointerstitial disease, 15% of patients have extrarenal components: retinal dystrophy (Senior-Loken syndrome), oculomotor apraxia (Cogan syndrome), situs inversus (infantile nephronophthisis), and rarely, congenital hepatic fibrosis.

Twenty mutated genes have been identified in nephronophthisis that encode for proteins expressed in the primary cilium, centrosome, and cell junctions of renal epithelial cells. These mutations, however, account for only 30% of nephronophthisis cases. Most mutations are responsible for some of the juvenile and adolescent forms, whereas NPHP2 and occasionally NPHP3 mutations are responsible for the infantile form. The juvenile and adolescent forms cannot be histologically distinguished. However, the infantile form has several distinctive features.

The kidneys in nephronophthisis are normally developed at birth. Cyst formation occurs in approximately 70% of patients but is usually delayed until advanced or end-stage disease develops. Sequential imaging shows that most patients lack cysts at presentation but many subsequently develop cysts, and that cyst frequency and size increase over time. Therefore early in the disease no cysts may be detectable to assist in the diagnosis.

Kidney size in the juvenile and adolescent forms is usually normal or smaller than normal. When cysts develop, they congregate at the corticomedullary junction and may range from 1 to several centimeters in diameter ( Fig. 1.57 ). In the infantile form the kidneys may be larger than normal because cyst formation occurs earlier in the disease, before contraction from tubulointerstitial scarring. If cysts develop they may involve the medulla but generally are cortical in location.

The primary histologic findings in nephronophthisis are nonspecific, so complete laboratory and clinical data are necessary. The juvenile and adolescent forms show a radial distribution of cortical injury with atrophic zones that alternate with zones of normal or hypertrophied tubules largely localized to medullary rays ( Fig. 1.58A ). Before end-stage renal disease the tubulointerstitial injury exceeds the extent of glomerulosclerosis, thus implicating a primary tubulointerstitial process ( Fig. 1.58A ). The tubules have an irregular profile sometimes described as figure-eight or T-shaped because of the tubule diverticula, particularly numerous in the limbs of Henle. Many small “cysts” are not true cysts but are localized segments of tubular dilatation with patent afferent and efferent tubule connections.

The irregularly shaped atrophic tubules show prominent multilayering of their tubular basement membranes, or the tubule basement membranes may range from thick and irregular, to thin and attenuated, to segmental absence of basement membrane ( Fig. 1.58B ). Dense interstitial fibrosis is present often with a prominent lymphoid cell infiltrate. Periglomerular fibrosis is a common finding, as it is in other chronic inflammatory interstitial diseases. As the tubulointerstitial disease progresses, glomeruli undergo sclerosis. Advanced cases show marked fibrointimal thickening of arteries and medial hypertrophy.

Medullary cysts, when present, arise from the loops of Henle and collecting ducts. The cyst cell lining is variable. A cuboidal cell lining is present in small cysts, but large cysts may have a flattened, nondescript cell lining surrounded by a rim of dense fibrous tissue. Medullary inflammation is not usually present.

In the infantile form of nephronophthisis the cysts affect tubules, predominantly distal tubules and collecting ducts, in the form of tubular dilation or ectasia ( Fig. 1.59 ). Macrocystic dilation of tubules occurs and may be visible grossly. The ectatic and grossly cystic tubules are lined by cuboidal to columnar epithelium typical of distal tubules and collecting ducts. The tubules between the cysts may be normal or atrophic. Atrophic tubules are small and lined by inconspicuous cuboidal epithelium with thin tubular basement membranes that lack the irregular basement membrane multilayering of the juvenile and adolescence forms. Glomeruli may develop microcysts in which the Bowman capsule is enlarged two to three times normal. Although mild interstitial inflammation occurs, it is usually less than in the juvenile and adolescent forms.

Autosomal Dominant Tubulointerstitial Disease

ADTID, previously referred to as medullary cystic kidney disease (MCKD), is like nephronophthisis, a chronic progressive tubulointerstitial disease in which cysts may develop. It is a rare disease primarily of adults, but the age of onset overlaps with older patients with nephronophthisis. There are four known causes of ADTID due to mutation of uromodulin (UROM; Tamm-Horsfall glycoprotein), mucin 1 (MUC1; epithelial membrane antigen), renin (REN), and hepatocyte nuclear factor 1β (HNF1B; Table 1.16 ). One or more additional mutations remain to be identified. The recommended terminology for these diseases is UROM kidney disease, MUC1 kidney disease, REN kidney disease, and HNF1B kidney disease.

Most patients present in the third to fourth decade of life with polyuria and polydipsia as a result of salt wasting and a concentration defect ( Table 1.16 ). They progress to end-stage disease, usually by the fourth to seventh decade, although the rate of progression varies within and between affected families. Hyperuricemia and gout are common, especially in UROM and REN kidney disease. REN kidney disease patients have anemia refractory to treatment, hyperkalemia, and often low BP.

The kidneys in ADTID may be enlarged if cysts are prominent. Although medullary cysts are common, they are usually present in small numbers and develop late in the disease. Within a family not all affected individuals have cysts. The cysts congregate at the corticomedullary junction and can be several centimeters ( Fig. 1.60A ). Microscopically, all four ADTIDs show a nonspecific chronic interstitial nephritis with tubular atrophy, interstitial fibrosis, and periglomerular fibrosis similar to nephronophthisis. If cysts are present, they are lined with a flattened to cuboidal epithelium. UROM kidney disease contains uromodulin intracellular aggregates in thick ascending limb of Henle cells ( Fig. 1.60B ). REN kidney disease shows reduced to absent renin staining in cells of the juxtaglomerular apparatus. MUC1 and HNF1B kidney disease have no defining histologic findings. However, patients with HNF1B kidney disease often have congenital anomalies of the kidney and/or lower urinary tract.

Von Hippel–Lindau disease

Von Hippel–Lindau disease is an uncommon autosomal dominant disorder due to germline mutation of the VHL gene in which renal and extrarenal cysts and neoplasms develop. The extrarenal manifestations include retinal, cerebellar, and spinal hemangioblastomas, pheochromocytoma, epididymal and pancreatic cysts, and cystadenomas. The renal manifestations consist of multiple and bilateral cysts that develop in 75% of patients, and renal cell carcinomas, often bilateral and multicentric, that develop in approximately 50% of patients ( Fig. 1.61 ). The mutant VHL gene has been localized to chromosome 3p25, adjacent to the gene implicated in development of sporadic clear cell renal cell carcinoma.

The renal cysts are lined with glycogen-rich cells like those of grade 1 to 2 clear cell renal cell carcinoma ( Fig. 1.62 ). These range from a benign-appearing lining of one to two cell layers of clear cells to multiple layers of cells. The broad spectrum of neoplastic proliferative lesions ranges from cysts with papillary tufts of mildly atypical cells, to cysts with solid mural nodules of clear cell renal cell carcinoma, to markedly cystic clear cell renal cell carcinoma. This morphologic spectrum represents a challenge in the classification of lesions in biopsy and nephrectomy material. Despite awareness of the high frequency of renal cell carcinoma in this syndrome, metastatic renal cell carcinoma remains the leading cause of death.

Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by mental retardation, epilepsy, angiofibromas, cardiac rhabdomyomas, renal angiomyolipomas, renal cell carcinomas and renal cysts. Two genes have been identified that cause TSC, TSC1 and TSC2, mapped to chromosomes 9 and 13 that encode for hamartin and tuberin, respectively. The latter locus is within a few nucleotides of the PKD1 locus. Although renal cysts are uncommon and usually not extensive, some individuals, usually children, have dual mutations involving TSC2 and PKD1. They develop a diffuse cystic kidney disease with numerous large cortical and medullary cysts that resemble autosomal dominant polycystic disease; this disorder is known as the TSC2/PKD1 contiguous gene syndrome.

Many tubules and cysts in tuberous sclerosis are distinctive and provide diagnostic specificity in the recognition of this disorder. The cysts are lined with large eosinophilic cells with large hyperchromatic nuclei ( Fig. 1.63 ). The cyst lining cells may form papillary or polyploid masses, and may show occasional mitotic activity. Renal cell carcinomas of several types also develop in TSC but are far less frequent than in von Hippel–Lindau disease.

Glomerulocystic Kidneys

A glomerulocystic kidney (GCK) is defined as the presence of glomerular cysts in more than 5% of glomeruli in the absence of another cystic kidney disease. A GCK may be primary or secondary. Glomerulocystic kidney disease is used in reference to the primary forms that include a sporadic form, a familial form, and forms caused by mutations of UROM and HNF1B ( Table 1.3 ). Secondary forms of glomerular cysts occur in many unrelated disorders such as ADPKD, ARPKD, TSC, a variety of syndromes, ischemic glomeruli, and renal dysplasias. In these diseases, glomerular cysts may be present, but glomerular cysts are not definitional of the entity.

A glomerular cyst is defined as cystic dilation of Bowman capsule to two to three times normal. The glomerular tuft itself may be normal or abnormally formed. In most cases of GCK the glomerular cysts are widespread and affect far more than 5% of glomeruli ( Fig. 1.64 ). The Bowman capsule dilation in some cases of GCK may be massive, sufficient to result in a grossly cystic kidney. In other cases the kidneys may be small and hypoplastic.