Vicente E. Torres Jared J. Grantham
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Classification of the Renal Cystic Diseases, 1428 |
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The Development of Renal Epithelial Cysts, 1428 |
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Hereditary Cystic Kidney Disorders, 1429 |
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Autosomal Dominant Polycystic Kidney Disease, 1429 |
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Autosomal Recessive Polycystic Kidney Disease, 1443 |
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Autosomal or X-Linked Dominant Diseases in the Differential Diagnosis of Autosomal Dominant Polycystic Kidney Disease, 1445 |
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Autosomal Recessive Diseases in the Differential Diagnosis of Autosomal Recessive Polycystic Disease, 1448 |
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Hereditary Cystic Diseases with Interstitial Nephritis, 1448 |
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Nephronophthisis, 1448 |
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Joubert Syndrome, 1449 |
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Bardet-Biedl Syndrome, 1449 |
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Alström Syndrome, 1450 |
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Medullary Cystic Disease, 1450 |
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Renal Cystic Dysplasias, 1450 |
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Multicystic Dysplastic Kidneys, 1451 |
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Renal Cystic Dysplasia Caused by Hepatocyte Nuclear Factor-1β Mutations, 1451 |
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Other Cystic Kidney Disorders, 1451 |
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Simple Cysts, 1451 |
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Localized or Unilateral Renal Cystic Disease, 1453 |
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Medullary Sponge Kidney, 1453 |
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Acquired Cystic Kidney Disease, 1454 |
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Renal Cystic Neoplasms, 1456 |
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Cystic Renal Cell Carcinoma, 1456 |
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Multilocular Cystic Nephroma, 1456 |
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Cystic Partially Differentiated Nephroblastoma, 1457 |
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Mixed Epithelial and Stromal Tumor, 1457 |
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Renal Cysts of Nontubular Origin, 1457 |
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Cystic Disease of the Renal Sinus, 1457 |
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Perirenal Lymphangiomas, 1457 |
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Subcapsular and Perirenal Urinomas (Uriniferous Pseudocysts), 1457 |
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Pyelocalyceal Cysts, 1457 |
CLASSIFICATION OF THE RENAL CYSTIC DISEASES
Renal cystic diseases encompass a large number of sporadic and genetically de-termined congenital, developmental, or acquired conditions that have in common the presence of cysts in one or both kidneys. Renal cysts are cavities lined by epithelium and filled with fluid or semisolid matter. Cysts derive primarily from tubules. Cystic kidneys of different etiologies may appear morphologically similar, whereas the same etiologic entity may cause a wide spectrum of renal abnormalities. Classifications of the renal cystic diseases incorporate morphologic, clinical, and genetic information ( Table 41-1 ), and will change as the understanding of the underlying etiologies and pathogeneses continues to expand.
TABLE 41-1 -- Classification of Cystic Kidney Disorders
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Autosomal dominant polycystic kidney disease |
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Autosomal recessive polycystic kidney disease |
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Pyelocalyceal cysts |
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ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease. |
THE DEVELOPMENT OF RENAL EPITHELIAL CYSTS
Epithelial cysts develop from pre-existing renal tubule segments and are composed of a layer of partially dedifferentiated epithelial cells enclosing a cavity filled with urine-like liquid or semisolid material. They may develop in any tubular segment between the Bowman capsule and the tip of the renal papilla depending on the nature of the underlying disorder. After achieving a size of perhaps a few millimeters, most cysts lose their attachments to their parent tubule segment.
The fundamental processes that are essential for the development and progressive enlargement of renal cysts include (1) proliferation of epithelial cells in segments of renal tubule, (2) accumulation of fluid within the expanding tubule segment, and (3) disturbed organization and metabolism of the extracellular matrix ( Fig. 41-1 ).
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FIGURE 41-1 Evolution of cysts from renal tubules. Abnormal proliferation of tubule epithelium begins in a single cell after a “second-hit” process disables the function of the normal allele. Repeated cycles of cell proliferation lead to expansion of the tubule wall into a cyst. The cystic epithelium is associated with thickening of the adjacent tubule basement membrane and with an influx of inflammatory cells into the interstitium. The cystic segment eventually separates from the original tubule, and net epithelial fluid secretion contributes to the accumulation of liquid within the cyst cavity. |
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Renal cysts have been considered to be benign neoplasms that arise from individual cells or restricted segments of renal tubule. Transgenic insertion of activated proto-oncogenes and growth factor genes into rodents results in the formation of renal cysts. Therefore, processes that stimulate coherent renal cell proliferation with the maintenance of epithelial polarity have the potential to generate the cyst phenotype.
The finding of fluid secretion in renal epithelial cysts led to a reinvestigation of fluid secretion mechanisms in otherwise normal renal tubules. Recent evidence indicates that, beyond the loop of Henle, tubule cells have the capacity to secrete solutes and fluid on stimulation with cyclic adenosine monophosphate (cAMP).[1] This secretory flux operates in competition with the more powerful mechanism by which Na+ is absorbed through apical epithelial Na+channels (ENaC). Under conditions in which Na+ absorption is diminished, the net secretion of NaCl and fluid can be observed at rates that could have a significant impact on the net economy of body salt and water content. Thus, renal cystic disease has led to a heightened appreciation of an ancient solute and water secretory mechanism that has been largely overlooked in modern studies of renal physiology.[2]
Abnormalities of the extracellular matrix in and about renal cysts are seen in all cystic disorders. In the early stages of renal cyst development, changes in expression of collagen I and IV, metalloproteinase activators and inhibitors, integrins, and β-catenin may forecast a vital role for extracellular matrix remodeling in the pathogenesis of renal cysts. Recently, a hypomorphic mutation in the mouse laminin α5 gene was found to cause polycystic kidney disease (PKD). [3] [4]
Until recently, the mechanisms responsible for the abnormal differentiation and functional behavior of the epithelial cells that give rise to the cysts were largely unknown. Evidence now strongly suggests that a long-neglected structure, the primary cilium, is essential to maintain epithelial cell differentiation. Structural and functional defects in the primary apical cilia of tubular epithelia may have a central role in determining cyst development and the abnormal differentiation and behavior of the cystic epithelium and in various forms of human and rodent cystic diseases.
The primary cilium is a single hair-like organelle that projects from the surface of most mammalian cells, including epithelial and endothelial cells, neurons, fibroblasts, chondrocytes, and osteocytes, and plays roles in left-right embryonic patterning, mechanosensation (renal tubular and bili-ary epithelia), photosensation (retinal pigmented epithelia), and chemosensation (olfactory neurons). [5] [6] [7] [8] [9] In renal tubule epi thelial cells, the cilium projects into the lumen and is thought to have a sensory role ( Fig. 41-2 ). The cilium arises from the mother centriole in the centrosome. The centrosome comprises a mother and a daughter centriole plus a “cloud” of pericentriolar material.[10] The centrosome serves as the microtubule-organizing center for interphase cells and is important for organizing the mitotic spindle during mitosis. The mother and daughter centrioles form the poles of the spindle during cell division; duplication of the centriole is coordinated with the cell cycle, and the ciliary axoneme is reabsorbed during cell division. A specific process of intraflagellar transport (IFT) involving anterograde transport of cargo toward the tip of the cilium (using a kinesin II motor complex) and retrograde movement (employing a dynein motor) is required for ciliary formation and function.
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FIGURE 41-2 Diagram depicting the primary cilium and hypothetical functions of the polycystins. Polycystin-1 and polycystin-2 are found on the primary cilium a single hair-like structure that projects from the apical surface of the cell into the lumen. It consists of a membrane continuous with the cell membrane and a central axoneme composed of nine peripheral microtubule doublets. It arises from the mother centriole in the centrosome, the microtubule organizing center of the cell. The centrosome comprises a mother and a daughter centriole plus a “cloud” of pericentriolar material. In response to mechanical stimulation of the primary cilium by flow, the polycystin-1 and -2 complex mediates Ca2+ entry into the cell. This triggers Ca2+-induced Ca2+ release from the smooth endoplasmic reticulum (ER) through ryanodine receptors. The function of the polycystins extends beyond the cilium, because polycystin-1 is also found in the plasma membrane and polycystin-2 is predominantly expressed in the endoplasmic reticulum. Polycystin-2 is an intracellular Ca2+ channel that is required for the normal pattern of [Ca2+]i responses involving RyRs and IP3 receptors and may also affect the activity of store-operated Ca2+ channels. (Reproduced from Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301, 2007.) |
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The first clue connecting PKD and cilia was that polycystin-1 and -2 homologs in Caenorhabditis elegans are located in cilia of male sensory neurons; loss of these proteins is associated with mating behavior defects.[11] Next, a known IFT protein, polaris, was found to be defective in a hypomorphic mouse mutant, orpk, that develops PKD, left-right patterning defects, and a variety of other abnormalities, and has shortened cilia in the kidney.[12]Subsequently, the proteins mutated in other rodent models of PKD, such as the cpk (centrin) and inv (inversin) mice, autosomal dominant PKD (ADPKD; polycystin 1 and polycystin 2), autosomal recessive PKD (ARPKD; fibrocystin), nephronophthisis (NPH; nephrocystin, inversin, nephrocystin-4/nephroretinin, nephrocystin-5, and nephrocystin-6), Bardet-Biedl syndrome (11 BBS proteins), and possibly, tuberous sclerosis complex (TSC) have been localized to the ciliary axoneme, the basal body, or centrosomal structures.[9] Conditional inactivation of the ciliary motor protein KIF3A in collecting duct epithelial cells reproduced all the clinical and biologic features of PKD.[13]The VHL protein has been found to be essential for ciliogenesis, and the epithelial cells lining VHL cysts have absent or stunted cilia. [14] [15] Analysis of cilia in Pkd1-/- cells indicates that they are normal in length; however, these cells lack the flow induced Ca2+ response that has been noted in normal cells. [12] [16] Study of the PCK model of ARPKD indicates that the cilia are shorter than normal and have abnormal structures, similar to those noted in some IFT mutants.[17] Silencing Pkhd1 in IMCD3 cells also results in shortened or loss of cilia.[18] The polycystin complex on cilia seems to function as a mechanosensor, detecting change in flow and transducing it into Ca2+ influx through the polycystin-2 channel, although a chemosensory role has not been excluded. The Ca2+ influx may in turn induce release of Ca2+ from intracellular stores. The increased Ca2+ concentration in intracellular microenvironments may then modulate specific signaling pathways that regulate cellular differentiation, proliferation, and apoptosis, such as cAMP, receptor-tyrosine kinase, and extracellular signal-regulated kinase (ERK) signaling.
Although this ciliocentric model of cystogenesis is attractive, it may be too reductionist. Several cyst associated proteins may have other functions, including participation in cell-cell and cell-matrix interactions at adherens junctions and focal adhesions. Dysfunction of these subcellular domains likely contributes to the dysregulated epithelial growth and altered tubular architecture that is common to virtually all forms of renal cystic disease. Although cilial dysfunction may be the initiating event in cystogenesis, defects in other cellular mechanisms may modulate the final cystic disease phenotype.
HEREDITARY CYSTIC KIDNEY DISORDERS
Autosomal Dominant Polycystic Kidney Disease
Epidemiology
ADPKD occurs worldwide and in all races, with prevalence estimated to be between 1:400 and 1:1,000.[19] Yearly incidence rates for end-stage renal disease (ESRD) due to ADPKD are 8.7 and 6.9 per million (1998–2001, United States),[20] 7.8 and 6.0 per million (1998–1999, Europe),[21] and 5.6 and 4.0 (1999–2000, Japan)[22] in men and women, respectively. Age-adjusted sex ratios greater than unity (1.2–1.3) suggest a more progressive disease in men than in women.
Genetics and Genetic Mechanisms
ADPKD is inherited as an autosomal dominant trait with complete penetrance. Therefore, each child of an affected parent has a 50% chance of inheriting the abnormal gene. In about 5% of patients, no family history of ADPKD can be found, even after radiologic investigation of both parents, suggesting a high spontaneous mutation rate. ADPKD is genetically heterogeneous with two genes identified, PKD1 (chromosome region 16p13.3; ∼85% cases) and PKD2 (4q21; ∼15% cases). [23] [24] [25] [26] It is uncertain whether a third gene accounts for a small number of unlinked families. Homozygous or compound heterozygous genotypes are lethal in utero.[27] Individuals heterozygous for a PKD1 and a PKD2 mutation are viable to adulthood but have more severe renal disease.[28]
ADPKD has large inter- and intrafamilial variability. Most individuals with PKD1 mutations experience renal failure by age 70 years, whereas more than 50% of individuals with PKD2 mutations have adequate renal function at that age (mean age of onset of ESRD 54.3 years, PKD1; 74.0 years, PKD2).[29] Patients with mutations in the 5′ region of PKD1 may have more severe disease (18.9% versus 39.7% with adequate renal function at 60 years) and be more likely to have intracranial aneurysms (ICAs) and aneurysm ruptures than patients with 3′ mutations. [30] [31] No clear correlations with mutation type or position were found in PKD2.[32]
Significant intrafamilial variability in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors. Analysis of the variability in renal function between monozygotic twins and siblings supports a role for genetic modifiers.[33] Forty-three to 50% of the variance in age to reach ESRD may be due to heritable modifying factors.[34] Parental hypertension, particularly of the nonaffected parent, increases the risk for hypertension and ESRD.[35] Parents are as likely to show more severe disease as children.[36]
Cysts in ADPKD kidneys appear to derive by clonal proliferation of single epithelial cells in less than 1% of the tubules. A two-hit model of cystogenesis has been proposed to explain the focal nature of the cysts. In this model, a mutated PKD1 (or PKD2) gene is inherited from one parent and a wild-type gene is inherited from the unaffected parent. During the lifetime of the individual, the wild-type gene undergoes a somatic mutation and becomes inactivated. Loss of heterozygosity owing to somatic mutations of the PKD1 and PKD2 genes has been identified in the cells lining the cysts in both the kidney and liver. [37] [38] The embryonic lethality and severe PKD of homozygous Pkd1 or Pkd2 knockout mice, the late development of cysts in the kidney or liver in heterozygous mutant mice, and the increased severity of the disease in compound heterozygous Pkd2WS25/- mice carrying a Pkd2 allele (WS25) prone to genomic rearrangement provide support for this model of cystogenesis.[39] Nevertheless, evidence suggests that other genetic mechanisms may also be involved. Most cysts in ADPKD kidneys overexpress polycystin 1 or polycystin 2. Transgenic overexpression of PKD1 induces renal cystic disease. [40] [41] The presence of somatic transheterozygous mutations in human polycystic kidneys (somatic mutation of the PKD gene not involved by the germline mutation) and the increased severity of the cystic disease in mice with transheterozygous mutations of Pkd1 and Pkd2 exceeding that predicted by a simple additive effect suggest that haploinsufficiency may play a role in cyst formation.[28] Comparative genomic hybridization and loss of heterozygosity analysis have shown multiple molecular cytogenic aberrations in epithelial cells from individual cysts in polycystic kidneys, suggesting the involvement of additional genes in the initiation and progression of the cystic disease.[42] Mice that are homozygous for Pkd1 hypomorphic alleles indicate that complete inactivation of both Pkd1 alleles is not required for cystogenesis in ADPKD. [43] [44] Pkd2 haploinsufficiency has been associated with an increased rate of cell proliferation in noncystic tubules of Pkd2+/- mice.[45] These observations suggest that diminished expression of native polycystins below a certain threshold is sufficient to induce renal cystic disease. This may be particularly relevant for the extrarenal manifestations of the disease. Reduction of the polycystin 2 levels to 50% of normal in the vascular smooth muscle of Pkd2+/- mice causes significant alterations in [Ca2+]i and cAMP; moreover, it results in higher rates of cell proliferation and apoptosis, contractility, and susceptibility of the vasculature to hemodynamic stress.[46]Intestinal smooth muscle contractility is impaired in Pkd2-haploinsufficient Drosophila.[47]
Pathogenesis
The PKD1 and PKD2 proteins, polycystin-1 (PC1, ∼460 kDa) [23] [24] and polycystin-2 (PC2, ∼110 kDa)[48] span 11 and 6 transmembrane domains, respectively, and probably form a functional complex ( Fig. 41-3 ). [49] [50] PC1 is likely a receptor for an unidentified ligand. PC2 is a transient receptor potential (TRP)–like Ca2+ channel. Like many other proteins implicated in renal cystic diseases, the polycystins are located in the plasma membranes overlying primary cilia. PC1 is also found in plasma membranes at focal adhesion, desmosome, and adherens junction sites, [16] [51] [52] [53] whereas PC2 is found in the endoplasmic reticulum. [54] [55] [56] PC1 in the plasma membrane may interact with PC2 in the adjacent endoplasmic reticulum. PC2 interacts with the TRP channel 1 (TRPC1), a store-operated Ca2+ channel.[57] Therefore, polycystin function likely extends beyond primary cilia. Cells overexpressing PC2 exhibit an amplified Ca2+ release from intracellular stores following agonist stimulation.[58] A 50% reduction in PC2 lowers capacitative calcium entry, sarcoplasmic reticulum Ca2+ stores, and [Ca2+]i in vascular smooth muscle cells.[46] [Ca2+]i increases evoked by platelet-activating factor are reduced in unciliated B-lymphoblastoid cells from patients with PKD1 or PKD2 mutations.[59] Loss of PC2 localization to the mitotic spindles by knockdown of the interacting cytoskeletal protein mDia1 blunts agonist-evoked [Ca2+]i increases in dividing cells that lack primary cilia.[60] [Ca2+]i is reduced in cyst-derived, primary cultured cells from PKD1 kidneys and in collecting ducts isolated from Pkd1+/- mice.[60a]
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FIGURE 41-3 Diagram of the ADPKD proteins polycystin-1 and -2 and the ARPKD protein, fibrocystin. The protein motifs and domains found in these proteins are described in the key. Polycystin-1 probably is a receptor for an extracellular ligand that signals intracellular processes through interaction with polycystin-2. Recently, it has been proposed that polycystin-1 may activate transcription directly by cleavage and translocation of the C-terminus to the nucleus, a process found in other transmembrane proteins The cleavage site in the GPS region and possible cleavage sites in the C-terminal tail of polycystin-1 are arrowed. (Modified from Torres VE, Harris PC: Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities. J Intern Med 261:17–31, 2007.) |
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Increased renal levels of cAMP are common in animal models of PKD. [62] [63] [64] This may be directly related to changes in [Ca2+]i homeostasis by stimulation of Ca2+-inhibitable adenylyl cyclase 6 and inhibition of Ca2+-dependent phosphodiesterase 1 ( Fig. 41-4 ). cAMP levels are also increased in vascular smooth muscle cells isolated from Pkd2+/- mice. [Ca2+]i regulates cAMP levels in both wild-type collecting duct principal cells and vascular smooth muscle cells. [65] [66] cAMP stimulates mitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling and cell proliferation in PKD renal epithelial cells, whereas it has an inhibitory effect in wild-type cells. [67] [68] The abnormal proliferative response to cAMP is directly linked to the alterations in [Ca2+]I, because it can be reproduced in wild-type cells by lowering [Ca2+]i.[68] Conversely, calcium ionophores or channel activators can rescue the abnormal response of cyst derived cells.[69] Up-regulation of the vasopressin V2 receptor and high circulating vasopressin levels may also contribute to the increased cAMP levels (see Fig. 41-4 ). Cyst-derived epithelial cells also exhibit increased expression and apical localization of the ErbB1 (epidermal growth factor receptor [EGFR]) and ErbB2 receptors. [71] [72] Activation of these receptors by EGF-related compounds present in cyst fluid likely contributes to the stimulation of MAPK/ERK signaling and cell proliferation.
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FIGURE 41-4 Diagram depicting hypothetical pathways up- or down-regulated in polycystic kidney disease and rationale for treatment with V2 receptor antagonists, somatostatin, ErbB tyrosine kinase, src or ERK inhibitors, and rapamycin. Dysregulation of [Ca2+]I, increased concentrations of cAMP, and mislocalization of ErbB receptors occur in cells/kidneys bearing PKD mutations. Increased accumulation of cAMP in polycystic kidneys may result from: (i) disruption of the polycystin complex, because PC1 may act as a Gi protein-coupled receptor; (ii) stimulation of Ca2+ inhibitable AC6 and/or inhibition of Ca2+-dependent PDE1 by a reduction in [Ca2+]I; (iii) increased levels of circulating vasopressin due to an intrinsic concentrating defect; (iv) up-regulation of vasopressin V2 receptors. Increased cAMP levels contribute to cystogenesis by stimulating chloride and fluid secretion. In addition, cAMP stimulates mitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling and cell proliferation in an Src- and Ras-dependent manner in cyst-derived cells or in wild-type tubular epithelial cells treated with Ca2+ channel blockers or in a low Ca2+ medium. Activation of mislocalized ErbB receptors by ligands present in cystic fluid also contributes to the stimulation of MAPK/ERK signaling and cell proliferation. Phosphorylation of tuberin by ERK (or inadequate targeting to the plasma membrane due to defective interaction with polycystin 1) may lead to the dissociation of tuberin and hamartin and lead to the activation of Rheb and mTOR. AC-VI, adenylate cyclase 6; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PC1, polycystin-1; PC2, polycystin-2; PDE, phosphodiesterase; PKA, protein kinase A; R, somatostatin sst2 receptor; TSC, tuberous sclerosis proteins tuberin (TSC2) and hamartin (TSC1); V2R, vasopressin V2 receptor; V2RA, vasopressin V2 receptor antagonists. (Reproduced from Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301, 2007.) |
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Additional ways extracellular cues detected by the polycystin complex may be transmitted to the nucleus include canonical and noncanonical Wnt, JAK/STAT, and NFAT pathways. [71] [72] A cleavage event in the GPS domain, separating the extracellular region from the transmembrane part of the protein, may be important for activation of PC1.[72] It has also been proposed that PC1 may activate transcription directly by cleavage at different sites and translocation of the C-terminal fragments to the nucleus, a process that may be regulated by flow. [74] [75]
Pathology
Cystic kidneys usually maintain their reniform shape ( Fig. 41-5 ). Their size ranges from minimally or moderately enlarged in early disease to more than 20 times the normal size in advanced disease. Although unusual, striking asymmetry of cyst development may be seen. Both the outer and the cut surfaces show numerous cysts ranging in size from barely visible to several centimeters in diameter. They are distributed evenly throughout both the cortical and medullary parenchyma. The papillae and pyramids are distinguishable in early cases but difficult or impossible to identify in advanced examples, and the calyces and pelves are often greatly distorted.
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FIGURE 41-5 Autosomal dominant polycystic kidney disease (ADPKD) in situ (A) and on cut section (B). Note diffuse, bilateral distribution of cysts. |
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Nephron reconstruction and microdissection studies revealed that cysts begin as outpouchings from preexisting renal tubules. With enlargement beyond a few millimeters in diameter, most cysts become detached from the tubule of origin. In the early stages of the disease, the noncystic parenchymal elements appear relatively normal because less than 1% of the tubules appear to become cystic. The cells in the vast majority of the cysts are not typical of fully differentiated, mature renal tubular epithelium and are thought to be partially dedifferentiated or relatively immature. A minority of the cysts continue to function, as evidenced by their capacity to generate transepithelial electrical gradients and to secrete NaCl and fluid in vitro. The majority of cysts (75%) with Na+ levels approximating that of plasma and relatively leaky apical junctions probably represent cysts with epithelium that is less well differentiated than cysts with low Na concentrations.
ADPKD cysts have been thought to arise from all segments of the nephron and collecting ducts. Microdissection studies of ADPKD kidneys in the 1960s and 1970s suggested that collecting ducts are diffusely enlarged and that collecting duct cysts are more numerous and larger than those derived from other tubular segments. Most cysts at least 1 mm in diameter stain positively for collecting duct markers. [76] [77] Studies of Pkd1 or Pkd2 rodent models with postnatal development of cystic disease have shown that most cysts originate from the collecting ducts and distal nephron. [39] [43] [44] [64] Cultured epithelial cells from human ADPKD cysts exhibit a larger cAMP response to 1-deamino-8-d-arginine vasopressin (DDAVP) and vasopressin than to parathyroid hormone, consistent with a collecting duct origin.[77] These observations indicate that the majority of cysts in ADPKD at early stages derive from the distal nephron and the collecting duct, whereas other segments of the nephron may undergo cystic dilatation at later stages of the disease ( Fig. 41-6 ).
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FIGURE 41-6 Scanning electron micrographs of cyst-lining epithelium in autosomal dominant polycystic kidney disease: A, typical of glomerular visceral layer (×250); B, typical of proximal tubule (×3000); C, typical of cortical collecting duct (×1000); D, epithelium not typical of any normal tubule segment (×1000); E, micropolyps (×250); F, cord-like hyperplasia (×80). (From Grantham JJ, Geiser JL, Evan AP: Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int 31:1145–1152, 1987, with permission.) |
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At the end stage of the disease, the kidneys are usually several times larger than normal and exhibit innumerable fluid-filled cysts that make up almost all of the total renal mass. In these far-advanced cases, only scant normal-appearing parenchyma may be found in isolated patches. There is abundant fibrous tissue plastered along the surface of the kidneys beneath the capsule, and on the cut surface of transected kidneys, cysts may be found encapsulated by fibrous bands. Tubulointerstitial fibrosis and arteriolar sclerosis are cardinal features of the end-stage polycystic kidney. The disappearance of noncystic parenchyma implicates apoptosis as a primary mechanism in progressive renal dysfunction in ADPKD.
Up to 90% of adults with ADPKD have cysts of the liver.[78] These cysts are lined by a single layer of epithelium resembling that of the biliary tract and contain fluid that resembles the bile salt independent fraction of the bile. The electrolyte composition and osmolality are similar to those in serum, whereas the concentrations of phosphorus, cholesterol, and glucose are lower.[79] They derive by progressive proliferation and dilatation of the biliary ductules (biliary microhamartomas or von Meyenburg complexes) and peribiliary glands. [81] [82] As in the case of the cysts in the kidney, they become detached as they grow, so that macroscopic liver cysts usually do not communicate with the biliary system. Minimal to moderate dilatation of the extrahepatic bile ducts is common. In rare kindreds, hepatic changes indistinguishable from those seen in congenital hepatic fibrosis (CHF) can be seen.
Diagnosis
The diagnosis of ADPKD in an individual with a positive family history relies on imaging testing. Counseling should be done before testing. Benefits of testing include certainty regarding diagnosis that may influence family planning, early detection and treatment of disease complications, and selection of genetically unaffected family members for living related donor renal transplantation. Potential discrimination in terms of insurability and employment associated with a positive diagnosis should be discussed. Renal ultrasound is commonly used because of price and safety ( Fig. 41-7 ). Sonographic diagnostic criteria for individuals at 50% risk for the disease include at least two unilateral or bilateral cysts in individuals younger than 30 years of age; two cysts in each kidney in individuals 30 to 59 years of age; four cysts in each kidney in individuals 60 years of age or older.[82] The sensitivity of these criteria is nearly 100% for individuals 30 years or older and for younger individuals with PKD1 mutations but only 67% for individuals with PKD2 mutations younger than 30 years.[83] These sonographic criteria are not applicable to more sensitive imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). In the absence of a family history of ADPKD, bilateral renal enlargement and cysts with or without hepatic cysts and absence of other manifestations suggesting a different renal cystic disease provide presumptive evidence for the diagnosis. Contrast enhanced CT and MRI provide better anatomic definition than ultrasound and are more helpful to ascertain the severity and prognosis of the disease (Fig. 41-8, 41-9 [8] [9]).
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FIGURE 41-7 Autosomal dominant polycystic kidney disease seen in a parasagittal or longitudinal sonogram. This view of the right kidney was obtained with the patient in the right anterior oblique position. The approximate outline of the kidney is shown by the broken line. Some of the larger renal cysts are indicated by C. The liver (L) is at the top of the figure. The right dome of the diaphragm (D) is at the lower left. |
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FIGURE 41-8 Computed tomography scans of polycystic kidneys. The patient (male) has autosomal dominant polycystic kidney disease, and the serum creatinine level is within the normal range. An oral contrast agent was given to highlight the intestine. A, Computed tomographic scan without contrast. B, Computed tomographic scan at the same level as A but after intravenous infusion of iodinated radiocontrast material. The cursor (box) is used to determine the relative density of cyst fluid, which in this case, is equal to that of water. Contrast enhancement highlights functioning parenchyma, which here is concentrated primarily in the right kidney. The renal collecting system also is highlighted by contrast material in both kidneys. |
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FIGURE 41-9 Magnetic resonance imaging studies of two female patients, with mild and moderately severe disease. In neither subject was the serum creatinine value higher than 1.1 mg/dL. In panels A and C, gadolinium was infused intravenously a few minutes before the scan was obtained. The residual, normal parenchyma between cysts is highlighted by gadolinium. In panels B and D, heavy-weighted T2 images are shown at the same kidney level as in A and C. The cysts are emphasized, illustrating that cysts smaller than 3 mm can be detected. |
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Genetic testing can be used when the imaging results are equivocal and when a definite diagnosis is required in a younger individual, such as a potential living related kidney donor. Prenatal and preimplantation genetic testing are rarely considered for ADPKD. [85] [86] Genetic testing can be performed by linkage or sequence analysis. Linkage analysis uses highly informative microsatellite markers flanking PKD1 and PKD2, and requires accurate diagnosis, availability, and willingness of sufficient affected family members to be tested. Because of these constraints, linkage analysis is suitable in fewer than 50% of families. The large size and complexity of PKD1 and marked allelic heterogeneity are obstacles to molecular testing by direct DNA analysis. Mutation scanning by methods such as DHPLC in research settings has yielded mutation detection rates of approximately 65% to 70% for PKD1 and PKD2.[87] [88] Higher rates of approximately 85% are now possible by direct sequencing.[88] However, because most mutations are unique and up to one third of PKD1 changes are missense, the pathogenicity of some changes is difficult to prove.
Renal Manifestations
Cyst Development and Growth
Many manifestations are directly related to the development and enlargement of renal cysts. A study of 241 nonazotemic patients followed prospectively with yearly MRI examinations by the Consortium of Imaging Studies to assess the Progression of Polycystic Kidney Disease (CRISP) has provided invaluable information to understand how the cysts develop and grow. [90] [91] Total kidney volume and cyst volumes increased exponentially ( Fig. 41-10 ). At baseline, total kidney volume was 1060 ± 642 mL and the mean increase over 3 years was 204 mL or 5.3% per year. The rates of change of total kidney and total cyst volumes, and of right and left kidney volumes, were strongly correlated. Baseline total kidney volume predicted the subsequent rate of increase in renal volume and was associated with declining glomerular filtration rate (GFR) in patients with baseline total kidney volume higher than 1500 mL.
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FIGURE 41-10 Progression of ADPKD. A, Combined left and right kidney (TKV) and cyst (TCV) volumes in relation to age in women (blue) and men (red). The lines connecting the four measurements for each patient in the 3 years of follow-up exhibit a concave upward sweep suggestive of an exponential growth process. B, Log10 combined total kidney (TKV) and cyst (TCV) volumes in relation to time. The linearity of the four measurements for each patient in the 3 years of follow-up is consistent with an exponential growth process. (Reproduced from Grantham JJ, Torres VE, Chapman AB, et al: Volume progression in polycystic kidney disease. N Engl J Med 354:2122–2130, 2006.) |
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Renal Function Abnormalities
Impaired urinary concentrating capacity is common even at early stages.[91] Sixty percent of children cannot maximally concentrate the urine. Plasma vasopressin levels are increased. The vasopressin-resistant concentrating defect is not explained by reduced cAMP or expression of concentration associated genes, which are consistently increased in animal models. Whether it is due to disruption of the medullary architecture by the cysts or to a cellular defect directly linked to the disruption of the polycycstin function has not been determined. Recent studies suggest that the urinary concentrating defect and elevated vasopressin levels may contribute to cystogenesis. They may also contribute to the glomerular hyperfiltration seen in children and young adults,[92] and to the development of hypertension and chronic kidney disease progression. Defective medullary trapping of ammonia and transfer to the urine caused by the concentrating defect may contribute to the low urine pH values, hypocitric aciduria, and predisposition to stone formation.
Reduced renal blood flow is another early functional defect.[93] It may be due to the changes in intrarenal pressures, to neurohumoral or local mediators, or to intrinsic vascular abnormalities. Mild to moderate persistent proteinuria (150–1500 mg/day) may be found in a significant number of patients in the middle to late stages of the disease. It is an indicator of more progressive disease.[94] Patients with proteinuria may also excrete doubly refractile lipid bodies (oval fat bodies).[95]
Hypertension
Hypertension (blood pressure [BP] > 140/90 mm Hg), present in approximately 50% of 20- to 34-year-old patients with ADPKD with normal renal function, increases to nearly 100% of patients with ESRD.[96] Hypertension development is accompanied by a reduction in renal blood flow, increased filtration fraction, abnormal renal handling of sodium, and extensive remodeling of the renal vasculature.
The association between renal size and prevalence of hypertension supports the hypothesis that stretching and compression of the vascular tree by cyst expansion causes ischemia and activation of the renin-angiotensin system.[97]The expression of PC1 and PC2 in vascular smooth muscle [99] [100] [101] and endothelium,[101] along with enhanced vascular smooth muscle contractility[102] and impaired endothelial dependent vasorelaxation,[103] suggest that a primary disruption of polycystin function in the vasculature may also play a role in the early development of hypertension and renal vascular remodeling.
Whether circulating angiotensin is instrumental in causing hypertension is controversial. [105] [106] Plasma renin activity and aldosterone are normal in most studies. Because blood pressures are higher than those of controls, it has been argued that the renin and aldosterone levels are not appropriately suppressed. A 1990 study showed higher levels following short-term or long-term administration of an angiotensin-converting enzyme inhibitor (ACEI) in normotensive and hypertensive ADPKD patients with normal renal function compared with normal subjects and patients with essential hypertension.[104] A more recent study found no differences in hormonal or blood pressure responses between patients with ADPKD and patients with essential hypertension matched in terms of renal function and blood pressure under conditions of high and low-sodium intake and after the administration of an ACEI.[105]Sodium intake was not controlled in the former study, and differences in selection and ethnic composition of the control groups have been offered as possible explanations for the different results.
There is stronger evidence for the local activation of the intrarenal renin-angiotensin system. This includes (1) partial reversal of the reduced renal blood flow, increased renal vascular resistance and increased filtration fraction by acute or chronic administration of an ACEI [105] [107] [108]; (2) shift of immunoreactive renin from the juxtaglomerular apparatus to the walls of the arterioles and small arteries [109] [110]; (3) ectopic synthesis of renin in the epithelium of dilated tubules and cysts [111] [112]; and (4) ACE-independent generation of angiotensin II by a chymase-like enzyme.[111]
Nitric oxide endothelium-dependent vasorelaxation has been shown to be impaired in small subcutaneous resistance vessels from patients with normal renal function before the development of hypertension. [113] [114] [115] Other factors proposed to contribute to hypertension in ADPKD include increased sympathetic nerve activity and plasma endothelin-1 levels and insulin resistance.[115]
The diagnosis of hypertension in ADPKD is often made late. Twenty-four-hour ambulatory blood pressure monitoring of children or young adults without hypertension may reveal elevated blood pressures, attenuated nocturnal blood pressure dipping, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction. Early detection and treatment of hypertension is important because cardiovascular disease is the main cause of death. [19] [117] Uncontrolled blood pressure increases the morbidity and mortality from valvular heart disease and aneurysms, and increases the risk of proteinuria, hematuria, and a faster decline of renal function. The presence of hypertension also increases the risk of fetal and maternal complications during pregnancy. Normotensive women with ADPKD usually have uncomplicated pregnancies.[117]
Pain
Pain is the most frequent symptom (∼60%) reported by adult patients. [119] [120] Acute pain may be associated with renal hemorrhage, passage of stones, and urinary tract infections. Some patients develop chronic flank pain without identifiable etiology other than the cysts.
Vascular endothelial growth factor (VEGF) produced by the cystic epithelium[120] may promote angiogenesis, hemorrhage into cysts, and gross hematuria. Symptomatic episodes likely underestimate the frequency of cyst hemorrhage because more than 90% of ADPKD patients have hyperdense (CT) or high-signal (MRI) cysts reflecting blood or high protein content. Most hemorrhages resolve within 2 to 7 days. If symptoms last longer than 1 week or if the initial episode occurs after the age of 50 years, investigation to exclude neoplasm should be undertaken.
Approximately 20% of ADPKD patients have kidney stones usually composed of uric acid and calcium oxalate. [122] [123] Metabolic factors include decreased ammonia excretion, low urinary pH, and low urinary citrate concentration. Urinary stasis secondary to the distorted renal anatomy may also play a role. A CT of the abdomen before and following contrast enhancement is the best imaging technique to detect small uric acid stones that may be very faint on plain films with tomograms and to differentiate stones from cyst wall and parenchymal calcifications. Stones may be missed if only a contrast-enhanced CT is obtained ( Fig. 41-11 ).
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FIGURE 41-11 Computed tomography (CT) scan of polycystic kidneys in a male patient with serum creatinine level within the normal range. A, CT scan without contrast shows a radiopaque stone in the pelvis of the right kidney (arrow). B, CT scan after intravenous administration of an iodinated radiocontrast agent. The stone now is obscured by contrast medium in the renal pelvis. |
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As in the general population, urinary tract infections affect women more frequently than men. Most are caused by entero bacteriaceae.[123] CT and MRI are useful to detect complicated cysts and provide anatomic definition, but the findings are not specific for infection ( Fig. 41-12 ). Nuclear imaging (67Ga or 111In-labeled leukocyte scans) may be helpful, but false-negative and false-positive results are possible. Cyst aspiration should be considered when the clinical setting and imaging are suggestive and blood and urine cultures are negative.
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FIGURE 41-12 Cyst infection. Contrast-enhanced CT demonstrates a 4 cm infected cyst in the anterior portion of the lower pole of the right kidney and inflammatory stranding in the perirenal fat (A, B). A repeat CT after three weeks of antibiotic therapy shows a decrease in the size of the cyst and improved enhancement of the renal parenchyma (C, D). |
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Renal cell carcinoma (RCC) is a rare cause of pain in ADPKD. It does not occur more frequently than in the general population, but it may present at an earlier age with frequent constitutional symptoms and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors.[124] A solid mass on ultrasound, speckled calcifications on CT and contrast enhancement, and tumor thrombus and regional lymphadenopathies on CT or MRI should raise the suspicion of carcinoma.
Renal Failure
The development of renal failure is highly variable. In most patients, renal function is maintained within the normal range because of compensatory adaptation, despite relent-less growth of cysts, until the 4th to 6th decade of life (Fig. 41-13 ). By the time renal function starts declining, the kidneys usually are markedly enlarged and distorted with little recognizable parenchyma on imaging studies. At this stage, the average rate of GFR decline is approximately 4.4 to 5.9 mL/min/year.[125] The mutated gene (PKD1 versus PKD2), position of the mutation in PKD1, and modifier genes determine to a significant extent the clinical course of ADPKD (see earlier). Other risk factors include male gender (particularly in PKD2), diagnosis before the age of 30 years, first episode of hematuria before the age of 30, onset of hypertension before the age of 35, hyperlipidemia, low level of high-density lipoprotein, and sickle cell trait. [127] [128] Whether blacks or individuals with specific ACE or ENOS genotypes are at an increased risk for disease progression is uncertain. Smoking increases the risk for ESRD at least in some patient subsets (male smokers with no history of ACE inhibitor treatment).[128]
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FIGURE 41-13 Effects of compensatory maintenance of glomerular filtration rate (GFR) on the pattern of progression in autosomal dominant polycystic kidney disease (ADPKD). It was assumed that, beginning at the age of 10 years, the patient loses an amount of parenchyma each year that normally contributes 2 mL/min of GFR. It was further assumed that each residual normal glomerulus can double the single-nephron GFR by compensatory mechanisms (as evinced in normal individuals by the maintenance of total GFR after uninephrectomy for kidney donation). As seen in the model, total GFR is maintained until parenchymal loss precludes complete compensation; at that point, total GFR begins to fall at a rate that appears more “precipitous” than what had actually occurred. This model illustrates that GFR is a poor indicator of ADPKD progression and that more sensitive markers of parenchymal loss are needed to facilitate earlier monitoring. |
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Several factors contribute to renal function decline. A strong relationship with renal enlargement has been noted. CRISP has confirmed this relationship and shown that kidney and cyst volumes are the strongest predictors of renal functional decline.[129] CRISP also found that renal blood flow (or vascular resistance) is an independent predictor.[93] This factor points to the importance of vascular remodeling in the progression of the disease and may account for cases in which the decline of renal function seems to be out of proportion to the severity of the cystic disease. Angiotensin II, transforming growth factor-β, and reactive oxygen species may contribute to the vascular lesions and interstitial inflammation and fibrosis by stimulating the synthesis of chemokines, extracellular matrix, and metalloproteinase inhibitors. The expression of monocyte chemotactic protein-1 (MCP-1) and osteopontin is increased in cyst epithelial cells. MCP-1 is found in cyst fluids in high concentrations, and the urinary excretion is increased.[130] Other factors such as heavy use of analgesics may contribute to chronic kidney disease (CKD) progression in some patients.
ADPKD patients with advanced CKD have less anemia compared with patients with other renal diseases because of enhanced production of erythropoietin by the polycystic kidneys.
Extrarenal Manifestations
Polycystic Liver Disease
Polycystic liver disease (PLD) is the most common extrarenal manifestation. It is associated with both PKD1 and non-PKD1 genotypes. PLD also occurs as a genetically distinct disease in the absence of renal cysts. Like ADPKD, ADPLD is genetically heterogeneous, with two genes identified (PRKCSH in chromosome 19 and Sec63 in chromosome 6) accounting for approximately one third of isolated ADPLD cases. [132] [133] [134]
Although rare in children, the frequency of hepatic cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study was 58%, 85%, and 94% in 15- to 24-year-old, 25- to 34-year-old, and 35- to 46-year-old participants, respectively.[78] Hepatic cysts are more prevalent and hepatic cyst volume is larger in women than in men. Women who have multiple pregnancies or who have used oral contraceptive agents or estrogen replacement therapy have more severe disease, suggesting an estrogen effect on hepatic cyst growth. [98] [135] Estrogen receptors are expressed in the epithelium lining the hepatic cysts, and estrogens stimulate hepatic cyst-derived cell proliferation.
Typically, PLD is asymptomatic, but symptoms have become more frequent as the lifespan of ADPKD patients has lengthened because of dialysis and transplantation. Symptoms may result from the mass effect or from complicating infection and hemorrhage ( Fig. 41-14 ). Symptoms typically caused by massive enlargement of the liver or by mass effect from a single or a limited number of dominant cysts include dyspnea, early satiety, gastroesophageal reflux, and mechanical low back pain. Other complications caused by mass effect include hepatic venous outflow obstruction, inferior vena cava compression, portal vein compression, or bile duct compression presenting as obstructive jaundice.[135]
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FIGURE 41-14 Computed tomography (CT) scan of polycystic liver and kidneys in female patient with autosomal dominant polycystic kidney disease. The serum creatinine level and liver function test results were within the normal range. An oral contrast agent was given to highlight the intestine, but no intravenous contrast was used. A, There is massive enlargement of the liver due to intraparenchymal cysts. B, CT scan at a lower level in the abdomen shows cystic kidneys and the lower portion of the cystic liver. |
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Symptomatic cyst complications include cyst hemorrhage, infection, and rarely torsion or rupture. The typical presentation of cyst infection is with localized pain, fever, leukocytosis, elevated sedimentation rate, and often elevated alkaline phosphatase. It is usually monomicrobial and caused by enterobacteriaceae.[136] MRI sensitively differentiates between a complicated and an uncomplicated hepatic cyst. On CT scanning, fluid-fluid levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density have been associated with infection. Radionuclide imaging and more recently 18F-fluorodoxyglucose positron emission tomography scanning have been used for diagnosis.[137]
Mild dilatation of the common bile duct has been observed in 40% of patients studied by CT and may rarely be associated with episodes of cholangitis.[138] Rare associations of PLD include CHF, adenomas of the ampulla of Vater, and cholangiocarcinoma.
Cysts in Other Organs
Cysts are found in pancreas in approximately 5%, arachnoid in approximately 8%, and seminal vesicles in approxi-mately 40%. [140] [141] [142] [143] [144] [145] Seminal vesicle cysts rarely result in infertility.[145] Defective sperm motility is another cause of male infertility in ADPKD.[146] Pancreatic cysts are almost always asymptomatic, with very rare occurrences of recurrent pancreatitis. It is uncertain whether the reported association of carcinoma of the pancreas represents more than chance. Arachnoid membrane cysts are asymptomatic but may increase the risk for subdural hematomas. [142] [148] Spinal meningeal diverticula may occur with increased frequency and rarely present with intracranial hypotension due to cerebrospinal fluid leak.[148] Ovarian cysts are not associated with ADPKD.
Vascular Manifestations
These include ICAs and dolichoectasias, thoracic aortic and cervicocephalic artery dissections, and coronary artery aneurysms. They are caused by alterations in the vasculature directly linked to mutations in PKD1 or PKD2. PC1 and PC2 are expressed in vascular smooth muscle cells (VSMCs). [99] [100] [101] Pkd2+/- VSMCs exhibit increased rates of proliferation and apoptosis, and Pkd2+/- mice have an increased susceptibility to vascular injury and premature death when induced to develop hypertension. [46] [66]
ICAs occur in approximately 6% of patients with a negative family history and 16% of those with a positive family history of aneurysms.[149] They are most often asymptomatic. Focal findings such as cranial nerve palsy or seizure result from compression of local structures. The risk of rupture depends on many factors (see later). Rupture carries a 35% to 55% risk of combined severe morbidity and mortality.[150] The mean age at rupture is lower than in the general population (39 years versus 51 years). Most patients have normal renal function, and up to 29% will have normal blood pressure at the time of rupture.
Cardiac Manifestations
Mitral valve prolapse observed by echocardiology is the most common valvular abnormality found in up to 25% of patients. [152] [153] Aortic insufficiency may occur in association with dilatation of the aortic root.[153] Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination.
Diverticular Disease
Colonic diverticulosis and diverticulitis are more common in ESRD patients with ADPKD than in those with other renal diseases. Whether this increased risk extends to patients before the onset of ESRD is uncertain.[154] There have been reports of extracolonic diverticular disease.[155] It may become clinically significant in a minority of patients. Subtle alterations in polycystin function may enhance the smooth muscle dysfunction from aging, which is thought to underlie the development of diverticula.
Treatment
Current therapy is directed toward limiting the morbidity and mortality from the complications of the disease.
Hypertension
There is no proven antihypertensive agent of choice. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) increase renal blood flow, have a low side effect profile, and may have renoprotective properties beyond blood pressure control. Some studies have shown better preservation of renal function or reduction in proteinuria and left ventricular hypertrophy with ACEIs or ARBs compared with diuretics or calcium channel blockers, [157] [158] [159] whereas others have been unable to detect the superiority of these drugs.[159] A meta-analysis of 142 ADPKD patients in eight randomized clinical trials showed that ACEIs were more effective in lowering urine protein excretion and slowing kidney disease progression in patients with higher levels of proteinuria, but the overall kidney disease progression was not significantly different (29% in the ACEI group versus 41% in the control group).[160] Most studies have been limited by inadequate power, short follow-ups, wide ranges of renal function, and doses with inadequate pharmacologic effects.
Equally uncertain is the optimal blood pressure target. In the modification of diet in renal disease (MDRD) study, ADPKD patients with a baseline GFR between 13 and 24 mL/min/1.73 m2 assigned to a low blood pressure target (<92 mm Hg) had faster decline in GFR than those assigned to a standard blood pressure goal (<107 mm Hg), may be due to the inability to autoregulate renal blood flow.[125] The rate of decline in participants with a baseline GFR between 25 and 55 mL/min/1.73 m2 was not affected by the blood pressure target over a mean intervention period of 2.2 years. However, an extended follow-up of these patients showed a delayed onset of kidney failure and a reduced composite outcome of kidney failure and all-cause mortality in the low blood pressure group (51% of them taking ACEIs), compared with those in the usual blood pressure group (32% of them taking ACEIs).[161] The magnitude of this beneficial effect was similar to that observed in patients with other renal diseases. A study of 513 ADPKD subjects at the University of Colorado over two periods, 1985 to 1992 and 1992 to 2001, demonstrated longer survival to ESRD associated with lower blood pressures and more frequent use of ACEIs.[162] A small prospective study from the same institution showed that rigorous blood pressure control caused a greater decrease in left ventricular mass without a detectable effect on renal function.[163]
Until more information becomes available, it seems reasonable to control the blood pressure to less than 130/80 mm Hg with a regimen that includes ACEIs or ARBs. An ongoing study (HALT-PKD) is designed to determine whether combined therapy with an ACEI and an ARB is superior to an ACEI alone in delaying the progression of the cystic disease in patients with CKD stage 1 or 2 or in slowing down the decline of renal function in patients with CKD stage 3. HALT-PKD will also determine whether a low blood pressure target (<110/75) is superior to a standard blood pressure target (<130/80) in the group of patients with preserved function.
Pain
Causes of pain that may require intervention such as infection, stone, or tumor should be excluded. Long-term administration of nephrotoxic agents should be avoided. Narcotic analgesics should be reserved for acute episodes. Psychological evaluation and an understanding and supportive attitude on the part of the physician are essential to minimize the risk for narcotic and analgesic dependence in patients with chronic pain. Reassurance, lifestyle modification, avoidance of aggravating activities, tricyclic antidepressants, and pain clinic interventions such as splanchnic nerve blockade with local anesthesia or steroids may be helpful. [119] [120]
When conservative measures fail, surgical interventions can be considered. Aspiration of large cysts under ultrasound or CT guidance is a simple procedure and may help to identify the cause of the pain. Sclerosing agents may be used to prevent the reaccumulation of fluid. When multiple cysts contribute to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incisions may be of benefit.[164] Laparoscopy is as effective as open surgical fenestration for patients with limited disease and has a shorter, less complicated recovery period. [166] [167] Laparoscopic renal denervation or thoracoscopic sympathosplanchnicectomy can be considered particularly in polycystic kidneys without large cysts. [168] [169] Surgical interventions do not accelerate the decline in renal function as was once thought, but they do not preserve declining renal function either. Laparoscopic or retroperitoneoscopic nephrectomy is indicated for symptomatic patients with ESRD. Arterial embolization is an alternative when the surgical risk is high, but its role has not been fully defined.
Cyst Hemorrhage
Cyst hemorrhages are usually self-limiting and respond to conservative management with bed rest, analgesics, and hydration. When there is a subcapsular or retroperitoneal hematoma causing significant decrease in hematocrit and hemodynamic instability, hospitalization, transfusion, and investigation by CT or angiography become necessary. DDAVP and aprotinin may be helpful. Segmental arterial embolization or surgery may be required in some cases.
Cyst Infection
Cyst infections are often difficult to treat.[123] Treatment failure may occur because poor antibiotic penetration into the cysts. Lipophilic agents penetrate the cysts consistently. If fever persists after 1 to 2 weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts or, in the case of end-stage polycystic kidneys, nephrectomy should be undertaken. If fever recurs after stopping antibiotics, complicating features such as obstruction, perinephric abscess, or stone should be excluded. If none is identified, several months of antibiotic therapy may be required to eradicate the infection.
Nephrolithiasis
Treatment is similar to that in patients without ADPKD. Potassium citrate is indicated for three causes of stones associated with ADPKD, uric acid lithiasis, hypocitraturic calcium oxalate nephrolithiasis and distal acidification defects. Extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy have been performed successfully without undue complications.
End-Stage Renal Disease
Patients with ADPKD do better on dialysis than patients with other causes of ESRD. This may be due to higher levels of erythropoietin and hemoglobin or to lower co-morbidity.[169] Despite renal size and increased risk for hernias, peritoneal dialysis is usually possible.
There is no difference in patient or graft survival between ADPKD patients and other ESRD populations. The number of living donor transplants for ADPKD in the United States has increased from 12% in 1990 to 30% in 1999. Complications after transplant are no greater than in the general population. Complications directly related to ADPKD are rare.
Pretransplant nephrectomy is reserved for patients with a history of infected cysts, frequent bleeding, severe hypertension, or massive renal enlargement. Hand-assisted laparoscopic nephrectomy is increasingly being used.[166]
Polycystic Liver Disease
Most cases of PLD require no treatment. Patients with severe PLD should avoid estrogens and compounds that promote cAMP accumulation (e.g., caffeine). Histamine H2 blockers and proton pump inhibitors may inhibit secretin production and fluid secretion into cysts. Rarely, symptomatic PLD requires interventions to reduce cyst volume and hepatic size. The choice of procedure (percutaneous cyst aspiration without or with sclerosis, laparoscopic cyst fenestration, combined liver resection and cyst fenestration, and liver transplantation) is dictated by the anatomy and distribution of the cysts. [171] [172] [173] [174] [175]
Combined percutaneous cyst drainage and antibiotic therapy provide the best treatment results for hepatic cyst infections.[136] Long-term oral antibiotic suppression or prophylaxis is indicated for relapsing or recurrent cases. Fluoroquinolones and trimethoprim-sulfamethoxazole are effective against the typical infecting organisms and have good penetration into the biliary tree and cysts.
Intracranial Aneurysm
Widespread presymptomatic screening is not indicated because it yields mostly small aneurysms in the anterior circulation with a low risk of rupture. Indications for screening in patients with good life expectancy include family history of aneurysm or subarachnoid hemorrhage, previous aneurysm rupture, preparation for major elective surgery, high-risk occupations (e.g., airline pilots), and patient anxiety despite adequate information.[149] MR angiography does not require intravenous contrast material. CT angiography is a satisfactory alternative when there is no contraindication to intravenous contrast.
When an asymptomatic aneurysm is found, a recommendation on whether to intervene depends on its size, site, and morphology; prior history of subarachnoid hemorrhage from another aneurysm; patient age and general health; and whether the aneurysm is coilable or clippable. The prospective arm of International Study of Unruptured Intracranial Aneurysms (ISUIA) has provided invaluable information to assist in the decision.[175] The 5-year cumulative rupture rates for patients without a previous history of subarachnoid hemorrhage with aneurysms located in the internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2.6%, 14.5%, and 44.0% for aneurysms less than 7 mm, 7 to 12 mm, 13 to 24 mm, and 25 mm or greater, respectively, compared with rates of 2.5%, 14.5%, 18.4%, and 50%, respectively, for the same size categories involving the posterior circulation and posterior communicating artery. Among unruptured noncavernous segment aneurysms less than 7 mm in diameter, the rupture risks were higher among those who had a previous subarachnoid hemorrhage from another aneurysm. These risks need to be balanced with those associated with surgical or endovascular surgery also reported by ISUIA. The 1-year mortality and combined morbidity (Rankin score 3 to 5 or impaired cognitive status) and mortality rates for surgical or endovascular repair were 2.7% and 12.6% for open surgery and 3.4% and 9.8% for endovascular repair.
The risk for development of new aneurysms or enlargement of an existing one in ADPKD patients is very low in those with small (<7 mm) aneurysms detected by presymptomatic screening and moderate in those with a previous rupture from a different site. [177] [178] Based on these and the ISUIA data, conservative management is usually recommended for ADPKD patients with small (<7 mm) aneurysms detected by presymptomatic screening, particularly in the anterior circulation. Semiannual or annual repeat imaging studies are appropriate initially, but reevaluation at less frequent intervals may be sufficient once the stability of the aneurysm has been documented. Elimination of tobacco use and aggressive treatment of hypertension and hyperlipidemia should be recommended.
The risk of developing a new aneurysm after an initial negative study is small, about 3% at 10 years in patients with a family history of ICAs.[178] Therefore, rescreening of patients with a family history of ICAs after an interval of 5 to 10 years seems reasonable.
Novel Therapies
A better understanding of the pathophysiology and the availability of animal models has facilitated the development of preclinical trials and identification of promising candidate drugs for clinical trials.
The effect of vasopressin, via V2 receptors, on cAMP levels in the collecting duct, the major site of cyst development in ADPKD, and the role of cAMP in cystogenesis provided the rationale for preclinical trials of vasopressin V2 receptor (VPV2R) antagonists. One of these drugs, OPC-31260, dramatically reduced levels of cAMP and inhibited cyst development in models of ARPKD, ADPKD, and NPH. [63] [64] [180] Recently, an antagonist with high potency and selectivity for the human VPV2R (tolvaptan) has also been shown to be an effective treatment in the PCK rat model of ARPKD[180] and the Pkd2 mouse model of ADPKD. These drugs have no effect on liver cysts, which is consistent with the absence of vasopressin V2 receptors in the liver. High water intake by itself also exerts a protective effect on the development of PKD in PCK rats likely due to suppression of vasopressin.[181] Phase II clinical trials with tolvaptan have been completed, and a phase III clinical trial is under way.
Somatostatin acting on SST2 receptors inhibits cAMP accumulation not only in the kidney but also in the liver. Octreotide, a synthetic metabolically stable somatostatin analog, halts the expansion of hepatic cysts from PCK rats in vitro and in vivo.[182] Similar effects were observed in the kidneys of the PCK rat. These observations are consistent with the inhibition of renal growth in a pilot study of long-acting octreotide for human ADPKD[183] and provide support for further clinical trials for PKD and PLD.
Patients with the contiguous PKD1-TSC2 gene syndrome exhibit a more severe form of PKD than those with ADPKD alone. This observation suggests a convergence of signaling pathways downstream from PC1 and tuberin. Recently, mTOR activation in polycystic kidneys and an interaction between PC1 and the tuberous sclerosis protein tuberin have been reported.[184] Furthermore, studies in three rodent models of PKD have shown that rapamycin significantly retards cyst expansion and protects renal function. [185] [186] [187] Phase 2 clinical trials of rapamycin and everolimus, two mTOR inhibitors, are being implemented.[187]
Other drugs shown to be effective in preclinical trials and of potential value for the treatment of human PKD include ErbB1 (EGRF) and ErbB2 tyrosine kinase inhibitors, Src kinase inhibitors, MEK inhibitors, and cyclin-dependent kinase inhibitors. [189] [190] [191] [192] These drugs which have been developed for the treatment of neoplastic diseases may also be considered for the treatment of PKD.
In planning for clinical trials for ADPKD, the use of renal function as the primary outcome becomes an issue. Decades of normal renal function, despite progressive enlargement and cystic transformation of the kidneys, characterize the natural history of ADPKD. By the time the GFR starts declining, the kidneys are markedly enlarged, distorted, and unlikely to benefit from treatment. On the other hand, early interventional trials would require unrealistic periods of follow-up if renal function was to be used as the primary outcome. The results of CRISP have shown that the rate of renal growth is a good predictor of functional decline and justify the use of kidney volume as a marker of disease progression in clinical trials for ADPKD.[90]
Autosomal Recessive Polycystic Kidney Disease
Epidemiology
ARPKD is generally characterized by relatively rapid, symmetric, bilateral renal enlargement in infants due to collecting duct cysts in association with CHF. [193] [194] [195] Nonobstructive intrahepatic bile duct dilatation (Caroli disease) is variably seen. A minority of individuals may present as older children, teenagers, or young adults, usually with manifestations of portal hypertension or cholangitis. Rarely, the presentation may be in older adults mostly with complications of the liver disease, but sometimes with renal manifestations such as proteinuria, nephrolithiasis, and renal insufficiency. [196] [197] Prevalence and carrier frequency are thought to be 1:20,000 and 1:70, respectively.[194] Recent molecular data indicate that ARPKD is likely to be found in all racial groups. [198] [199]
Genetics
ARPKD is inherited as an autosomal recessive trait and, therefore, may occur in siblings but not in the parents. The disease is observed in one fourth of the offspring of carrier parents. All cases of typical ARPKD are due to mutations in a gene on chromosome 6p21.1-p12 (PKHD1). [200] [201] [202] Recent studies have shown that PKHD1 mutations are also responsible for nonsyndromic CHF and Caroli disease.[196]
PKHD1 is among the largest genes in the human genome, extending over at least 470 kb and including a minimum of 86 exons. [203] [204] Mutations are scattered throughout the gene without hot spots. [198] [199] Most have been described in just a single family, but some are more frequent in particular populations (R496X in Finland and 9689delA in Spain, for instance). [205] [206] One missense substitution T36M has been found on approximately 16% of mutant alleles and seems to be an ancestral mutation that arose in Europe more than a 1000 years ago.[206] There is evidence of genotype-phenotype correlations. Patients with two truncating mutations consistently have a severe renal presentation, and the majority of patients with a severe renal presentation have at least one truncating mutation, [205] [206] whereas those with moderate renal presentation most often have missense mutations.[207] Despite the importance of the germline mutations, affected sibling pairs may exhibit phenotypes of markedly discordant severity, most likely due to the effect of modifier genes.
Pathogenesis
The ARPKD protein, fibrocystin (∼460 kDa), has a single transmembrane pass, a large extracellular region containing IPT/TIG (immunoglobin-like fold shared by plexins and transcription factors) and PbH1 (Parallel Beta-Helix 1) repeats, and an intracellular carboxyl tail with potential phosphorylation sites (see Fig. 41-2 ). [203] [204] This suggests that fibrocystin may be a cell surface receptor implicated in protein-protein interactions. Like the polycystins, fibrocystin is localized in primary cilia. Fibrocystin, polycystin 2, and the kinesin-2 motor subunit KIF3B form a protein complex in which KIF3B acts as a linker between fibrocystin and polycystin 2.[208] The physical interaction between fibrocystin and the motor protein KIF3B may explain the structural abnormalities described in the primary cilia of PCK rat cholangiocytes.[17] Within the fibrocystin/KIF3B/polycystin 2 complex, fibrocystin is capable of enhancing the channel function of polycystin 2. Fibrocystin has also been shown to interact with calcium-modulating cyclophilin ligand, a protein that participates in the regulation of cytosolic calcium pools.[209] These observations suggest that an alteration of the intracellular calcium homeostasis plays an important role in ARPKD, as also seems to be the case in ADPKD. The expression of fibrocystin in ureteric bud branches, intra- and extrahepatic biliary ducts, and pancreatic ducts during embryogenesis is consistent with the histologic features of ARPKD.[210]
Pathology
ARPKD affects both the kidneys and the liver in approximately inverse proportions. That is, the disease may be viewed as a spectrum ranging from severe renal damage and mild liver change at one end to mild renal damage and severe liver change at the other. The form with severe renal damage is the more common and is the form that is manifested at or near the time of birth. The form with less severe renal damage and more severe liver damage is less common and usually is manifested in infancy, childhood, or later.
The kidneys in the perinatal and neonatal forms of ARPKD are symmetrically and bilaterally enlarged up to more than 20 times normal ( Fig. 41-15 ) and may be the cause of dystocia because of their size. Average combined weight of the kidneys in one series was about 300 g (range, 240 to 563 g), compared with a normal combined weight of about 25 g. The renal enlargement is due to fusiform dilatation of collecting ducts to 1 to 2 mm in the cortex and medulla. Almost 100% of collecting ducts are affected in the most severely affected cases. Dilatation of the collecting ducts occurs in the fetal period, and the glomeruli and more proximal tubular elements of the nephron appear normal. However, there is evidence in early human fetuses (14–24 weeks) that proximal tubule cysts occur, as in some rodent models of recessive PKD, [212] [213] [214] but these are no longer evident after 34 weeks' gestation.[214]The dilated collecting ducts are lined by typical cuboidal cells. [216] [217] In many neonatal cases, an overall reduction in size may occur as the children age and macroscopic cysts may develop. Renal calcifications are common in children with ARPKD.
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FIGURE 41-15 Autosomal recessive polycystic kidney disease in a 32-week-old fetus. A, Sonogram showing cystic kidneys (K) of fetus in utero. Gross (B) and microscopic (C) sections show radially oriented cysts of collecting ducts. |
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In later presentations of ARPKD, mainly with complications of portal hypertension due to CHF or episodes of cholangitis due to Caroli disease, the renal involvement may be much less prominent and consists of medullary ductal ectasia with minimal or no renal enlargement. The picture resembles and may be confused with medullary sponge kidney (MSK), a distinct disease with a far different prognosis (see later).
The hepatic lesion is diffuse but limited to the portal areas. Congenital hepatic fibrosis is characterized by enlarged and fibrotic portal areas with apparent proliferation of bile ducts, absence of central bile ducts, hypoplasia of the portal vein branches, and sometimes prominent fibrosis around the central veins. Bulbar protrusions from the walls of dilated ducts also occur, and bridges sometimes form. This malformation has been found to occur occasionally as an isolated event (Caroli disease), but most often it is associated with ARPKD.
Diagnosis
The diagnosis is often made by sonography in utero or shortly after birth. The typical sonogram (see Fig. 41-15 ) shows enlarged kidneys with increased echogenicity in the cortex and medulla, with poor definition of the collecting system and fuzzy delineation of the kidneys from surrounding tissues. Although the appearance of the kidneys on sonography, CT, and MR may be very suggestive of ARPKD, a definite diagnosis based on renal imaging alone is not possible, particularly in utero and in the neonate when the appearance of the kidney may be indistinguishable from ADPKD and other recessive renal cystic diseases. The family history, sonographic or histologic evaluation of the liver for the presence of hepatic fibrosis, and the absence of extrarenal malformations associated with multiple malformation syndromes and with renal dysplasia help in the diagnosis.
Older children and adolescents may present with symptoms and signs referable to the hepatic fibrosis and portal hypertension, including gastrointestinal bleeding from varices, hepatosplenomegaly, and hypersplenism, with or without associated renal manifestations such as a urinary concentrating defect, nephrolithiasis, hypertension, and renal insufficiency. Collecting duct ectasia and macrocystic changes may be observed in the kidneys of these patients (Fig. 41-16 ).
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FIGURE 41-16 Computed tomography (CT) scan of autosomal recessive polycystic kidney disease in an 18-year-old male patient with serum creatinine and liver function test results within normal ranges. The patient had clinical evidence of portal hypertension (gastric varices, enlarged spleen). Oral contrast was given to highlight the intestines. A, CT scan without contrast enhancement. The liver is enlarged but not cystic. The kidneys are slightly enlarged and contain focal radiodense areas (nephrolithiasis). B, CT scan with intravenous iodinated radiocontrast showing cystic areas in both kidneys. The renal calcifications are now obscured by contrast medium in the collecting systems. |
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Owing to the severity of disease in ARPKD, there is significant demand for prenatal diagnostics. This interest is largely from couples with a previously affected pregnancy, either detected in utero (that may have resulted in termination) or the birth of an affected child (who may have died in the neonatal period).[217] There is also demand for molecular diagnostics in older patients with less severe disease to differentiate ARPKD from other causes of childhood PKD. Molecular diagnostics has been offered since PKHD1 was localized using a linkage-based approach with flanking markers. This method requires material from an affected individual with a firm diagnosis of ARPKD and can be complicated by crossovers between flanking markers. With the gene discovery, mutation-based diagnostics has become possible.[218] This method has the advantage that DNA from a previously affected family member is not required and that patients with an uncertain diagnosis can be tested. However, it is complicated by the marked allelic heterogeneity and prevalence of novel missense mutations of uncertain pathogenicity. If two clearly pathogenic mutations are identified, the diagnosis is highly reliable. When only one mutation is identified, diagnosis is often possible in combination with a focused linkage approach.[206] In a recent study, a definitive prenatal diagnosis (presence or absence of two identified mutations) was feasible in 72% and an improved risk assignment (presence or absence of one identified mutation) was possible in an additional 25% of the studied families.[197]
Manifestations
Affected children typically present in utero with enlarged, echogenic kidneys. In the most severe cases, poor urine output may result in oligohydramnios and the Potter sequence, characterized by a typical facies, wrinkled skin, compression deformities of the limbs, and pulmonary hypoplasia. The presentation of ARPKD at birth may be dominated by respiratory difficulties from pulmonary hypoplasia or from restrictive disease due to massive kidney enlargement. The need for neonatal ventilation predicts the development of CKD and death. Approximately 30% of the affected neonates die shortly after birth. [220] [221] [222]
Most patients who survive the neonatal period live to adulthood. Hypertension, electrolyte abnormalities and renal insufficiency are the major disease complications in surviving infants, with liver disease became more important in older patients. Between 55% and 86% of patients developed hypertension with elevated levels often seen at birth or at diagnosis. [221] [222] Its pathogenesis remains undefined. The ectopic expression of components of the renin-angiotensin system in cystic-dilated tubules may suggest that increased intrarenal angiotensin II production contributes to its development.[222] However, the circulating plasma renin level is usually low[219] and the intravascular volume expanded, particularly in the patients with concomitant hyponatremia.[220] Increased sodium reabsorption in the ectatic collecting ducts may contribute to the hypertension, [224] [225] but conflicting data have been reported.[225] Inability to concentrate and to dilute the urine can cause major electrolyte abnormalities. During the first year or two of life, renal function can improve and renal size relative to body mass often decreases. [217] [227] [228] The renal function may remain stable for many years or slowly progress to renal failure. The consequences of chronic renal insufficiency, growth failure, anemia, and osteodystrophy become apparent during childhood. Because complications from liver disease become more important as these children age, careful examination for splenomegaly and blood counts for cytopenias should be regularly performed.
Adolescents and adults present most often with complications of portal hypertension (variceal esophageal bleeding, splenomegaly and hypersplenism with leukopenia, thrombocytopenia, or anemia).[196] Up to 50% of patients with congenital hepatic fibrosis may exhibit segmental dilatation of intrahepatic bile ducts (Caroli disease), sometimes with episodes of cholangitis/sepsis and complications of biliary sludge/lithiasis. Hepatocellular function is rarely deranged, and enzyme values are only occasionally mildly elevated. Increased bilirubin or enzyme values suggest the possibility of cholangitis. The kidneys in these patients may be normal or exhibit various degrees of medullary collecting duct ectasia or macrocystic disease without marked renal enlargement.
Two reports have described ARPKD cases with multiple ICAs. [229] [230] It is not clear whether the prevalence of ICAs is increased in ARPKD or whether these cases are coincidental findings.
Treatment
Recent studies suggest that the prognosis of ARPKD for children who survive the first month of life is far less bleak than was initially thought. [193] [220] [222] In patients with respiratory insufficiency, the cause (pulmonary hypoplasia, abdominal mass, pneumothorax, pneumomediastinum, atelectasis, pneumonia, heart failure) should be assessed fully, and artificial ventilation and aggressive resuscitative measures are indicated. Severely affected neonates may require unilateral or bilateral nephrectomies because of respiratory and nutritional compromise. An aggressive nutritional program and correction of acidosis and other electrolyte disorders are needed to optimize linear growth. The hypertension generally responds to salt restriction and the usual antihypertensive drugs. Like patients with other renal cystic disorders, ARPKD patients are usually susceptible to urinary tract infections, and instrumentation is used only for strong indications.
For infants with ESRF, peritoneal dialysis is preferable, whereas either peritoneal dialysis or hemodialysis are options for children with renal failure. Renal transplantation is the treatment of choice. Pretransplant splenectomy may be indicated for patients with marked leukopenia or thrombocytopenia due to hypersplenism; these patients should receive pneumococcal vaccinations. Rejection rates and survival beyond 3 years are not different from patients undergoing transplant surgery with other renal diseases. Biliary sepsis is a frequent contributor to the mortality in the ARPKD patients who undergo transplant surgery.[230]
Surviving patients and those who present during adolescence are likely to require a portosystemic shunting procedure to prevent life-threatening hemorrhages from esophageal varices. The renal disease may progress to renal failure years after successful shunting. Patients with associated nonobstructive intrahepatic biliary dilatation (Caroli disease) may have recurrent episodes of cholangitis and may require antimicrobial therapy or segmental hepatic resection. Combined kidney/liver transplantation has been advocated for ESRD patients with significant bile duct dilatation and episodes of cholangitis.
Autosomal or X-Linked Dominant Diseases in the Differential Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Oro-facial-digital Syndrome Type 1
Oro-facial-digital syndrome type 1 is a rare X-linked dominant disorder with prenatal lethality in boys.[231] Affected girls may have kidneys indistinguishable from autosomal dominant polycystic kidneys. The correct diagnosis should be suggested by the extrarenal manifestations, which may include oral (hyperplastic frenula, cleft tongue, cleft palate or lip and malposed teeth), facial (broad nasal root with hypoplasia of nasal alae and malar bone), and digital (brachydactyly, syndactyly, clinodactyly, camptodactyly, poly-dactyly) anomalies. They may also have liver cysts. Mental retardation and tremor can be present in up to 30% to 50% of the patients. OFD1 has been mapped to chromosome Xp22, and the OFD1 gene has been identified. The 120-kDa OFD1 protein contains an N-terminal LisH motif, which is important in microtubule dynamics. The OFD1 protein is a core component of the human centrosome throughout the cell cycle.[232] Most reported OFD1 mutations are predicted to cause protein truncation with loss of coiled-coil domains necessary for centrosomal localization. Recently, a novel X-linked mental retardation syndrome associated recurrent respiratory tract infections and macrocephaly due to ciliary dyskinesia, but no renal phenotype, has been associated with an OFD1 mutation.[232a]
Tuberous Sclerosis Complex
Epidemiology
TSC is an autosomal dominant disease that affects up to one in 6000 individuals.
Genetics
It is caused by mutations in one of two genes. TSC1 is located on chromosome 9q34 and encodes hamartin; TSC2 is located on chromosome 16p13 and encodes tuberin. The disease tends to be less severe in patients with TSC1 mutations than in those with TSC2 mutations. [235] [236] [237]
Pathogenesis
Hamartin and tuberin physically interact, and this interaction is important for their function. The hamartin/tuberin complex antagonizes an insulin-signaling pathway that plays an important role in the regulation of cell size, cell number, and organ size. [238] [239] In the absence of growth factor stimulation, tuberin/hamartin complexes maintain Rheb (“Ras homolog enriched in the brain”) in an inactive GDP-bound state by stimulating its intrinsic GTPase activity and inhibit downstream signaling from Rheb via mTOR (target of rapamycin). Growth factor stimulation of phosphoinositide 3-kinase (PI3K) signaling leads to Akt-dependent phosphorylation of tuberin, dissociation of the tuberin/hamartin complex, and activation of Rheb and mTOR. Tuberin or hamartin mutations also prevent the formation of tuberin/hamartin complexes and lead to constitutive activation of mTOR.
Diagnosis
A definite diagnosis of TSC requires two major features (renal angiomyolipoma, facial angiofibromas or forehead plaques, nontraumatic ungual or periungual fibroma, three or more hypomelanotic macules, shagreen patch, multiple retinal nodular hamartomas, cortical tuber, subependymal nodule, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis) or one major plus two minor features (multiple renal cysts, nonrenal hamartoma, hamartomatous rectal polyps, retinal achromic patch, cerebral white matter radial migration tracts, bone cysts, gingival fibromas, “confetti” skin lesions, multiple enamel pits).
Manifestations
Renal involvement is second only to the involvement of the central nervous system (CNS) as a cause of death in patients with TSC. The main renal manifestations include angiomyolipomas, cysts, RCCs with various histological patterns, epithelioid angiomyolipomas, lymphangiomatous cysts, and rarely focal segmental glomerulosclerosis. [240] [241] [242] [243]
Angiomyolipomas in TSC are extremely common, are usually multiple and bilateral, and affect both genders, in contrast to the general population, where they are uncommon, usually single, and mainly found in middle-age women. They develop after the first year of age, and by the third decade, 60% of the patients have renal angiomyolipomas. Women have more and larger angiomyolipomas than men. Small angiomyolipomas are most often cortical and frequently have a wedge-shaped appearance, with the base of the wedge facing the surface of the kidney. As the lesions increase in size, they penetrate deeper into the renal parenchyma or become exophytic extending into the perirenal fat. The main manifestations relate to their potential for hemorrhage (hematuria, intratumoral or retroperitoneal) and mass effect (abdominal or flank mass and tenderness, hypertension, renal insufficiency). The diagnosis can be established by sonography, CT, or MRI and requires demonstration of fat in the tumor.
Unlike angiomyolipomas, renal cysts may be present in the first year of life, and cystic disease may be the presenting manifestation of TSC. TSC2 and PKD1 lie adjacent to each other in a tail-to-tail orientation on chromosome 16 at 16p13.3. Deletions inactivating both genes are associated with polycystic kidneys diagnosed during the first year of life or early childhood (TSC2/PKD1 contiguous gene syndrome). [244] [245] Therefore, TSC should be considered in children with renal cysts and no family history of PKD. Rarely, TSC2/PKD1 contiguous gene syndrome can be diagnosed in adults.[244] Patients with the contiguous gene syndrome usually reach ESRD at an earlier age than that of patients with ADPKD alone. Patients with TSC1 or TSC2 mutations without the contiguous gene syndrome also have an increased frequency of renal cysts. The renal cysts in TSC can be lined by a very distinct, perhaps unique epithelium of markedly hypertrophic and hyperplastic cells with prominent eosinophilic cytoplasm. The combination of cystic kidneys and angiomyolipomas has been said to be virtually pathognomonic for tuberous sclerosis.
The association with RCC is well established. Compared with sporadic RCCs, there is a female predominance, earlier age of presentation and increased bilaterality. Early detection is essential. They should be suspected in cases of enlarging lesions without demonstrable fat and in the presence of intratumoral calcifications.
Treatment
Angiomyolipomas are benign lesions and often require no treatment. Because of their increased frequency and size in women and reports of hemorrhagic complications during pregnancy, patients with multiple angiomyolipomas should be cautioned about the potential risk of pregnancy and estrogen administration. Annual reevaluations with ultrasound or CT are necessary to assess for growth and development of complications. Renal sparing surgery is indicated for symptoms such as pain or hemorrhage, growth with compromise of functioning renal parenchyma, and inability to exclude an associated RCC. Because angiomyolipomas larger than 4 cm are more likely to grow and cause symptoms, some authors suggest that prophylactic intervention should be considered in these cases. Some lesions, because of their size or central location, may be more amenable to selective arterial embolization.
The main clinical problems associated with cystic disease in TSC are hypertension and renal failure. The treatment consists of strict control of the hypertension. Bilateral nephrectomy should be considered before transplantation surgery because of the risk of life-threatening hemorrhage and the development of RCC.
Elucidation of TSC protein function at a molecular level has identified mTOR as a target for intervention in TSC. When rapamycin is given to Eker rats (an animal model of TSC caused by a TSC2 mutation) before the onset of disease, subsequent development of macroscopic renal tumors is reduced, without affecting the number of microscopic precursor lesions.[245] Clinical trials of rapamycin for the treatment of angiomyolipomas in TSC are in progress.
von Hippel-Lindau Syndrome
Epidemiology
Von Hippel-Lindau syndrome (VHL) is a rare autosomal dominant disease with a prevalence of 1:36,000. It is characterized by retinal hemangioma, clear cell RCC, cerebellar and spinal hemangioblastoma, pheochromocytoma, endocrine pancreatic tumors, and epididymal cystadenoma.[246]
Genetics
VHL is encoded by a tumor suppressor gene found on chromosome 3p25-p26 that is highly conserved across species. Genotype-phenotype correlations in VHL disease have classified four VHL syndrome subtypes.[247] Patients with VHL type 1 have no pheochromocytomas. Mutations in patients with VHL type 1 are mostly the loss of function type, leading to a truncated pVHL or no pVHL at all. Patients with complete germline deletions have a lower rate of RCC than patients with partial deletions (22.6% versus 49%). Mutations in patients with VHL type 2 are mostly missense mutations with some residual function. Type 2 families have pheochromocytomas and are divided into subtypes with a low (type 2A) or high (type 2B) risk of RCC, whereas type 2C families present with pheochromocytoma only. Dysregulation of VHL-dependent degradation of of hypoxia-induced factor (HIFa) is observed in subtypes 1, 2A, and 2B. VHL syndrome subtypes 1 and 2B show increased incidence of RCC compared with subtypes 2A and 2C, which are weakly associated with RCC. By contrast, VHL-dependent HIFa degradation is observed in type 2C VHL mutants, although fibronectin matrix assembly is abnormal. In addition, decreased microtubule stability has been associated with VHL subtype 2A mutations.
Pathogenesis
VHL encodes two proteins with relative molecular masses of approximately 30 and 19 kD. Although these isoforms may have different functions, both are capable of suppressing RCC growth in vivo. However, the best characterized function of pVHL is to act as an essential component in the degradation of HIFa subunits. In the presence of oxygen, pVHL captures a subunits of the transcription factor HIF, resulting in their degradation by the proteasome. The molecular signal for pVHL-mediated capture is the hydroxylation of two prolyl residues in the central part of HIF-α subunits, by a family of oxygen-dependent dioxygenases, PHD1-3 (prolyl hydroxylase domain-containing proteins). When oxygenation is reduced or pVHL is absent, HIF becomes stabilized and promotes the transcription of multiple target genes The VHL protein associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex that is involved in the ubiquitination of HIF. HIF, in turn, controls the expression of several proteins, including proteins controlling angiogenesis (such as VEGF), erythropoiesis (such as erythropoietin), glucose uptake and metabolism (such as the Glut1 glucose transporter and various glycolytic enzymes), extracellular pH (such as carbonic anhydrase IX and XII), and mitogenesis (such as transforming growth factor-β, TGF-b, and platelet-derived growth factor-β [PDGF-b]).
Up-regulation of HIF is not sufficient but is necessary to induce the RCC and CNS tumors associated with VHL mutations. A homozygous VHL mutation (598C > T) causes Chuvash polycythemia. This condition is endemic to the Chuvash population of Russia, but it occurs worldwide.[248] VHL 598C > T homozygosity causes elevated HIF, VEGF, erythropoietin and hemoglobin levels, vertebral hemangiomas, varicose veins, low blood pressure, and premature mortality (42 years, range 26-70 years) related to cerebral vascular events and peripheral thrombosis. The absence of renal carcinomas, spinocerebellar hemangioblastomas, and pheochromocytomas typical of classical VHL syndrome, however, suggest that overexpression of HIF and VEGF is not sufficient for tumorigenesis. On the other hand, HIF upregulation is required for the development of VHL associated RCC and short hairpin HIF RNAs suppress tumor formation by VHL-defective renal carcinoma cells.
The demonstration that HIF up-regulation is not sufficient to induce RCC suggests that VHL has other cellular functions in addition to controlling HIF levels. It has been known for some time that VHL interacts physically with intracellular fibronectin in vivo and affects the ability of cells to assemble an extracellular fibronectin matrix. Fibronectin binds to and signals through cell surface integrins and decreases the proliferative behavior of malignant cells. A recent study has shown that VHL also regulates fibronectin at the transcriptional level.[249] VHL type 2C mutations associated with pheochromocytomas retain the ability to down-regulate HIF but are defective for the promotion of fibronectin matrix assembly.
Loss of heterozygosity at the VHL locus in microscopic renal cysts from patients with inherited VHL disease established cyst formation as an early step in the pathogenesis of RCC. Renal cysts and RCC from patients with VHL disease show increased concentrations of both HIF1a and HIF2a. initial loss of VHL, which results in the loss of primary cilium and dedifferentiation of an epithelial cell within the kidney tubule epithelium. Resulting from this event is the accumulation of HIFa and activation of hypoxia-inducible target genes that stimulate increased growth and cell division of dedifferentiated kidney epithelial cells and increased angiogenesis.
Diagnosis
The diagnosis should be made in a person with multiple CNS or retinal hemangioblastomas, or a single hemangioblastoma plus one of the other characteristic physical abnormalities or family history of VHL disease. In some cases, the diagnosis may be warranted in a patient with a positive family history but without CNS or retinal lesions, who has one or more of the less specific findings, with the exception of epididymal cysts, which are too nonspecific.
The molecular genetic diagnosis of VHL has greatly facilitated the evaluation and management of VHL families. Using a variety of techniques, the current detection rate of mutations is nearly 100%. Candidates for mutation analysis are patients with classic VHL disease (meeting clinical diagnostic criteria) and their first-degree family members, and members of a family in which a germline VHL gene mutation has been identified (presymptomatic test). Genetic testing should also be considered for patients with findings suggestive but not diagnostic for VHL. (i.e., multicentric tumors in one organ, bilateral tumors, two organ systems affected, one hemangioblastoma or pheochromocytoma in a patient ypunger than 50 years old or one RCC in a patient younter than 30 years old), and for members from a family with hemangioblastomas, RCCs, or pheochromocytomas only.
Manifestations
Renal cysts usually, but not always, precede the development of renal tumors. VHL-associated RCC presents early in life, with a mean age of diagnosis of 35 years. The histology is uniformly clear cell. The cumulative probability of developing RCCs rises progressively from age 20, reaching 70% by the age of 60 years. In contrast to the general population, RCC in VHL is more often multicentric and bilateral. Metastatic RCC is the leading cause of death from VHL.
Treatment
Patients with VHL disease need an annual physical and ophthalmologic examination, peripheral blood cell count, urinalysis, yearly CT or ultrasound of the abdomen, and yearly or biannual CT or MRI of the head and upper spine. Early detection of complications, especially RCC and CNS lesions, followed by appropriate treatment are essential to reduce mortality from VHL disease. Because it tends to be recurrent, bilateral, and multifocal, strategies have been developed to preserve renal parenchyma and minimize the number of invasive procedures. The National Cancer Institute developed the 3-centimeter rule for surgical intervention based on absence of documented metastasis from tumors smaller than 3 cm. Renal sparing surgery provides effective initial treatment with 5- and 10-year cancer-specific survival rates similar to those obtained with radical nephrectomy. Minimally invasive techniques that include percutaneous or laparoscopically guided cryotherapy or radiofrequency ablation are being evaluated for the treatment of VHL-associated tumors. [252] [253] [254]
The demonstration that HIF is required for VHL-associated carcinogenesis provides a rationale for therapies targeting this transcription factor.[253] HIF can be down-regulated by mTOR inhibitors such as rapamycin, heat shock protein 90 inhibitors such as geldenamycin and 17-(allylamino)-17-demethoxygeldanamycin, HDAC inhibitors, topoisomerase I inhibitors, thioredoxin-1 inhibitors, and microtubule disrupters. Treatments can be directed against HIF-responsive gene products, such as VEGF or receptors for VEGF, PDGG, or TGF-a.
Familial Renal Hamartomas Associated with Hyperparathyroidism-Jaw Tumor Syndrome
This is an autosomal dominant disease characterized by primary hyperparathyroidism (parathyroid adenoma or carcinoma) and ossifying fibroma of the jaw. Kidney lesions may also occur in as bilateral cysts, renal hamartomas, or Wilms tumors.[254] Renal cysts are a common finding, and in some cases, they have been clinically diagnosed as PKD. The gene mutated in this disease (Hrpt2) is ubiquitously expressed, evolutionarily conserved, and encodes a protein of 531 amino acids (parafibromin) with moderate identity and similarity to a protein of Saccharomyces cerevisiae (cdc73p) important in transcriptional initiation and elongation.[255]
Autosomal Recessive Diseases in the Differential Diagnosis of Autosomal Recessive Polycystic Disease
The phenotype of greatly enlarged and echogenic kidneys in the neonate is not pathognomonic for ARPKD, and other possible cystic disorders should also be considered. Rarely (<1% cases), ADPKD present in utero or in the neonatal period with clinical symptoms very similar to ARPKD. [258] [259] In approximately 50% of these cases, an affected parent is recognized only after the diagnosis of a severely affected child.[258] In addition, rare de novo, early-onset ADPKD cases may occur. Congenital hepatic fibrosis is not normally part of the ADPKD phenotype, but rare reports of an association have been described. Patients with contiguous deletions of the ADPKD gene, PKD1, and the adjacent tuberous sclerosis gene, TSC2, can present with an ARPKD-like renal phenotype, and the majority of cases are due to de novo mutation. [244] [245] Glomerulocystic kidney disease can rarely present in the neonatal period with an ARPKD-like phenotype.[259] Infantile NPH may also be confused with ARPKD. Rare families of with ARPKD-like disease and skeletal and facial anomalies [262] [263] or recessively inherited renal and hepatic cystic disease with hypoglycemia [207] [264] that are unlinked to PKHD1, have been described. A number of syndromic congenital hepatorenal disorders that are lethal in infancy can be associated with renal abnormalities resembling ARPKD and with congenital hepatic fibrosis. These include the Meckel-Gruber, Elejalde (acrocephalopolysyndactily), and Ivemark (renal-hepatic-pancreatic dysplasia) syndromes, and glutaric aciduria type II, among others.
Meckel-Gruber Syndrome
Meckel-Gruber syndrome is characterized by CNS defects, including the neural tube defect encephalocele, polycystic kidneys, biliary dysgenesis, and polydactyly. It is genetically heterogeneous with at least three genes involved. MKS1 and MKS3 have been identified. [265] [266] MKS1 is a cytosolic protein and MKS3 (meckelin) a 7 transmembrane spanner. Although their roles are unknown, comparative genomic and proteomic data (and consistent with the phenotype features) indicate a likely ciliary/basal body function.
HEREDITARY CYSTIC DISEASES WITH INTERSTITIAL NEPHRITIS
NPH/medullary cystic disease (MCKD) is a group of genetic disorders with shared and distinguishing features. The shared features include the pathologic appearance of the kidneys (small to normal size with cysts at the corticomedullary junction, irregular thickening of the tubular basement membrane and marked tubular atrophy and interstitial fibrosis) and the clinical manifestations (early polydipsia and polyuria and later development of renal insufficiency with low grade proteinuria and a benign urine sediment). The distinguishing features are the mode of inheritance (autosomal recessive NPH and autosomal dominant MCKD), the age of onset of ESRD, and the type of extrarenal organ involvement. Both NPH and MCKD are genetically heterogeneous. A renal disease with polyuria and an insidious clinical course similar to that of NPH can be observed in two other recessive disorders—JS and BBS.
Nephronophthisis
NPH is an autosomal recessive disorder that accounts for 10% to 20% of cases of renal failure in childhood. In approximately 15% of the families, it is associated with retinitis pigmentosa (Senior-Löken syndrome) and more rarely with ocular motor apraxia (Cogan syndrome), other neurologic defects varying from subtle cerebellar involvement to clear Joubert syndrome (JS) phenotypes (see later), congenital hepatic fibrosis, peripheral dysostosis (cone-shaped epiphyses), or truncal cerebellar ataxia.[265]
NPH is genetically heterogeneous, and six genes res-ponsible for different types of NPH have been identified. [268] [269] [270] [271] [272] [273] [274] The NPHP1 gene encodes nephrocystin; NPHP2/INVS, inversin; NPHP3, nephrocystin-3; NPHP4, nephrocystin-4/nephroretinin; NPHP5/IQCB1, nephrocystin-5; and NPHP6/CEP290, nephrocystin-6. NPHP1 mutations are found in approximately one half of the patients. The majority of them are homozygous for an NPHP1 deletion.[273] No mutations in any of the known genes are found in approxi-mately 40% of the patients, indicating that other genes remain to be discovered. NPHP1, NPHP4, NPHP5, and NPHP6 mutations may be associated with the Senior-Loken syndrome. NPHP1 and NPHP6 mutations can be associated with JS. [274] [276]
The nephrocystins form a multifunctional complex localized in primary cilia, centrosomes, and actin- and microtubule-based structures involved in cell-cell and cell-matrix adhesion signaling as well as in cell division. [270] [272] [273] [274] [277] [278] [279] In the kidney, these functional roles could be particularly important for establishing and maintaining the differentiated state of tubular epithelial cells. Localization of nephrocystins to the photoreceptor cilia (rods and cones are modified cilia) explains the association with retinitis pigmentosa.
The kidneys are small with a granular capsular surface. On cut section, the cortex and medulla are thinned, and the corticomedullary margin is indistinct with a variable number of small, thin-walled cysts of distal convoluted and collecting tubule origin. Similar cysts also may be present in the medulla. Perhaps 25% have no grossly visible cysts. The tubule basement membranes are thickened, even fairly early in the course of the disease, and tubule segments of a single nephron may be encompassed by very dense sclerotic interstitium with sparse chronic inflammatory cell infiltrates.
Excretory urography and sonography frequently fail to detect cysts because they are small. [280] [281] Excretory urography may show inhomogeneous streaking in the medulla due to accumulation of contrast material in the collecting ducts. Contrast-enhanced CT and MRI scans are more sensitive to detect small corticomedullary and medullary cysts, but failure to detect cysts does not exclude the diagnosis.
The onset of the disease is insidious. Polyuria and polydypsia are the presenting symptoms. Hypertension is often absent, and if present, it is not a prominent feature. Sodium wasting is common. The urine sediment is characteristically benign. Proteinuria is absent or low grade. There is no microhematuria. Progression to end-stage renal failure occurs within the first 2 decades of life. According to the age at onset of ESRD, three forms of NPH have been described: Infantile, juvenile (the most frequent), and adolescent ( Table 41-2 ). In the juvenile form, caused by mutations in NPHP1 and less frequently NPHP4 or NPHP5, polyuria and polydipsia start at 4 to 6 years and ESRD occurs at a median age of 13 years of age. In the adolescent form, caused by mutations in NPHP3, ESRD is reached at a median age of 19 years. The clinical and histologic features of the infantile form, caused by mutations in NPHP2/INV are very different from the other two; the kidneys are enlarged and cystic, and ESRD occurs in the first 1 to 3 years of life.
TABLE 41-2 -- Classification of Nephronophthisis and Medullary Cystic Kidney Disease
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Disease |
Inheritance |
Gene |
Protein |
Phenotype, mean age at ESRD (yrs) |
Extrarenal Associations |
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NPH1 |
AR |
NPHP1[*] |
Nephrocystin |
Juvenile, 13 |
Senior-Loken syndrome; Joubert syndrome |
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NPH2 |
AR |
NPHP2/INVS |
Inversin |
Infantile, renal enlargement, 2 |
Situs inversus |
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NPH3 |
AR |
NPHP3 |
Nephrocystin-3 |
Adolescent, 19 |
Senior-Loken syndrome |
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NPH4 |
AR |
NPHP4 |
Nephrocystin- 4/nephroretinin |
Juvenile |
Senior-Loken syndrome |
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NPH5 |
AR |
NPHP5/IQCB1 |
Nephrocystin-5 |
Juvenile |
Senior-Loken syndrome |
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NPH6 |
AR |
NPHP6/CEP290[*] |
Nephrocystin-6 |
Juvenile |
Senior-Loken syndrome; Joubert syndrome |
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MCKD1 |
AD |
Unknown |
? |
62 |
Gout, hyperuicemia |
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MCKD2 |
AD |
MCKD2/UMOD[†] |
Uromodulin |
32 |
Gout, hyperuricemia |
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AD, autosomal dominant; AR, autosomal recessive; ESRD, end-stage renal disease. |
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* |
Also associated with Joubert syndrome. |
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† |
Also the site of mutations causing familial juvenile hyperuricemic nephropathy. |
The treatment of NPH is supportive. Because of the tendency to sodium wasting, volume contraction, and renal azotemia, unnecessary sodium restriction or use of diuretics should be avoided. If kidneys from siblings are considered for transplant surgery, precautions should be taken to obtain them only from unaffected, older relatives, who should be subjected to meticulous diagnostic evaluation.
Joubert Syndrome
JS is an autosomal recessive, multisystem disorder characterized by cerebellar vermis aplasia/hypoplasia with abnormal superior cerebellar peduncles (the “molar tooth sign” [MTS]), mental retardation, hypotonia, irregular breathing pattern, and eye-movement abnormalities. Like NPH, JS is genetically heterogeneous. Three causative loci have been mapped, including JBTS1/CORS1 at 9q34.3, JBTS2/CORS2 at 11p12-q13.3, and JBTS3/CORS3 at 6q23. The phenotypes of the families mapping to JBTS1 and JBTS3 are similar, with minimal extra-CNS involvement. In comparison, families mapping to JBTS2 display NPH, retinal degeneration, and optic coloboma. [282] [283] Together, the data indicate that the JBTS1 and JBTS3 phenotypes usually do not involve retinal or renal abnormalities, whereas these are frequently components of the JBTS2 phenotype. In addition, NPHP1 and NPHP6/CEP290 mutations have been found in patients with JS and NPH. [274] [276]
Bardet-Biedl Syndrome
BBS is characterized by pigmentary retinopathy, distal limb anomalies, renal abnormalities, obesity, hypogenitalism in men, and mental retardation. Four of these six cardinal signs are required for the diagnosis. Although rare (1:120,000 live births), its prevalence in certain geographically isolated communities such as the Canadian province of Newfoundland or in Kuwait is more common (1:13,500–1:17,500).[282]
BBS is a genetically heterogeneous. Eleven genes have been cloned (BBS1–BBS11) and more are likely to be discovered.[283] The disease appears to be primarily inherited in an autosomal recessive manner and also in a more complex, non-mendelian, oligogenic form of inheritance (triallelism and tetrallelism). [286] [287] BBS1, BBS10, and BBS2 are the most common BBS loci, accounting for approximately 40%, 20%, and 10% of BBS cases, respectively. All of the BBS genes contain a 14-bp regulatory called the X box, which is common to genes expressed in ciliated neurons. This and the localization of the BBS proteins at a subcellular level point to a role in the function of the cilium-centrosome axis, which is not yet understood.
The diagnosis is often missed in childhood and made only later in life. Targeted fetal sonography in the second trimester of pregnancy to detect digital and renal abnormalities has been proposed for the prenatal diagnosis of BBS. The prenatal appearance of enlarged hyperechoic kidneys without corticomedullary differentiation should prompt the diagnosis in a family with BBS, especially when polydactyly is present. [284] [288] In nonaffected families, BBS should be included in the differential diagnosis whenever such an appearance is discovered in utero. The postnatal evolution of the renal sonographic findings is variable, and normalization generally occurs by the age of 2 years.
Renal abnormalities (calyceal clubbing, diverticula, or cysts) can be detected in 96% of the cases. The most common and earliest functional abnormality is a reduced ability to concentrate the urine, resulting in polyuria and polydipsia. Hypertension develops in approximately 50% and chronic renal insufficiency in 25% to 50% of the patients. Despite mental retardation, obesity, and severe visual problems, hemodialysis is well tolerated. Renal transplantation can be performed, but special attention has to be given to controlling hyperphagia and obesity.
Alström Syndrome
Alström syndrome (ALMS) is an autosomal recessive disease characterized by obesity, type 2 diabetes mellitus, retinitis pigmentosa, nerve deafness, and frequently, a slowly progressive chronic tubulointerstitial nephropathy.[287]The ALMS1 protein is of unknown function, is widely expressed in human and mouse tissues, and localizes to centrosomes and the base of cilia. It may provide useful insights into new pathways important for maintaining insulin sensitivity.
Medullary Cystic Disease
MCKD is an autosomal dominant disorder that shares with NPH the pathologic appearance of the kidneys (small to normal size with cysts at the corticomedullary junction, irregular thickening of the tubular basement membrane, and marked tubular atrophy and interstitial fibrosis, see Fig. 41-16 ) and the clinical manifestations (polydipsia and polyuria, followed by development of renal insufficiency, with low-grade proteinuria and a benign urine sediment). The distinguishing features are the pattern of inheritance, the later age of diagnosis and ESRD, and the absence of extrarenal organ involvement except for gout.
MDKD is genetically heterogeneous (see Table 41-2 ). The candidate interval for the MCKD1 locus has been narrowed to 2.1-Mb. UMOD is the gene mutated in MCKD2 and in familial juvenile hyperuricemic nephropathy, previously considered to be distinct entities and now shown to be the same disease. [290] [291] It encodes uromodulin, also known as Tamm-Horsfall protein. Pathogenic UMOD mutations exert a dominant negative effect and result in retention in the endoplasmic reticulum and marked reduction in urinary excretion of uromodulin.[290] This explains that Umod+/- mice do not have a MCKD phenotype, although they are more susceptible to urinary tract infection and stone formation. [293] [294] [295] More than 30 UMOD mutations have been described, with a cluster in exons 4 and 5. A consanguineous family with multiple heterozygous cases and three more severely affected but viable homozygous cases for the same mutation has been described.[294] The association of an UMOD mutation and glomerulocystic kidney disease has been described in one family.[295]
As in NPH, polydypsia, polyuria, and a tendency to waste sodium are common manifestations of the disease. MCKD1 and MCKD2 can both be associated with hyperuricemia and gout. Normal serum uric acid concentrations in some families suggest the existence of allelic heterogeneity. The mechanisms by which uromodulin affects the tubular reabsorption of water, sodium, and uric acid are not known. MCKD1 and MCKD2 patients reach ESRD at median ages of 62 and 32 years, respectively.
The treatment of choice of ESRD secondary to MCKD is kidney transplantation.[296] If kidneys from living related donors are considered for transplantation, precautions should be taken to obtain them only from older relatives, who should be subjected to meticulous diagnostic evaluation.
RENAL CYSTIC DYSPLASIAS
Renal cystic dysplasias result from an interference with a normal ampullary activity leading to abnormal metanephric differentiation. When the inhibition of the ampullary activity occurs very early, few collecting ducts are formed and few nephrons develop. The kidney becomes a cluster of cysts with little or no residual parenchyma, and the ureter is absent or atretic. These kidneys may be normal size or larger than normal (multicystic dysplastic kidney) or markedly shrunken (hypodysplastic kidney). These variations probably represent different stages of the same pathologic process, because renal cysts can involute and disappear completely during intrauterine life. When the interference with the ampullary activity occurs later, for example as the result of urethral or ureteral obstruction, there may be a mild irregularity in branching with a mild generalized dilatation of the collecting tubules in the medulla, but most nephrons, except the last to be formed, are normal. The cysts are found under the capsule and generally derive from Bowman's spaces (glomerular cysts), loops of Henle, or terminal ends of collecting tubules. A variety of renal abnormalities in the contralateral kidney can be found in association cystic dysplastic kidneys. These include renal agenesis, ectopy or fusion, and ureteral duplication or obstruction that may result from injury to the ureteral bud during various stages of development. When the injury to the ureteral bud occurs before a communication with the metanephric blastema has been established, secondary atrophy of the metanephric blastema and renal agenesis ensue. On the other hand, if the injury of the bud or ureteral obstruction occurs after renal development is completed, dysplasia does not occur. Thus, a spectrum of renal abnormalities ranging from agenesis and severe dysplasia to mild cystic dysplasia with glomerular cysts and a variety of related renal and ureteral abnormalities may result from interferences with normal ampullary activity and metanephric differentiation.
Renal cystic dysplasias may be the consequence of an intrinsic (malformation) or extrinsic (disruption) defect in organogenesis. An intrinsic defect may be due to a single gene mutation, a chromosomal aberration, or a combination of genetic and environmental factors (multifactorial determination). Extrinsic causes include, among others, teratogenic chemicals, metabolic abnormalities, and infections. Evidence for intrinsic or extrinsic defects should be sought by careful review of the pregnancy, family history, and physical examination (pattern of associated abnormalities), as well as by the study of the karyotype. Renal cystic dysplasias frequently occur as sporadic events, but they can also occur in the context of many multiorgan malformation syndromes, several of which have defined genetic bases.[297]
Although most dysplastic kidneys are grossly deformed in a fairly characteristic way, most authors accept only two absolute criteria for dysplasia, and both of those require histologic confirmation (see Fig. 41-10 ). Of greater importance is the finding of primitive ducts encompassed by mantles of variably differentiated mesenchyma and lined by cuboidal to columnar, sometimes ciliated, epithelium unlike that in any normally developing or mature ducts. Somewhat less important, because of its variable presence, is the finding of metaplastic cartilage ( Fig. 41-17 ). Primitive or fetal glomeruli with cuboidal epithelium, primitive tubules, and duct ulessurrounded by narrow collars of laminated connective tissue. Cysts of glomerular, tubule, and ductal origin may also be present, but because they might represent either a maldevelopment or a histologically similar degenerative change in previously normal but immature structures, they do not provide absolute evidence of parenchymal maldevelopment.
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FIGURE 41-17 Outer and cut surface of kidney with severe medullary cystic disease. |
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Multicystic Dysplastic Kidneys
Multicystic dysplastic kidneys (MDKs) is the most common cause of an abdominal mass in infancy and the most common type of bilateral cystic disease in newborns ( Fig. 41-18 ). With the widespread use of fetal sonography, MDK is now most often diagnosed in utero. The diagnosis is usually made during the third trimester. MDK is more often unilateral than bilateral, and boys are more frequently affected than girls. Because MDKs tend to involute over weeks or months prenatally and postnatally, the prevalence of unilateral MDK is higher on fetal screening (1:1–2000) than on neonatal screening (1:4000).
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FIGURE 41-18 Renal dysplasia. The diagnostic microscopic features include primitive ducts (A) and metaplastic cartilage (B). |
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Differentiation of MDK from hydronephrosis in the fetus and newborn is essential because the therapeutic approaches to these conditions differ. The most useful sonographic criteria for identifying a MDK include the presence of interphases between cysts, nonmedial location of the larger cysts, and absence of identifiable renal sinus in 100% of the cases, and the absence of parenchymal tissue. The diagnosis can be confirmed by retrograde pyelography showing an absent or atretic proximal ureter and by angiography revealing an absent or hypoplastic renal artery. Cyst walls often calcify in older patients and may appear as ring-like densities in the region of the kidney.
The manifestations of MDK depend on whether it is bilateral or unilateral. Bilateral MDK results in oligohydramnios and the Potter sequence, and is incompatible with life. Unilateral MDK may be diagnosed in the newborn during an evaluation of a renal mass or go unnoticed until later in life during evaluation for abdominal or flank discomfort due to the mass effect of the lesion.[298] Serial sonograms show that 33% of the MDKs have completely involuted at 2 years of age, 47% at 5 years, and 59% at 10 years. The development of hypertension or malignant degeneration is very rare.[299] Because of its low risk and tendency to involute, children with MDK are usually managed conservatively.[300] When indicated, laparoscopic nephrectomy is preferable to open nephrectomy. Attention should be paid to an increased risk for associated urinary tract malformations of the contralateral kidney, for example, pelviureteric junction obstruction and vesicoureteric reflux, but voiding cystography is indicated only when the sonogram of the contralateral kidney or ureter is abnormal.[301]
Renal Cystic Dysplasia Caused by Hepatocyte Nuclear Factor-1βMutations
Recently, mutations in the gene encoding hepatocyte nuclear factor (HNF)-1β have been associated with maturity-onset diabetes of the young (MODY), abnormal renal development, and genital tract malformations. MODY is a form of non-insulin-dependent diabetes mellitus characterized by autosomal dominant inheritance and a young age of onset, usually diagnosed before the age of 25 years. It is a genetically heterogeneous disease, caused by mutations in the glucokinase (MODY2), HNF-1α (MODY3), HNF-4α (MODY1), insulin promoter factor-1 (MODY4), or HNF-1β (MODY5). Urinary tract malformations are seen only in association with MODY5. The renal phenotype is variable both within and between families and includes multicystic renal dysplasia, hypoplastic glomerulocystic kidneys with abnormal calyces and papillae, oligomeganephronia, and renal agenesis.[302] The genital tract malformations may include absence of fallopian tubes or uterus, vaginal atresia, fusion abnormalities such as bicornuate uterus or biseptate vagina, and male genital tract abnormalities. HNF-1β is expressed in the wolffian duct, the developing meso- and metanephros, and in the müllerian ducts from the earliest stages of differentiation. In adults, it is expressed in kidney tubules and collecting ducts, oviducts, uterus, epididymis, vas deferens, seminal vesicles, prostate, and testes. Rare families may have mutations in the HNF-1β gene and features of urogenital adysplasia but no history of diabetes.
OTHER CYSTIC KIDNEY DISORDERS
Simple Cysts
Prevalence
Simple cysts are the most common cystic abnormality encountered in human kidneys.[303] They may be solitary or multiple and are filled with a fluid that is chemically similar to an ultrafiltrate of plasma. They are very rare in children, but the frequency increases with age.[304] In autopsy studies and as incidental CT findings, they are found in approximately 25% and 50% in patients 40 and 50 years of age, respectively. Ultrasound is less sensitive than CT or MR and turns up lower percentages.
Pathogenesis
Simple renal cysts are acquired, although the contribution of genetic factors has not been studied. Several hypotheses have been proposed to explain their pathogenesis. Tubular obstruction and ischemia might play a role. Microdissection studies revealed that diverticula of distal convoluted and collecting tubules are frequent after the age of 20 years and increase in number with age. Cysts are thought to derive from progressive dilatation and detachment of these diverticula. The cyst walls also appear to be relatively impermeable to low-molecular-weight solutes and to antibiotics. Nonetheless, the turnover of cyst fluid may be as great as 20 times per day, as measured by 3H2O diffusion.
Pathology
Simple renal cysts are usually lined by a single layer of epithelial cells and filled with a clear, serous fluid. They grow slowly, but huge cysts of up to 30 cm in diameter have been described. The inner surface of these cysts is glistening and usually smooth, but some cysts may be trabeculated by partial septa that divide the cavity into broadly interconnecting locules. These septated simple cysts should not be confused with multilocular cysts. The cysts are often cortical and distort the renal contour, but they may be deep cortical or apparently medullary in origin. They do not communicate with the renal pelvis. The walls typically are thin and transparent but may become thickened, fibrotic, and even calcified possibly from earlier hemorrhage or infection.
Diagnosis
Most simple cysts are found on routine imaging studies ( Fig. 41-19 ). Differentiation of simple cysts from a RCC is a common problem. Because the appearance of a renal mass on the excretory urogram alone never excludes a malignancy, ultrasonography, computerized tomography or magnetic resonance is commonly required to characterize the lesion. Acceptance of definite criteria for the diagnosis of a simple cyst by these imaging techniques has eliminated the use of renal angiography and percutaneous cyst aspiration to characterize renal masses. Two percent of simple cysts and 10% of RCCs contain calcium deposits, but calcification in simple cysts appears to be peripheral, whereas that in tumors is more central. Improvements in the imaging techniques have also reduced the indications for surgery in the management of benign simple cysts. When the cysts are numerous and bilateral, differentiation from ADPKD may be difficult if liver cysts are not also found. Because of the obvious implications, it is important to avoid a diagnosis of ADPKD in questionable cases unless a familial history consistent with autosomal dominant transmission can be documented or the diagnosis confirmed by genetic testing.
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FIGURE 41-19 Severe renal cystic dysplasia (multicystic kidney). The renal architecture is markedly distorted. |
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Manifestations
The cysts are usually asymptomatic, being discovered at the time of a nephro-urologic evaluation for some unrelated problem. They should not distract from the diagnosis of more important intrarenal or extrarenal lesions. Large renal cysts may cause abdominal or flank discomfort, often described as a sensation of weight or a dull ache. Frequently, however, this pain can be explained by a coexisting abnormality such as nephrolithiasis. Rare cases of gross hematuria due to vascular erosion by an enlarging cyst have been documented; however, hematuria is usually due to another cause. When the simple cysts lie at or near the hilus, a urographic pattern of caliceal obstruction or hydronephrosis is frequently found. In most but not all cases, these apparent obstructive changes are of no functional significance. A dynamic hippuran/DTP A radioactive renal scan before and after administration of furosemide can help to assess the degree of obstruction. Rare cases of renin-dependent hypertension caused by solitary intrarenal simple cysts have been described. The proposed mechanism is arterial compression by the cyst causing segmental renal ischemia. Infection is a rare but dramatic complication of a renal cyst. Simple cysts are not thought to impair renal function, but the presence of simple cysts has been associated with reduced renal function in hospitalized patients younger than 60 years of age.[305] Simple cysts infrequently become infected, and the patient presents with high fever, flank pain and tenderness, and frequently, a sympathetic pleural effusion. Most patients are women, and the most common pathogen is Escherichia coli. Urine cultures can be negative. Carcinomas do not arise from benign simple cysts. For asymptomatic patients with unequivocal simple cysts periodic follow-up by sonography is reasonable.
Treatment
Treatment is indicated only for symptomatic cysts or for cysts causing obstruction. Intermediate-sized cysts can be aspirated percutaneously, and a sclerosing agent can be instilled into the cavity in an attempt to prevent recurrence. Cysts greater than 500 mL in volume are usually drained surgically. Laparoscopic methods are now used routinely. Hypertension has sometimes disappeared after successful aspiration of the cyst fluid or operative removal of the cyst. Renal vein plasma renin activity is usually elevated in such cases, and the mechanism is thought to be compression of adjacent vessels by cysts with selective renal ischemia and increased renin production. An operative approach to infected renal cysts is usually taken, but percutaneous aspiration and drainage of infected cysts also have been used.
Localized or Unilateral Renal Cystic Disease
This is a rare condition that involves part or, more rarely, the whole of one kidney with cysts that are indistinguishable from those in ADPKD.[306] The absence of a family history and the fact that the remaining renal tissue and the liver appear intact help to differentiate this condition from asymmetric forms of ADPKD. Its etiology and pathogenesis are not understood. The clinical presentation includes a palpable mass, flank pain, gross or microscopic hematuria, and hypertension with well-preserved renal function.
Medullary Sponge Kidney
Epidemiology
MSK or precalyceal canalicular ectasia is a common disorder characterized by tubular dilatation of the collecting ducts and cyst formation strictly confined to the medullary pyramids, especially to their inner, papillary portions.[307]In studies using strict criteria for the quality of acceptable intravenous urograms, the incidence of MSK has been about 13% in patients with calcium urolithiasis but only about 2% in otherwise normal patients. Among all calcium stone formers, women have a greater incidence of MSK than do men.
Pathogenesis
It is usually regarded as a nonhereditary disease, but autosomal dominant inheritance has been suggested in several families. The rarity of reported cases of this disorder among children favors the interpretation that this is an acquired rather than a congenital disease. MSK has been associated with primary hyperparathyroidism. There have been several reports of MSK in patients with Ehlers-Danlos syndrome and in patients with hemihypertrophy. Precaliceal canalicular ectasia can be observed frequently in patients with ADPKD. Progression of the tubular ectasia and development of tubule dilatation and medullary cysts have been documented in some patients.
Pathology
Despite its name, the affected kidney does not closely resemble a sea sponge. The renal size is usually normal or slightly enlarged. The precalyceal canalicular ectasia may involve one or more renal papillae in one or both kidneys. The lesions are bilateral in 70% of cases. The dilated ducts communicate proximally with collecting tubules of normal size and often show a relative constriction to approximately normal diameter at the point of their communication with the calyx. Their diameter is often 1 to 3 mm, occasionally 5 mm, and rarely up to 7.5 mm. They often contain small calculi and may be surrounded by normally appearing medullary interstitium or, in cases of more prominent cystic disease, inflammatory cell infiltration or interstitial fibrosis.
Diagnosis
A definitive diagnosis of MSK can be made when the dilated collecting ducts are visualized on early and delayed films without the use of compression and in the absence of ureteral obstruction ( Fig. 41-20 ). Deposition of calcium salts within these dilated tubules may give the radiographic appearance of renal calculi or nephrocalcinosis. The distribution of the renal calculi in these patients is characteristic, in clusters fanning away from the calyx. In rare cases, MSK can mimic the urography appearance of ADPKD. The fact that many patients with ADPKD exhibit precalyceal canalicular ectasia on excretory urography further complicates the differential diagnosis. The absence of a family history of ADPKD and a CT showing that the cortical layer is free of cysts help to confirm a diagnosis of MSK.
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FIGURE 41-20 Simple renal cysts. A, Solitary cortical cyst of right kidney seen by intravenous urography. B, Solitary cyst of right renal cortex seen by computed tomography with intravenous contrast enhancement. Oral contrast material was given to highlight the intestine. |
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Manifestations
MSK is usually a benign disorder that may remain asymptomatic and undetected for life. Impairment of tubular functions, such as a mild concentration defect, a reduced capacity to lower the urine pH after administration of ammonium chloride as compared with controls, and possibly a low maximal excretion of potassium after short-term intravenous potassium chloride loading may be documented in these patients. Incomplete distal renal tubular acidosis may be found in as many as 30% to 40% of the patients. The disease is associated with gross and microscopic hematuria that may be recurrent and with urinary tract infections that often are the first signs of an underlying abnormality. Renal stones consisting of calcium oxalate, calcium phosphate, and other types of calcium salts commonly form in the ectatic collecting ducts in this disease. Although patients with MSKs and renal stones probably have the same spectrum of metabolic abnormalities as appears in the overall population of stone formers, some studies have emphasized the importance of distal renal tubular acidosis and hypercalciuria. It has also been suggested that hypercalciuria from a calcium leak may lead to the development of parathyroid adenomas. However, a critical examination of calcium excretion in patients with MSK and other stone-forming disorders showed that absorptive hypercalciuria was the most common abnormality in MSK, occurring in 59% of patients, whereas only 18% had hypercalciuria resulted from a renal calcium+ leak. MSK seldom progresses to ESRD, although reduced GFRs have been observed, and few patients have a relatively poor prognosis because of recurring urolithiasis, bacteriuria, and pyelonephritis.
Treatment
There is no specific treatment for MSK. Most patients discovered incidentally to have MSK can be advised that the disorder is benign and that they can anticipate no serious morbidity or mortality from it. The treatment of nephrolithiasis and urinary tract infection, when present, is the same as it would be in the general population. As a general rule, patients with nephrolithiasis should excrete about 2.5L of urine each day to reduce the risk of stone formation. Thiazides and inorganic phosphates have been found to be effective in preventing stones in these patients. Alkaline therapy may be helpful in patients with MSK and distal renal tubular acidosis by increasing urinary citrate, but careful observation is necessary to ensure that the increase in urinary pH will not promote further calculus formation in patients who have calcium phosphate stones in their ectatic tubules. Patients with MSK appear to be more susceptible to urinary tract infections, and routine preventive measures seem warranted, especially in female patients. Repeated unnecessary investigations for hematuria should be avoided. Relapsing urinary tract infections may be due to infected renal stones and may require chronic antimicrobial suppression when the source of the relapsing infections cannot be eliminated.
Acquired Cystic Kidney Disease
Epidemiology
Acquired cystic kidney disease (ACKD) is characterized by small cysts distributed throughout the renal cortex and medulla of patients with ESRD unrelated to inherited renal cystic diseases. There is no agreement on the extent of cystic change required for the diagnosis, ranging from one to five cysts per kidney in radiologic studies to cystic changes in 25% to 40% of renal volume for tissue-based studies. Its prevalence and severity are higher in men than in women and increase with the duration of azotemia. Acquired cysts are found in 7% to 22% of patients with renal failure and serum creatinine values exceeding 3 mg/dL before dialysis, in 35% with less than 2 years of dialysis, 58% with 2 to 4 years, 75% with 4 to 8 years, and 92% with dialysis for longer than 8 years. It is unrelated to age, dialysis methods, race, or the causes of renal failure. The cysts can regress after successful renal transplant surgery but conversely can develop in chronically rejected kidneys. Cyclosporine has been incriminated as predisposing native kidneys to cyst formation.
A very important additional feature in ACKD has been the occurrence of renal tumors. The overall prevalence of RCC in hemodialysis patients evaluated radiologically or at autopsy is approximately 1%. Carcinoma in dialysis patients is three times more common in the presence than in the absence of acquired renal cysts, and it is six times more common in large cystic kidneys than in small cystic kidneys. Overall, the incidence of renal malignancy in dialysis patients has been estimated to be 50 to 100 times greater than in the general population. The RCCs associated with ACKD have a lower risk for metastasis and a better prognosis compared with RCCs not associated ACKD.
Pathogenesis
The development of the cysts and tumors seems to be tied to the pronounced epithelial hyperplasia observed microscopically. The hyperplasia, in turn, seems to be a result of the uremic state, even though there appears to be no relation between the occurrence of acquired cysts and the efficacy of dialysis. If ACKD is present at the time of successful transplantation, that process seems to regress or at least not to increase in severity. Conceivably, the loss of renal mass causes the production of renotropic factors that stimulate hyperplasia.
Pathology
The kidneys usually are equally involved. They may be small, large, or normal in size, even when totally involved by cysts. Most weigh less than 100 g, and about 30% of reported examples weigh less than 50 g. On the other hand, about 25% weigh more than 150 g, and a few exceptional specimens weigh more than 1000 g ( Fig. 41-21 ). In nephrectomy and autopsy specimens, the cysts vary in number and type from a few subcapsular cysts up to 2 to 3 cm in diameter to numerous smaller cysts that are diffusely distributed. The cysts are generally smaller than those in ADPKD. Microdissection studies have demonstrated the continuity of the cysts with both proximal and distal tubules, and have suggested their origin both in the fusiform dilation of tubule segments and in multiple small tubule diverticula. Some, but not all immunohistochemical studies have shown that the cysts in ACKD derive mostly from the proximal tubules.[308]
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FIGURE 41-21 Medullary sponge kidney. A, Plain roentgenogram of a large solitary left kidney containing several calcific densities. B, Urogram showing the pronounced tubular ectasia of all papillae that is typical of medullary sponge kidney. |
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In a significant fraction of reported cases, the cysts contain single or, more often, multiple papillary, tubular, or solid neoplasms arising from the cyst lining and consistent with renal cell “adenomas” or adenocarcinomas. The genetic changes underlying the development of most of these tumors are different from those occurring in sporadic clear cell RCCs. Whether tumors are more common in the dialyzed patients than in the uremic, nondialyzed patients also is not clear, and conflicting reports have appeared. Compared with sporadic RCC, ACKD-associated RCC tends to display lower Fuhrman nuclear grade, less proliferative activity, and diploidy in most cases, reflecting less aggressive behavior. The predominant type appears to be papillary, with most of the other cases being clear cell type and less frequently other types or oncocytomas. In addition, a RCC with distinctive histologic features has been associated with ACKD. These tumors are characterized by abundant eosinophilic cytoplasm, a variably solid, cribriform, tubulocystic and papillary architecture, and deposits of calcium oxalate crystals. [311] [312]
Diagnosis
Sonography reveals the bilateral cystic process in advanced cases and is useful in the detection of neoplasms, particularly in patients who have chronic renal failure not treated with dialysis and in whom the use of contrast medium might cause a further deterioration in renal function. However, CT, with and without contrast enhancement, is better for distinguishing kidneys with a few simple cysts from those with multiple acquired cysts (Figs. 41-22, 41-23 [22] [23]). MRI, with and without gadolinium enhancement, may also be useful, particularly for the diagnosis of neoplasms, as an alternative to contrast-enhanced CT in nondialyzed patients and in those cases in which the CT findings are indeterminate. CT and MRI also should be used to stage the malignancy more accurately.
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FIGURE 41-22 Acquired cystic disease in 320-γ kidney from a patient with a 10-year history of hemodialysis. There were bilateral, multifocal renal cell carcinomas (arrow) with multiple systemic metastases. |
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FIGURE 41-23 Acquired renal cystic disease. A, Computed tomogram with intravenous contrast. This male patient had renal failure due to diabetic nephropathy and had received hemodialysis for 6 years before this examination. There is bilateral renal enlargement with diffuse cysts in cortex and medulla. A solid tissue tumor (cursor) is seen in the anterior part of the left kidney. B, Computed tomogram of original kidneys in a patient with a functioning renal allograft. Note the marked atrophy of the renal parenchyma, in contrast to the cystic changes seen in A. |
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Because RCC is an important complication of ACKD, CT screening has been recommended after 3 years of dialysis, followed by screening for neoplasm at 1- or 2-year intervals thereafter. However, because RCC is actually a relatively rare cause of death among dialysis patients, it also has been suggested that a more aggressive renal imaging program and, indeed, even an annual screening program, would be unlikely to reduce the mortality of dialysis patients significantly and therefore would not be cost effective. In the end, the clinical decision must be based on the individual patient, with consideration given both to the known risk factors for carcinoma, including prolonged dialysis, the presence of ACKD, large kidneys, male sex, and to the patient's age and general fitness.
Manifestations
ACKD develops insidiously. Most patients have no symptoms. When symptoms occur, gross hematuria, flank pain, renal colic, fever, palpable renal mass, and rising hematocrit are most common. Retroperitoneal hemorrhage may present with acute pain, hypotension, and shock. Rarely the presentation can be with symptoms from metastatic RCC. Approximately 20% of ACKD-associated RCCs metastasize (versus 50% for sporadic RCC).
Treatment
Bleeding episodes, either intrarenal or perirenal, are often treated conservatively with bed rest and analgesics. Persistent hemorrhage, however, may require nephrectomy or therapeutic renal embolization and infarction. Because the risk of undetected RCC is high in patients with retroperitoneal hemorrhage, nephrectomy is recommended in those cases in which carcinoma cannot be ruled out. If a few larger cysts are associated with flank pain, percutaneous aspiration (with cytologic examination) is a reasonable temporizing measure. ACKD may regress after successful renal transplantation (see Fig. 41-22 ).
Renal masses larger than 3 cm detected in ACKD are treated by excision. For tumors smaller than 3 cm, some physicians advise nephrectomy for the acceptable surgical candidate, whereas others recommend annual CT follow-up with resection if the lesions enlarge. Although metastases are statistically less likely to occur from small than from large tumors, small tumor size is not a guarantee against metastasis. Resection even of small neoplasms seems prudent in preparation for transplantation. Because carcinoma in the setting of ACKD is often multicentric and bilateral, some authors recommend bilateral nephrectomy in these cases. If this is not performed, frequent monitoring of the contralateral kidney is advised. Laparoscopic bilateral radical nephrectomy in patients with ESRD, ACKD, and suspicious tumors has been recently proposed as a more desirable alternative to traditional open surgery.[311]
RENAL CYSTIC NEOPLASMS
The renal cystic neoplasms encompass a number of entities that cannot be reliably distinguished from one another on preoperative imaging studies. These entities include cystic RCC, multilocular cystic nephroma, cystic partially differentiated nephroblastoma, and mixed epithelial and stromal tumor.[312]
Cystic Renal Cell Carcinoma
Multilocular and unilocular RCC may account for approximately 5% of RCCs and are characterized by its cystic nature with less than 25% of solid component and by the absence of necrosis. They are usually clear cell type and low grade, confined to the kidney, and virtually never metastasize or cause death.[313] They should be distinguished from RCCs with a large cystic component due to extensive necrosis (pseudocystic necrotic carcinoma), which have an aggressive behavior often leading to metastasis and death. Surgical excision is usually needed for diagnosis because fine-needle aspiration is not sufficiently accurate.
Multilocular Cystic Nephroma
Cystic nephroma is a rare benign cystic neoplasm encountered in children and adults, with a bimodal distribution of age and gender (65% in patients <4 years of age with a male/female ratio of 2:1, the remainder in patients >30 years of age with a male/female ratio of 1:8). Cystic nephroma appears as an encapsulated multilocular mass, the locules of which are not connected to one another or to the pyelocaliceal system. They are lined by a single layer of nondescript, flattened or cuboidal cells, and “hobnail” cells with abundant eosinophilic cytoplasm and large apical nuclei. The septa are composed of connective tissue and may contain scattered atrophic renal tubules. Multilocular cystic nephroma is a benign lesion but malignant transformation can occur in rare cases.
Cystic Partially Differentiated Nephroblastoma
Cystic partially differentiated nephroblastoma is a rare benign cystic renal neoplasm that is histologically identical to cystic nephroma, except for Wilms tumor elements within the septa. It mostly affects boys and girls less than 2 years of age, although it can rarely occur in adults. It is cured by complete excision.
Mixed Epithelial and Stromal Tumor
Mixed epithelial and stromal tumor is a rare type of cystic renal neoplasm, with about 50 cases reported. Contrary to cystic nephroma and cystic partially differentiated nephroblastoma, which are purely cystic and have thin septa, mixed epithelial and stromal tumor is partly cystic and has thicker wall-forming solid areas. All except one patient are female, with a mean age of 46 years. The role of female hormone in the pathogenesis of this tumor is supported by a female predominance, a history of long-term estrogen treatment in many patients, and the expression of estrogen/progesterone receptors by tumor stromal cells. Mixed epithelial and stromal tumors are benign and resection is curative.
RENAL CYSTS OF NONTUBULAR ORIGIN
Cystic Disease of the Renal Sinus
The cystic disorders of the renal sinus are benign conditions that by modern imaging techniques can be clearly distinguished from more serious mass-occupying lesions of the renal pelvis or renal parenchyma. Two types of cystic lesions have been described in this area: the hilus cysts and the parapelvic cysts.
Hilus cysts have only been identified at autopsy and have been thought to be due to regressive changes in the fat tissue of the renal sinus, especially in kidneys with abundant fat in the renal sinus associated with renal atrophy. The cysts result from fluid replacement of adipose tissue that undergoes regressive changes owing to localized vascular disease and atrophy due to recent wasting. The wall of such a cyst is lined by a single layer of flattened mesenchymal cells, and the cystic fluid is clear and contains abundant lipid droplets.
Parapelvic cysts are much more common and of lymphatic origin. The wall of the cysts is very thin and lined by flat endothelial cells. The composition of the cystic fluid resembles that of lymph. The mechanism responsible for the dilatation of the lymphatics is not known. Parapelvic cysts may be multiple and bilateral. They are in direct contact with the extrarenal pelvic surface and extend into the renal sinus, distorting the infundibula and calices. The kidneys may appear slightly enlarged, but the enlargement is exclusively due to the expansion of the renal sinus, whereas the area of the renal parenchyma remains normal. Bilateral parapelvic cysts (cystic disease of the renal sinus) can be confused with ADPKD on excretory urography, but the distinction of the two entities is straightforward by CT or MRI.
Parapelvic cysts are most frequently diagnosed after the fourth decade of life. They are usually discovered in the course of evaluations for conditions such as urinary tract infections, nephrolithiasis, hypertension, and prostatism. Despite considerable calyceal distortion, the pressure in these lymphatic cysts is low and not likely to result in significant functional obstruction. Indeed, renal function in patients with bilateral multiple parapelvic cysts is usually normal. Occasionally, parapelvic cysts are the only finding in the course of evaluation for otherwise unexplained lumbar or flank pain. The therapeutic approach to parapelvic cysts should be conservative.
Perirenal Lymphangiomas
Perirenal lymphangiomas are characterized by dilatation of the lymphatic channels around the kidneys, leading to the development of unilocular or multilocular cystic masses.[314] Lymphatic obstruction may play a role in its pathogenesis. An observation in two siblings may point to a genetic component. Perirenal lymphangiomas have also been observed in patients with TSC.[315] Pregnancy is reported to exacerbate the condition, possibly because the renal lymphatics play a role in handling an enhanced interstitial fluid flow during this condition.[316] Mild renal functional impairment and hypertension can occur transiently and revert to normal in the postpartum period.
Subcapsular and Perirenal Urinomas (Uriniferous Pseudocysts)
Subcapsular and perirenal urinomas are encapsulated collections of extravasated urine in the subcapsular or perirenal space. They are usually secondary to obstructive uropathies, such as posterior urethral valve, pelviureteric junction, or vesicoureteric junction obstruction, ureteric calculus, or trauma. They are due to pyelosinus backflow that can occur when the intrapelvic pressure rises to 35 cmH2O or greater, leading to rupture of caliceal fornices. Subcapsular urinomas are situated between the renal parenchyma and renal capsule, whereas perirenal urinomas are located between the renal capsule and Gerota fascia. Treatment includes temporary decompression by placement of a pigtail catheter in the most dependent point of the urinoma and correction of the underlying disorder.
Pyelocalyceal Cysts
Also termed pyelocalyceal diverticula or calyceal or pyelorenal cysts or diverticula, these lesions represent congenital, probably developmental, saccular diverticula from a minor calyx (type I) or from the pelvis or adjacent major calyx (type II). Type I is more common, is usually located in the poles (especially the upper), and tends to be smaller and less often symptomatic than the centrally located type II variety. Both types are usually smaller than 1 cm in diameter but occasionally may be quite large. The cysts are encompassed by a muscularis, are lined by a usually chronically inflamed transitional epithelium, and usually contain urine or cloudy fluid.
Pyelocalyceal cysts occur sporadically, affect all age groups, and usually are unilateral. They may be detected in as many as 0.5% of excretory urograms but usually are asymptomatic unless complicated by nephrolithiasis or infection. The frequency of stone formation in caliceal diverticulae has been reported to be between 10% and 40%. Transitional cell carcinoma arising in a pyelocalyceal cyst has been reported rarely. Surgical intervention is indicated only when conservative management of this complication fails.
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