Virtually all renal cystic illnesses are monogenic diseases (Table 470-1). A recent unifying theory of their pathophysiology suggests that all gene products (“cystoproteins”) that are mutated in cystic kidney diseases are expressed in primary cilia, basal bodies, or centrosomes.1-4 Primary cilia are antennalike cellular organelles produced by virtually every epithelial cell type in the body. The structure and function of primary cilia and basal bodies is delineated in eFig. 470.1 .5,6 They are important for perceiving extracellular cues, including photosensation, mechanosensation, osmosensation, and olfactory sensation. Cilia are assembled from basal bodies, which represent one of the two centrosomes. Centrosomes and basal bodies contain the same protein complexes that are part of the mitotic spindle in mitosis. These protein complexes are crucial for planar cell polarity, or the orientation of epithelial cells in three-dimensional space. Disruption of their function leads to cyst development and to extrarenal defects that have been summarized under the term ciliopathies. In general, it seems that the pathogenesis of ciliopathies is based on an inability of epithelial cells to sense or process extracellular cues.7
Table 470-1. Cystic Renal Disorders
Cystic disorders of the kidney are among the most common causes for end-stage kidney disease (ESKD) in children. Since most renal cystic diseases are monogenic disorders, pedigree analysis to determine the pattern of inheritance should be emphasized when obtaining the history. In autosomal dominant diseases, a genetic defect in only one of the two alleles of the disease gene leads to the disease phenotype. Typically, there are affected individuals in more than one generation. Father-to-son transmission may be present (as opposed to X-linked diseases), and the disease course is usually milder and has later onset than in recessive variants of the disease. In autosomal recessive diseases, defects in both alleles of a gene (on both parental chromosomes) are necessary for the disease to occur. Typically, there are affected individuals in only one generation, the disease course is usually more severe than in a dominant variant of the condition, and onset occurs already in childhood and adolescence. Knowing the mode of inheritance is an important guide for differential diagnosis, for genetic counseling, and for obtaining a molecular genetic diagnosis. In some diseases, defects in different genes localized at different chromosomal loci can give rise to identical or very similar disease phenotypes in different patients. This phenomenon is called genetic locus heterogeneityand is exemplified by autosomal dominant polycystic kidney disease (ADPKD) types 1 and 2.
In some renal cystic disorders, the responsible gene has been identified, so a definitive diagnosis may be made by direct molecular genetic testing that identifies the disease-causing mutation in affected patients. (Updates on laboratories that perform molecular genetic diagnoses can be found at http://www.genetests.org/ and www.genetests.org/. renalgenes.org.) Molecular genetic diagnosis should be initiated only within the context of genetic counseling by a certified genetic counselor, because there are many difficult ethical issues to consider.
All renal cystic disorders manifest with characteristic changes on ultrasound examination and present at specific age ranges. Therefore, an algorithm for differential diagnosis in cystic diseases of the kidney is based on results of renal ultrasound and is stratified by certain age groups and on molecular genetic diagnostics. A diagnostic algorithm for renal cystic disease is shown in Figure 470-1.
Renal cystic disorders eventually lead to end-stage kidney disease (ESKD). No treatment is available that changes disease progression or treats the underlying cause of these disorders. Therefore, therapy is symptomatic and is aimed at complications that might accelerate progression. This includes controlling blood pressure in patients with autosomal dominant polycystic kidney disease (ADPKD) to decelerate progression into renal failure. In the phase of compensated chronic renal insufficiency, symptomatic treatment for anemia, acidosis, growth retardation, and renal osteodystrophy is most important (see Chapter 477). Eventually, renal replacement therapy by dialysis and transplantation becomes necessary (see Chapters 129 and 478). Recently, it was shown that renal cystic mouse models are responsive to treatment with a vasopressor type 2 antagonist,8,9 with everolimus, or with roscovitine.10 Phase 2 treatment trials for cystic kidney disease in adults have been initiated with some of these agents.
MULTICYSTIC DYSPLASTIC KIDNEY (MCDK)
MCDK, also termed cystic dysplasia, is a developmental defect in kidney organogenesis that is discussed in Chapter 469.
AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE
Autosomal recessive polycystic kidney disease (ARPKD) occurs in 1 in 6000 to 40,000 live births. In a study of 66 boys and 49 girls with ARPKD, age at diagnosis was 11% prenatal, 41% neonatal, 23% infantile, and 25% juvenile (Fig. 470-2). Uniformly, there is bilateral kidney enlargement as a result of transformation of collecting ducts into fusiform cysts. Among extrarenal organ manifestations, congenital hepatic fibrosis is the most important one. ARPKD is always associated with hepatic fibrosis, which may not be clinically evident initially, because renal failure frequently develops earlier than clinical sequelae of hepatic fibrosis. Over time, cystic dilation of the biliary tree (Caroli disease) develops, followed by portal hypertension with a risk of GI bleeding from esophageal varices. Liver cell function is initially normal until cirrhosis develops. Rarely, cysts are present in the pancreas or spleen. A few patients will not manifest the renal components of their disease and will have reasonably well-preserved renal function but will present with symptoms related to congenital hepatic fibrosis and portal hypertension.
FIGURE 470-1. Algorithm for the evaluation of renal cystic disorders based on renal ultrasound and clinical and molecular genetics. Resultant diagnoses are shown on gray background. GC/MA, initiate genetic counseling (GC) and perform mutation analysis (MA) of the gene(s) indicated in italics (http://www.renalgenes.org; www.genetests.org). ADPKD, autosomal dominant polycystic kidney disease; infantile ADPKD, ADPKD due to homozygous deletions; ARPKD, autosomal recessive polycystic kidney disease; BBS, Bardet-Biedl syndrome; GCKD, glomerulocystic kidney disease; MCKD, medullary cystic kidney disease; MKS, Meckel-Gruber syndrome; MODYS, maturity-onset diabetes of the young; MR, mental retardation; NPHP1, 2, etc, nephronophthisis types 1, 2, etc, respectively; OMN, oligomeganephronia; SLSN, Senior-Løken syndrome.
A single recessive gene, PKHD1, has been identified by positional cloning as causing ARPDK. Because ARPKD is a recessive disease, an a priori risk of 25% exists for a sibling of an affected individual. Autosomal recessive polycystic kidney disease carries a high lethality in the perinatal period if two truncating mutations are present in the PKHD1 gene. If at least one missense mutation is present, end stage renal disease (ESRD) develops later in childhood or adolescence.12
FIGURE 470-2. Time course of renal failure in renal cystic disorders. Range for age of onset of end-stage renal disease is given as color rectangular symbols. Range for age at diagnosis is shown as color rectangular symbols. Numbers indicate median age in years. ARPKD, autosomal recessive polycystic kidney disease. ADPKD, autosomal dominant polycystic kidney disease. BBS, Bardet-Biedl syndrome; GCKD, familial hypoplastic glomerulocystic kidney disease; NPHP, nephronophthisis; MCDK, multicystic dysplastic kidney; MCKD, medullary cystic kidney disease.
Diagnosis of ARPKD rests on clinical signs and symptoms, renal and hepatic imaging, and molecular genetic diagnostics, as outlined in Figure 470-1. Prenatal findings in ARPKD include oligohydramnios and a renal sonographic echotexture known as salt-and-pepper appearance. Enlargement of fetal kidneys may not occur until after 24 to 28 weeks of gestation, making early diagnosis difficult. Oligohydramnios from intrauterine renal failure is associated with insufficient lung development and the typical “Potter facies,” which is characterized by low-set ears, a flat nose, and a retracted chin. In these severe prenatal cases, abnormal kidney growth can already be detected by ultrasound in the second half of pregnancy. A definitive diagnosis of ARPKD is theoretically possible by direct mutation analysis of the PKHD1 gene,12 with an approximate 80% detection rate. Mutation analysis of the PKHD1 gene should be initiated with the guidance of a genetic counselor, for both pre- and postnatal testing. For the diagnosis of ARPKD, a negative renal ultrasound in the parents is obligatory in order to distinguish the disease from early-onset autosomal dominant polycystic kidney disease (ADPKD).
Initial symptoms and signs that lead to the diagnosis of autosomal recessive polycystic kidney disease (ARPKD) in infants and children include a palpable abdominal mass, hypertension, urinary tract infections, an affected sibling, liver involvement, and growth failure. Bilaterally enlarged hyperechogenic kidneys maintain a reniform shape even when grossly enlarged. On ultrasound, kidneys continue to exhibit a salt-and-pepper appearance until later stages, when distinct, rounded cysts appear. In ARPKD, kidneys can be grossly enlarged so that palpable abdominal masses are common, as are hypertension and urinary tract infections. On hepatic ultrasound, the liver is hyperechogenic, and later visible biliary cysts may develop. Renal and hepatic changes can also be confirmed by magnetic resonance imaging, where the radial arrangement of fusiformly dilated collecting ducts can be noted. Kidney biopsy plays a decreasing role in diagnosis due to molecular genetic diagnostics. On renal histology, there is fusiform dilation and cyst development, involving 10% to 90% of collecting ducts, depending on severity and age of onset. Liver histology exhibits portal and interlobular fibrosis as well as biliary duct hyperplasia. Liver biopsy is useful to assess the degree of liver failure in later stages.
Other cystic diseases that occur in infancy and early childhood need to be considered (Fig. 470-3). Specifically, medullary cystic kidney disease, infantile nephronophthisis, and Meckel-Gruber syndrome can be confused with ARPKD (Table 470-1). Multicystic dysplastic kidney can be distinguished from ARPKD by reduced kidney size and loss of the reniform shape. Autosomal dominant polycystic kidney disease (ADPKD) may occur rarely in infants if large deletions are present in the PKD1 gene. Meckel-Gruber syndrome, in addition to renal agenesis and dysgenesis shows a wide variety of extrarenal organ involvement, including occipital encephalocele, cleft palate, polydactyly, and ocular anomalies and usually leads to perinatal lethality. A rare but important differential diagnosis is infantile NPHP, which can be diagnosed by mutation analysis of the NPHP2/INVS gene (www.renalgenes.org). Bilateral Wilms tumor is rare and can be distinguished from ARPKD by a highly irregular parenchymal pattern on imaging techniques. Bardet-Biedl syndrome can clearly be distinguished from ARPKD by the presence of retinitis pigmentosa and polydactyly, together with obesity, diabetes mellitus, mental retardation, and hypogonadism.
Chronic renal failure with anemia, growth retardation, and osteodystrophy is common. There is a high risk of urinary tract infection. Urinary outflow obstruction from renal cysts may also occur. Hypertension is frequent, and nephrolithiasis occurs in about 15% of cases. Esophageal variceal bleeding and hyper-splenism can result from liver fibrosis. Ascending cholangitis occurs from infections of hepatic cysts. Fertility- and pregnancy-related problems are also common.
The severe hypertension that occurs in young infants with ARPKD requires aggressive management to optimally preserve renal function. Early detection and aggressive treatment of urinary tract infections is also important. Managing portal hypertension frequently becomes a major problem. In end-stage renal disease, renal replacement therapy by dialysis and transplantation becomes necessary. Depending on whether liver failure has developed, combined kidney and liver transplantation or secondary liver transplantation after initial kidney transplantation may be warranted. Some experimental treatment forms for ADPKD are being developed in mouse models (see above; http://www.nih.gov/news/pr/jan2006/niddk-24.htm).
Children presenting perinatally have a 30% to 50% mortality rate in the first month of life.12 Those who survive through the first month have a 1-year survival rate of 85% and a 10-year survival rate of 82%. Chronic renal failure is first detected at a mean age of 4 years. First renal replacement therapy was necessary by 5 years of age in 86% of cases. Three quarters of cases developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 45% of patients and were related to age.
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent lethal disease of autosomal dominant inheritance in the United States and Europe,13 with a prevalence of 1:1000 in the general population. About 10% to 15% of all patients in adult chronic dialysis programs have ADPKD. ESKD usually develops between age 60 and 70 years. Clinically, ADPKD2 is very similar to ADPKD1 but follows a somewhat milder course toward renal failure and does not present in childhood. ADPKD usually manifests in late adulthood but can lead to clinical symptoms in older children and young adults, including abdominal pain, palpable abdominal mass, hematuria, urinary tract infections, hypertension, and abdominal or inguinal hernias. Cerebral aneurysms and diverticulosis of the gut may develop in adults with ADPKD.
The PKD1 gene is localized on chromosome 16p13.1 and codes for polycystin-1, a protein with a large transmembrane domain and a complex extracellular domain. Polycystin-1 interacts with the gene product (polycystin-2) of the PKD2 gene. Although a germ-line mutation segregates in affected families in an autosomal dominant fashion, the disease mechanism, by which renal cysts develop gradually over several decades, is due to the loss of heterozygosity (LOH) of the second allele in individual cells, consistent with a “second hit mechanism” (see Chapter 170). In rare instances, ADPKD can occur in infancy if patients carry large deletions, which affect the PKD1 gene and the neighboring TSC2 gene, in way of a “contiguous gene deletion syndrome” (see Chapter 170). Among patients with tuberous sclerosis, apparently only individuals carrying such extensive deletions develop large bilateral renal cysts and exhibit infantile onset of ADPKD.14
In children who are known to be genetically at risk due to ADPKD in a parent, the presence of even a single cyst in normal-sized kidneys is highly predictive for the development of ADPKD. Hepatic, pancreatic, or ovarian cysts are rarely detected before puberty. A diagnostic algorithm based on renal ultrasound and mutation analysis is shown in Figure 470-1. Molecular genetic diagnostics of PKD1 can be initiated after genetic counseling. Early genetic diagnosis may be valuable to monitor for complications such as hypertension, UTI, and cerebral aneurysms and to evaluate living related kidney transplant donors.
Although in ADPKD chronic renal failure develops at a median age of approximately 65 years, at-risk children and young adults should be followed annually for hematuria and hypertension, and at greater intervals by renal ultrasound, especially during pregnancy. Aggressive treatment of hypertension or urinary tract infection is indicated, because both pose considerable risk for accelerated progression into ESKD. In families with a history of cerebral aneurysms, or if symptoms warrant, cranial CT or MRI should be followed, but routine screening is not usually undertaken. Phase 2 trials have been initiated for some experimental treatment approaches in adult patients with cystic kidney diseases.
NEPHRONOPHTHISIS AND MEDULLARY CYSTIC KIDNEY DISEASE
Diseases of the “nephronophthisis/medullary cystic kidney disease (NPHP/MCKD) complex” are renal cystic diseases that share a virtually identical renal histology15 characterized by thickening and disintegration of the tubular basement membrane, interstitial lymphocytic infiltrations with fibrosis, and distal tubular atrophy with cysts (Fig. 470-3A). Over time, chronic sclerosing tubulointerstitial nephropathy develops. In contrast to polycystic kidney disease, cysts occur primarily at the corticomedullary junction of the kidneys, and kidney size remains normal or is slightly diminished (Fig. 470-3B). Although histology is similar in all forms of the disease, the two different disease groups of recessive nephronophthisis (NPHP) and dominant medullary cystic kidney disease (MCKD) can be clearly distinguished by age of onset or pattern of inheritance.
FIGURE 470-3. Morphology of nephronophthisis. A: Renal histology in NPHP shows the characteristic triad of renal tubular cysts, tubular membrane disruption, and tubulointerstitial cell infiltrates with interstitial fibrosis and periglomerular fibrosis. B: Renal ultrasound demonstrates increased echogenicity, loss of corticomedullary differentiation, and the presence of corticomedullary cysts. In contrast to polycystic kidney disease, kidneys are not enlarged. (A is courtesy of D. Bockenhauer, London).
Autosomal recessive nephronophthisis (NPHP) leads to ESKD at a median age of 13 years. In NPHP, a history of polyuria, polydipsia, anemia, and growth retardation is common. Patients often describe nighttime fluid intake starting at about 6 years of age. Partially due to excessive salt loss, these children do not develop the usually typical symptoms of chronic renal disease (hematuria, proteinuria, hypertension, or edema). Therefore, the diagnosis is usually only made late in the course of the disease. Renal ultrasound is an important aid in diagnosing NPHP (Fig. 470-3B) and is integrated into the diagnostic algorithm (Fig. 470-1). The ultrasonographic characteristics of NPHP are normal or slightly reduced kidney size; increased echogenicity; a lack of corticomedullary differentiation; and, beyond the age of 9 years, cysts at the corticomedullary border of the kidneys. A history of similar disease in preceding generations suggests a diagnosis of dominant MCKD, whereas a lack of family history suggests recessive NPHP (Fig. 470-1).
Extrarenal manifestations may occur in all forms of recessive NPHP, so ophthalmologic examination and brain MRI are warranted. Recessive NPHP can be associated with extrarenal organ involvement. Retinitis pigmentosa is associated with NPHP in Senior-Løken syndrome (SLSN)20 and cerebellar vermis aplasia and coloboma of the eye in Joubert syndrome.21 The inability to perform horizontal eye movements (ocular motor apraxia type Cogan) was found in infants and toddlers with homozygous deletions in the NPHP1 gene. An association of NPHP with hepatic fibrosis or cone-shaped epiphyses has also been described. In addition, truncating mutations in NPHP3, NPHP6, and NPHP8 can lead to Meckel-Gruber syndrome (Fig. 470-1). If obesity, diabetes mellitus, infertility, or polydactyly are present, Bardet-Biedl syndrome should be considered (Fig. 470-1) and may be confirmed by mutation analysis. In addition, Jeune syndrome (asphyxiating thoracic dysplasia)22 and Ellis-van Creveld syndrome can be part of the differential diagnosis.
Mutations in nine different recessive genes have been identified as causing NPHP.15 These are NPHP1, NPHP2/inversin, NPHP3, NPHP4, NPHP5, NPHP6/CEP290, NPHP7/GLIS2, NPHP8/RPGRIP1L, and NPHP9/NEK8, defining NPHP types 1 through 9, respectively (Table 470-1).2 Gene identification generated new insights into disease mechanisms of NPHP, as described above and shown in eFigure 470.1 . Gene identification has made definite molecular genetic diagnostics possible for approximately 30% of cases. Deletions of the NPHP1 gene on both parental chromosomes account for approximately 21% of all NPHP cases, whereas the other genes NPHP2-9 (Table 470-1) contribute about 1% each. The causative genes are still unknown in about 70% of cases. Following genetic counseling, mutation analysis will first be performed in the most frequent form, NPHP1. Mutation analysis will unequivocally confirm the diagnosis of NPHP in approximately 30% of children with NPHP. If changes on renal ultrasound are seen before the age of 4 years, mutation analysis is warranted in NPHP2/INVS (Fig. 470-1).
MEDULLARY CYSTIC KIDNEY DISEASE (MCKD)
MCKD is characterized by autosomal dominant inheritance, adult-onset of ESKD. The extrarenal involvement seen in NPHP is absent. However, MCKD can be associated with hyperuricemia and gouty arthritis in most affected individuals. A gene locus (MCKD1) for MCKD type 1 has been mapped to chromosome 1q21, but the gene is unknown. Mutations of the UMOD gene encoding uromodulin/Tamm-Horsfall protein were detected as the cause of MCKD type 2. Histology of MCKD is indistinguishable from the one seen in NPHP (Fig. 470-3A). Definitive molecular genetic diagnostics is possible by UMOD mutation analysis. Mutations in UMOD my also cause the clinical picture of glomerulocystic kidney disease (GCKD; see the following section).
GLOMERULOCYSTIC KIDNEY DISEASE
The term glomerulocystic kidney disease (GCKD) describes a heterogeneous group of diseases characterized by multiple small cortical cysts that result from cystic dilation of the Bowman space and the initial proximal convoluted tubule. The lack of further tubular involvement differentiates GCKD from other cystic diseases, in which cysts arise from tubular dilation. Although this histological picture is found in families with ARPKD and in several rare diseases, including orofacial-digital syndrome type I, a distinct disease entity called familial hypoplastic glomerulocystic disease exists and follows autosomal dominant inheritance.
The typical presentation of nonautosomal dominant GCKD is an infant with an abdominal mass and renal insufficiency. Hypertension is common at presentation. Hepatic cysts have been described. Some patients present only as adults with hypertension, flank pain, and hematuria. The degree of renal dysfunction is variable. Children with familial hypoplastic GCKD (autosomal dominant) have chronic renal failure early in life, but some have stable courses without progression to ESRD. Renal ultrasound shows small kidneys and an abnormality of medullary pyramids with collecting systems and absent papillae (Fig. 470-1). Dominant mutations of HNF1B/TCF2 have been described as the cause of GCKD in association with maturity-onset diabetes of the young type 5 (MODY5). Also, mutations of UMOD are known to cause isolated GCKD. This may be understood within the ciliopathy theory of cystic kidney diseases, as UMOD is under the transcriptional control of HNF1B/TCF2.
OTHER RENAL CYSTIC DISORDERS
MECKEL-GRUBER SYNDROME (MKS)
MKS is an autosomal recessive inherited disorder featuring developmental defects of different organs, including the kidney, and usually leads to perinatal death. Diagnosis is based on early onset; renal ultrasonography; and the presence of cystic dysplasia of the kidney, hepatic fibrosis, occipital encephalocele, and postaxial polydactyly.23 Renal or liver biopsy sometimes has a diagnostic role. Prognosis is guarded in cases with onset of renal insufficiency in the neonatal period. In the differential diagnosis of Meckel-Gruber syndrome, ARPKD, Joubert syndrome, and carbohydrate-deficient glycoprotein disease have to be considered. Two causative genes (MKS1 and MKS3/TMEM67) have been identified, and one gene locus has been mapped (MKS2). In addition, mutations in NPHP3, NPHP6, and NPHP8 can lead to Meckel-Gruber syndrome if two truncating mutations are present, whereas the disease variant is milder in the presence of at least one missense mutation, showing the features of Joubert syndrome or Senior-Løken syndrome (Fig. 470-1).
BARDET-BIEDL SYNDROME (BBS)
BBS is an autosomal recessive disease characterized by obesity, retinitis pigmentosa, infertility, polydactyly, mental retardation, and the occurrence of cystic dysplasia of the kidney or an NPHP-like histology24 (Fig. 470-1). Twelve different causative recessive genes (BBS1–BBS12) have been identified by positional cloning. Direct molecular genetic diagnosis of BBS is possible in certain cases. Regarding its pathophysiology, BBS is also considered a “ciliopathy,” in which multiple organ involvement can be explained through defects in the function of primary cilia in multiple organs (Fig. 470-3).25
MEDULLARY SPONGE KIDNEY
Medullary sponge kidney is a rare congenital cystic disorder in which there is ectasia of cortical ducts within the inner medulla of the kidney, resulting in a spongelike appearance. Calcifications, which develop in these locations, are visible on plain x-ray films. There is a strong propensity to renal calculi and urinary tract infections. Recently, familial cases have been described within the familial ureteral abnormalities syndrome (FUAS), which raises the question of whether there might exist a monogenic form of this disorder. The characteristic pyelogram with linear striations from dilated collecting ducts and enlarged calices is usually diagnostic of the disease. Generally there is no role for sonography, CT, or arteriography. The prognosis is good, because in the absence of complications, renal function is normal, and there is no increased morbidity or mortality resulting from the disease.