Chapter 309: Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development

The polycystic kidney diseases are a group of genetically heterogeneous disorders and a leading cause of kidney failure. The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, affecting 12 million people worldwide. The autosomal recessive form of polycystic kidney disease (ARPKD) is rarer but affects the pediatric population. Kidney cysts are often seen in a wide range of syndromic diseases. Recent studies have shown that defects in the structure or function of the primary cilia may underline this group of genetic diseases collectively termed ciliopathies (Table 309-1).

Etiology and Pathogenesis

ADPDK is characterized by progressive formation of epithelial lined cysts in the kidney (Fig. 309-1). Although cysts only occur in 5% of the tubules in the kidney, the enormous growth of these cysts ultimately leads to the loss of normal surrounding tissues and loss of renal function. The cellular defects in ADPKD that have been known for a long time are increased cell proliferation and fluid secretion, decreased cell differentiation, and abnormal extracellular matrix. ADPKD is caused by mutations in PKD1 and PKD2 which, respectively, code for polycystin-1 (PC1) and polycystin-2 (PC2). PC1 is a large 11- transmembrane protein that functions like a G-protein coupled receptor. PC2 is a calcium-permeable six transmembrane protein that structurally belongs to the transient receptor potential (TRP) cation channel family. PC1 and PC2 are widely expressed in almost all tissues and organs. PC1 expression is high in development and low in the adult, whereas PC2 expression is relatively constant. PC1/2 are found on the primary cilium, a hair-like structure present on the apical membrane of a cell, in addition to the cell membranes and cell-cell junctions of tubular epithelial cells. Defects in the primary cilia are linked to a wide spectrum of human diseases, collectively termed ciliopathies. The most common phenotype shared by many ciliopathies is kidney cysts. PC1 and PC2 bind to each other via their respective C-terminal tails to form a receptor-channel complex and regulate each other’s function. The PC1/2 protein complex serves as a mechanosensor or chemical sensor and regulates calcium and G-protein signaling. The PC1/2 protein complex may also directly regulate a number of cellular functions including the cell cycle, the actin cytoskeleton, planar cell polarity (PCP), and cell migration. This protein complex has also been implicated in regulating a number of signaling pathways, including Wnt, mammalian target of rapamycin (mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K/Akt), G protein–coupled receptor (GPCR), and epidermal growth factor receptor (EGFR), as well as in the localization and activity of cystic fibrosis transmembrane conductance regulator (CFTR). One hypothesis is that loss of ciliary function of PC1 and PC2 leads to aberrant calcium signaling and a subsequent increase of adenylyl cyclase activity and decrease of phosphodiesterase activity, which, in turn, causes increased cellular cAMP. Increased cAMP promotes protein kinase A activity, among other effectors, and, in turn, leads to cyst growth by promoting proliferation and fluid secretion of cyst-lining cells through chloride and aquarporin channels in ADPKD kidneys.

ADPKD is inherited as an autosomal dominant trait with complete penetrance, but variable expressivity. The disease affects all ethnic groups worldwide with an estimated prevalence of 1:1000 to 1:400. Only half of the patients with ADPKD are clinically diagnosed during their lifetime. ADPKD is genetically heterogeneous. The first disease gene (PKD1) was localized to the region of the alpha-globin gene on chromosome 16p13 in 1985, and a second disease gene (PKD2) locus was mapped to chromosome 4q21-q23 in 1993. Mutations of PKD1 and PKD2 are responsible for ~85% and ~15% of ADPKD cases, respectively. However, patients with PKD2 mutations may be >15% because they tend to have milder clinical disease and, as a result, under-diagnosed. Embryonic lethality of Pkd1 and Pkd2 knockout mice suggest human homozygotes may be lethal, thus not clinically recognized.

PKD1 is comprised of 46 exons occupying ~52 kb of genomic DNA. It produces a ~14 kb transcript that encodes polycystin-1, a protein of ~4300 amino acids. A feature of the PKD1 gene is that the 5’ three-quarters of PKD1 have been duplicated at six other sites on chromosome 16p, and many of them produce mRNA transcripts, which provides a major challenge for genetic analysis of the duplicated region. PKD2 is a single-copy gene with 15 exons producing a ~5.3 kb mRNA transcript that encodes polycystin-2, a protein of 968 amino acids. A third gene GANAB, encoding the glucosidase IIa subunit, was recently reported to cause ADPKD, but patients with mutations in this gene all appear to have polycystic liver disease, and their kidney disease is milder than that in classic ADPKD.

In ADPKD patients, every cell carries a germline mutant allele of either PKD1 or PKD2. However, cysts develop in only a small fraction of the nephrons. Cysts are thought to originate from clonal growth of single cells that have received a somatic “second hit” mutation in the “normal” allele of the PKD1 or PKD2 gene. Accumulating evidence in mouse models now shows that partial loss of function of the second allele of Pkd1 in a proliferative environment is sufficient for cystogenesis, suggesting that a critical amount of PKD1 is needed in a cell. Somatic inactivation of the second allele of Pkd1 in adult mice results in very slow onset of cyst development in the kidney, but a “third hit” such as an additional genetic or epigenetic event, the inactivation of a growth suppressor gene, the activation of a growth promoting gene(s), or an event like renal injury that activates the developmental program, may promote rapid cyst formation.

Clinical Manifestations

ADPKD is characterized by the progressive bilateral formation of renal cysts. Focal renal cysts are typically detected in affected subjects aged <30 years. Hundreds to thousands of cysts are usually present in the kidneys of most patients in the fifth decade (Fig. 309-2). Enlarged kidneys can each reach a fourfold increase in length, and weigh up to 20 times the normal weight. The clinical presentations of ADPKD are highly variable. While many patients are asymptomatic until the fourth to fifth decade of life and are diagnosed by incidental discoveries of hypertension or abdominal masses, back or flank pain is a frequent symptom in ~60% of patients with ADPKD. The pain may result from renal cyst infection, hemorrhage, or nephrolithiasis. Gross hematuria resulting from cyst rupture occurs in ~ 40% of patients during the course of their disease, and many of them will have recurrent episodes. Flank pain and hematuria may coexist if the cyst that ruptures is connected with the collecting system. Proteinuria is usually a minor feature of ADPKD. Infection is the second most common cause of death for patients with ADPKD. Up to half of patients with ADPKD will have one or more episodes of renal infection during their lifetime. An infected cyst and acute pyelonephritis are the most common renal infections often due to gram-negative bacteria, which are associated with fever and flank pain, with or without bacteremia. These complications and renal insufficiency often correlate with structural abnormality of the renal parenchyma. Kidney stones occur in ~20% of patients with ADPKD. Different from the general population, more than half of the stones in patients with ADPKD are composed of uric acid, with the remainder due to calcium oxalate. Distal acidification defects, abnormal ammonium transport, low urine pH, and hypocitraturia may be important in the pathogenesis of renal stones in ADPKD. Renal cell carcinoma is a rare complication of ADPKD with no apparent increased frequency compared to the general population. However, in ADPKD these tumors are more often bilateral at presentation, multicentric, and sarcomatoid in type. Radiological imaging is often not helpful in distinguishing cyst infection and cyst hemorrhage because of their complexity. CT scan and magnetic resonance imaging (MRI) are often useful in distinguishing a malignancy from a complex cyst. Cardiovascular complications are the major cause of mortality in patients with ADPKD. Hypertension is common, and typically occurs before any reduction in glomerular filtration rate (GFR). Hypertension is a risk factor for both cardiovascular and kidney disease progression in ADPKD. Notably, some normotensive patients with ADPKD may also have left ventricular hypertrophy. Hypertension in ADPKD may result from the increased activation of the renin-angiotensin-aldosterone system, increased sympathetic nerve activity, and impaired endothelial cilium function-dependent relaxation of small resistant blood vessels.

The progression of ADPKD has striking inter- and intrafamilial variability. The disease can present as early as in utero, but end-stage renal disease (ESRD) typically occurs in late middle age. Risk factors include early diagnosis of ADPKD, hypertension, gross hematuria, multiple pregnancies, and large kidney size. Liver cysts derived from the biliary epithelia are the most common extrarenal complication. Polycystic liver disease associated with ADPKD is different from autosomal dominant polycystic liver disease (ADPLD), which is caused by mutations in at least two distinct genes (PRKCSH and SEC63) and does not progress to renal failure. Massive polycystic liver disease occurs almost exclusively in women with ADPKD, particularly those with multiple pregnancies. Heterozygous loss-of-function variants in PKHD1, ALG8, GANAB, and SEC61B are now found in ADPLD. ALG8, GANAB, and SEC61B, all encode ER proteins that are involved in the same pathway as GIIβ and SEC63, and each appears to affect PC1 biogenesis.

Intracranial aneurysm (ICA) occurs four to five times more frequent in APDKD patients than that seen in the general population and cause high mortality. The disease gene products PC1 and PC2 may be directly responsible for defects in arterial smooth muscle cells and myofibroblasts. The focal nature and the natural history of ICA in ADPKD remain unclear. A family history of ICA is a risk factor of aneurysm rupture in ADPKD, whether hypertension and cigarette smoking are independent risk factors is not clear. About 20–50% of patients may experience “warning headaches” preceding the index episode of subarachnoid hemorrhage due to ruptured ICA. A CT scan is generally used as the first diagnostic test. A lumbar puncture may be used to confirm the diagnosis. The role of radiological screening for ICA in asymptomatic patients with ADPKD remains unclear. ADPKD patients with a positive family history of ICAs may undergo pre-symptomatic screening of ICAs by MR angiography. Other vascular abnormalities in ADPKD patients include diffuse arterial dolichoectasias of the anterior and posterior cerebral circulation, which can predispose to arterial dissection and stroke. Mitral valve prolapse occurs in up to 30% of patients with ADPKD, and tricuspid valve prolapse is less common. Other valvular abnormalities occurring with increased frequency in ADPKD patients include insufficiency of the mitral, aortic, and tricuspid valves. Most patients are asymptomatic but some may progress and require valve replacement. The prevalence of colonic diverticulae and abdominal wall hernias are also increased in ADPKD patients.

Diagnosis

Diagnosis is typically made from a positive family history consistent with autosomal dominant inheritance and multiple kidney cysts bilaterally. Renal ultrasonography is often used for presymptomatic screening of at-risk subjects and for evaluation of potential living-related kidney donors from ADPKD families. The presence of at least two renal cysts (unilateral or bilateral) is sufficient for diagnosis among at-risk subjects between 15 and 29 years of age with a sensitivity value of 96% and specificity value of 100%. The presence of at least two cysts in each kidney and at least four cysts in each kidney, respectively, are required for the diagnosis among at-risk subjects aged 30–59 years and aged ≥60 years with a sensitivity value of 100% and specificity value of 100%. This is because there is an increased frequency of developing simple renal cysts with age. Conversely, in subjects aged between 30 and 59 years the absence of at least two cysts in each kidney, which is associated with a false negative rate of 0%, can be used for disease exclusion. These criteria have a lower sensitivity for patients with a PKD2 mutation because a late onset of ADPKD2. CT scan and T2-MRI, with and without contrast enhancement, are more sensitive than ultrasonography and can detect cysts of smaller size. However, a CT scan exposes the patient to radiation and radiocontrast, which may cause serious allergic reactions and nephrotoxicity in patients with renal insufficiency. T2-MRI, with gadolinium as a contrast agent, has minimal renal toxicity and can detect cysts of only 2–3 mm in diameter. However, a large majority of cysts may still be below the detection level. Genetic testing by linkage analyses and mutational analyses are available for ambiguous cases. Because of the large size of PKD1 gene and the presence of multiple highly homologous pseudogenes, mutational analysis of PKD1 gene is difficult and costly. Application of new technologies such as paired-end next generation sequencing with multiplexing individually bar-coded long range PCR libraries may reduce the costs and improve the sensitivity for clinical genetic testing.

TREATMENT

Genetic Considerations

ARPKD is a significant hereditary renal disease in childhood, with an estimated prevalence of 1 in 20,000 live births. A carrier frequency of up to 1:70 has been reported. Mutations in a single gene, PKHD1, are responsible for all the clinical presentations of ARPKD. PKHD1, localized on human chromosome region 6p21.1-6p12.2, is one of the largest genes in the genome, occupies ~450 kb of DNA, and contains at least 86 exons. It produces multiple alternatively spliced transcripts. The largest transcript encodes fibrocystin/polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. FPC has a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. FPC is localized on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, similar to polycystins and several other ciliopathy proteins. FPC is also expressed on the basal body and plasma membrane. The large extracellular domain of FPC is presumed to bind to an as yet unknown ligand(s), and is involved in cell-cell and cell-matrix interactions. FPC interacts with ADPKD protein PC2, and may also participate in regulation of the mechanosensory function of the primary cilia, calcium signaling, and PCP, suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. FPC is also found on the centrosomes and mitotic spindle, and may regulate centrosome duplication and mitotic spindle assembly during cell division. A large number of various mutations have been found throughout PKHD1, and are unique to individual families. Most patients are compound heterozygotes for PKHD1 mutations. Patients with two truncation mutations appear to have an earlier onset of the disease.

Clinical Features

Classic ARPKD is generally diagnosed in utero or within the neonatal period, and characterized by greatly enlarged echogenic kidneys in diseased fetuses. Reduced fetal urine production may contribute to oligohydroaminos and pulmonary hypoplasia. About 30% of affected neonates die shortly after birth due to respiratory insufficiency. Close to 60% of mortality occurs within the first month of life. In the classic group, most patients are born with renal insufficiency and ESRD. However, infants often have a transient improvement in their GFR; death from renal insufficiency at this stage is rare. Some patients are diagnosed after the neonatal stage, which form the older group. Morbidity and mortality in this group often involve systemic hypertension, progressive renal insufficiency, and liver manifestations. The hallmarks of ARPKD liver disease are biliary dysgenesis due to a primary ductal plate malformation with associated periportal fibrosis, namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic bile ducts (Caroli disease). CHF and Caroli disease can then lead to portal hypertension exhibiting hepatosplenomegaly, variceal bleeding, and cholangitis. Some patients with the diagnosis of ARPKD at 1 year of age with nephromegaly exhibit slowly declining renal function over 20 years with only minimally enlarged kidneys at ESRD, and markedly atrophic kidneys following renal transplantation. The slow progression of renal disease is likely due to increasing fibrosis rather than the development of cysts. Systemic hypertension is common in all ARPKD patients, even those with normal renal function.

Diagnosis

Ultrasonography, CT, and MRI all can be used for diagnosis. Ultrasonography reveals large, echogenic kidneys with poor corticomedullary differentiation. The diagnosis can be made in utero after 24 weeks of gestation in severe cases. Macrocysts generally are not common at birth in ARPKD patients. The absence of renal cysts in either parent, particularly if they are >40 years of age on ultrasonography helps distinguish ARPKD from ADPKD in older patients. Clinical, laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathology demonstrating characteristic ductal plate abnormalities, family history of affected siblings, or parental consanguinity suggestive of autosomal recessive inheritance is helpful. The lack of mutational hot spots and the large and complex genomic structure of PKHD1 make molecular diagnosis difficult, however, presymptomatic screen of other at-risk members in a family with already identified ARPKD mutations is straightforward and inexpensive.

TREATMENT

TUBEROUS SCLEROSIS

Tuberous sclerosis (TS) is a rare autosomal dominant syndrome caused by mutations in one of two genes, TSC1, encoding hamartin, or, TSC2, encoding tuberin. Published estimates of prevalence vary widely, but it certainly occurs in <1:5,000 births. Kidney cysts are a frequent feature of this condition, as are two other abnormalities of kidney growth, renal cell carcinoma and renal angiomyolipomas. TS is a syndrome affecting multiple organ systems. Other features of TS include benign growths in the nervous system, eyes, heart, lung, liver, and the skin. Essentially all TS patients have such skin lesions, and a large proportion of patients have neurologic and cognitive manifestations. The TSC2 gene is adjacent to PKD1 in the human genome. Some patients have deletions in their genomic DNA that inactivate these two genes. Such individuals may have manifestations of both ADPKD and TS.

The most common kidney finding in TS is the presence of angiomyolipomas. These growths tend to be multiple and bilateral. While they are usually benign, they may bleed. Surgical removal is often recommended as a prophylactic measure in people with angiomyolipomas >4 cm in diameter. The cysts in TS are radiographically similar to those seen in ADPKD. In contrast to ADPKD, there is a clearly increased risk of renal cell carcinoma in TS patients. Regular periodic imaging is recommended in TS patients with kidney involvement to screen for the development of renal cell carcinoma. These cysts may rarely become large and hemorrhagic, occasionally requiring nephrectomy when nephron-sparing surgery is not possible.

Although not common, TS may lead to significant chronic kidney disease (CKD) and progress to end-stage kidney failure. Patients with TS and CKD typically have an unremarkable urine sediment and only minimal to mild amounts of proteinuria.

Mechanistically, the TSC1 and TSC2 gene products tuberin and hamartin interact physically. This protein complex is localized to the base of the cilia and inhibits intracellular signaling processes mediated by mTOR (mammalian target of rapamycin), leading to abnormal growth in a number of tissues. Investigation of mTOR inhibitors as therapy for TS is ongoing. There is increasing optimism that this class of drugs will become commonplace for prevention of the renal and non-renal manifestations of TS.

VON HIPPEL-LINDAU DISEASE

Von Hippel-Lindau disease (VHL) is an inherited cancer syndrome with renal manifestations. VHL is an autosomal dominant condition caused by mutations in the VHL tumor-suppressor gene. VHL is localized to the primary cilia and is necessary for the formation of primary cilia. Like many autosomal dominant cancer syndromes, VHL is recessive at the cellular level: a somatic mutation in the second VHL allele leads to loss of VHL in the cell and abnormal growth. Kidney manifestations of VHL include multiple bilateral kidney cysts, and renal cell carcinomas. Kidney cysts and carcinoma affects the majority of VHL patients. Non-renal features of VHL include pheochromocytomas, cerebellar hemangioblastomas, and retinal hemangiomas. While much rarer than ADPKD, it is important for this entity to be considered in the differential diagnosis of an individual with newly recognized kidney cysts.

In these patients, annual screening of the kidneys by imaging with CT or MRI scanning is recommended for early detection of renal cell carcinomas. Increasingly, nephron-sparing surgical approaches are being used for removal of cancerous lesions in order to preserve kidney function.

ADPKD is by far the most common adult onset single gene form of adult onset kidney disease. The large cysts that are sometimes seen in VHL and TS are similar in appearance to the cysts seen in ADPKD. A variety of other inherited disorders affecting primarily tubule and renal interstitial function can lead to CKD and eventual end-stage kidney disease in the absence of large tubule-derived cysts.

Inherited diseases affecting the tubulointerstitial compartment of the kidney can lead to secondary glomerular stress and glomerulosclerosis with some degree of concomitant proteinuria. Similarly, disorders of glomerular function will typically lead to secondary interstitial fibrosis and tubule atrophy. From a clinical perspective, therefore, distinguishing between a genetic disease of the renal tubules and a disease of the glomerulus may not be easy, particularly in the absence of a gross phenotype such as large kidney cysts.

AUTOSOMAL DOMINANT INTERSTITIAL KIDNEY DISEASE (MEDULLARY CYSTIC KIDNEY DISEASE)

The medullary cystic kidney diseases (MCKD) are autosomal dominant disorders. The term autosomal dominant tubulointerstitial kidney disease (ADTKD) is replacing MCKD as the preferred designation. Despite the old nosology, kidney cysts are not invariably present. Older literature often grouped MCKD together with the childhood-onset disorders known as the nephronophthises, but these are distinct clinical and genetic entities.

ADTKD-MUC1

Patients with medullary cystic kidney disease type I (MCKD I) have mutations in the mucin 1 gene MUC1. In contrast to MCKD II patients, individuals with MCKD I do not have elevated uric acid levels. The disease-causing MUC1 mutations that have been reported all alter a highly repetitive region within the MUC1 gene, leading to a large “neoprotein” fragment that may lead to toxic effects on the kidney tubule.

Clinically, patients with MCKD I exhibit slowly progressive CKD in adulthood, with only minimal amounts of increased urine protein and occasional renal cysts seen on ultrasound examination. Kidney histology shows tubulointerstitial fibrosis and tubular atrophy. The mechanisms by which MUC1 mutations cause human kidney disease are not known. Disease does not recur in transplanted kidneys.

ADTKD-UMOD

ADTKD-IUMOD (also called MCKD II) is caused by mutations in the UMOD gene, which encodes the protein uromodulin, also known as Tamm-Horsfall protein. Uromodulin is also found on the centrosome, the mitotic spindle, and the primary cilia; it colocalizes with nephrocystin-1 and KIF3A on the cilia. UMOD mutations also cause the conditions that have been referred to as familial juvenile hyperuricemic nephropathy (HNFJ1) and glomerulocystic kidney disease (GCKD), although it is not clear that these different names represent clearly distinct disorders. The term uromodulin-associated kidney disease (or UAKD) has been suggested as a better name for MCKD II and the various other related UMOD-associated diseases. Despite the name, kidney cysts are not a common feature of MCKD II. MCKD II should be suspected clinically in patients with a family history of late onset kidney disease, benign urine sediments, absence of significant proteinuria, and hyperuricemia. Large genome-wide association studies have suggested that certain common non-coding sequence variants in UMOD are associated with a moderately increased risk of CKD in the general population. UMOD-associated disease is often associated with gout.

Other Forms of Familial Tubulointerstitial Kidney Disease

A small number of families have been identified with autosomal dominant tubulointerstitial kidney disease and hyperuricemia who lack UMOD mutations. Some of these families carry disease-segregating mutations in the renin gene REN (disease designation ADTKD-REN). ADKTKD-REN patients demonstrate hyporeninemia with mild hyperkalemia, and often have hyperuricemia and gout. There are other families who lack mutations in UMOD, MUC1, or REN mutation. Thus, mutations in other yet-to-be identified genes are able to produce similar interstitial kidney disease, both with and without hyperuricemia.

Kidney biopsies in patients with any of various forms of MCKD typically show interstitial fibrosis. These histologic features are not diagnostic of any particular genetic entity, and the specific diagnosis must be made by other means. Genetic tests for alterations in specific genes are increasingly available in the clinical setting.

Those patients with autosomal dominant interstitial kidney disease, UMOD or REN mutations, with hyperuricemia and gout should be treated similarly to others with these findings, with uric-acid lowering agents, such as allopurinol or febuxostat.

A large and growing number of genetically distinct but related set of autosomal recessive disorders are referred to as nephronophthisis, or nephronophthisis-related ciliopathies. These entities should not be confused with the adult onset autosomal dominant MCKD discussed above, despite the often confusing nomenclature seen in older medical literature. Each of the individual forms of nephronophthisis is quite rare, but together this category constitutes the most common inherited childhood form of kidney failure requiring kidney replacement therapy.

Like ADPKD and ARPKD, the various genetically heterogeneous entities that fall under the category of nephronophthisis (NPHP) are disorders of ciliary function. Mutations in >90 genes have been identified that lead to NPHP under an autosomal recessive pattern of inheritance. Some of these gene defects cause limited kidney disease, while many cause ciliopathies characterized by multiple organ involvement. The various forms of NPHP share common features, including tubulointerstitial fibrosis, corticomedullary cysts, and progressive CKD, leading to renal failure. Proteinuria is absent or mild, and the urine sediment is not active.

NPHP is often divided into infantile, juvenile, and adolescent forms. The juvenile form is the most frequent, and usually caused by mutations in the NPHP2 gene. The infantile form, usually caused by NPHP2 mutations, is associated with end-stage kidney failure in early childhood. Patients with the adolescent form of NPHP typically develop end–stage kidney failure in early adulthood. Hypertension, if present, tends to be a late finding in the course of the NPHPs. The products of the NPHP genes are referred to as nephrocystins. NPHP1 through NPHP20 have been reported; some are referred to by other names, as well.

NPHP can present as an isolated finding, or be part of several multi-organ syndromes. Neurologic abnormalities are present in a significant number of patients. Bone and liver abnormities are seen in some NPHP patients. Senior-Loken syndrome is defined by the presence of NPHP with retinitis pigmentosa. Joubert syndrome is defined by multiple neurologic findings, including hypoplasia of the cerebellar vermis. Some forms of this genetically heterogeneous syndrome include NPHP as a component.

The multisystem disease Bardet-Biedl syndrome (BBS) is defined clinically by a spectrum of features, including truncal obesity, cognitive impairment, retinal dystrophy, polydactyly, developmental urogenital abnormalities, and kidney cysts. The kidney phenotype is NPHP-like, with small cysts deriving from the tubules, tubulointerstitial and often secondary glomerular disease, and urine concentrating defects. There are 19 BBS genes cloned. BBS follows autosomal recessive inheritance. Like ADPKD, ARPKD, and NPHP, BBS is a disease of abnormal ciliary function.

The multiple genes and gene products (nephrocystins) that are responsible for NPHP are expressed in cilia, basal bodies, and the centrosomes of kidney tubules cells. It has been hypothesized that all of the NPHP gene defects lead to a clinical phenotype by interfering with the regulation of PCP.

There are no specific clinical tests that define nephronophthisis. Genetic diagnosis is possible, cumbersome because of the large number of genes that can be responsible, but increasingly feasible due to new DNA sequencing technologies. There are no specific therapies for NPHP. Rather, therapy is aimed at treating signs of these diseases as well as those systemic abnormalities seen with all CKDs. Chronic dialysis or kidney transplantation are eventually required for NPHP-affected individuals.

Karyomegalic tubulointerstitial nephritis is an exceptionally rare form of kidney disease with adult-onset progressive kidney failure. Kidney biopsy shows chronic tubulointerstitial nephritis, as well as interstitial fibrosis. This is a recessive disorder caused by inheritance of two mutant copies of the FAN1 gene. FAN1 encodes a component of a DNA repair machinery complex. Individuals with two mutant FAN1 gene are genetically sensitized to the effect of DNA damage. Kidney histology shows karyomegaly in addition to the non-specific findings of interstitial fibrosis and tubular atrophy.

Medullary sponge kidney (MSK) is often grouped together with inherited disorders of the kidney affecting tubule growth and development, although it is usually a sporadic finding rather than an inherited phenotype. MSK is caused by developmental malformation and cystic dilatation of the renal collecting ducts. The medullary cysts seen in this entity can be quite variable in size.

MSK is usually a benign entity. The diagnosis of MSK is often made incidentally. In the past, the diagnosis of MSK was often made by intravenous pyelography (IVP). CT urography, which has replaced IVPs for much routine kidney imaging, is not as sensitive in detecting MSK.

MSK is associated with an increased frequency of calcium phosphate and calcium oxalate kidney stones. Altered flow characteristics in the kidney tubules may lead to the development of formation of a nidus for stone formation. Kidney stones in this group are treated the same as are kidney stones in the general population. MSK patients also often exhibit reduced kidney concentrating ability and an increased frequency of urinary tract infections.

The structural abnormalities known as CAKUT (Congenital Abnormalities of the Kidney and Urinary Tract) are a group of etiologically and phenotypically heterogeneous disorders. Some form of CAKUT is estimated to occur in up to 1 in 500 live births. Specific abnormalities classified as part of the CAKUT spectrum include kidney hypoplasia, kidney agenesis, ureteropelvic junction obstruction, and vesicoureteral reflux.

CAKUT can be the cause of clinically significant problems in both adults and children. However, it is a major contributor to kidney failure in children, accounting for more than one-third of end-stage kidney disease in this group.

CAKUT is typically a sporadic finding, but can also cluster in families. Familial forms can be observed as parts of multisystem developmental syndromes. A growing list of specific genes have been identified which when mutated lead to syndromic forms of CAKUT. For example, the branchio-oto-renal syndrome, characterized by developmental abnormalities in the neck, ears, and kidney, can be caused by mutations in the EYA1 and SIX1 genes. Mutations in the PAX2 transcription factor gene can cause the autosomal dominant renal coloboma syndrome, characterized by optic nerve malformations and hypoplastic kidneys. Recent work has demonstrated that a non-trivial fraction of children with CKD have an unsuspected genomic imbalance, often disrupting genes known to relevant to CAKUT and kidney development. It is not uncommon for such genetic lesions that affect both kidney and neurocognitive function.

In many instances, CAKUT is caused by environmental influences rather than genetic alterations. For example, renal tubular dysgenesis, defined by altered tubule development, can be caused by prenatal exposure of angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

Inherited disorders of the mitochondrial genome (discussed elsewhere in this text [see also Chap. 472]) commonly affect kidney function. Thirteen of the genes involved in encoding components of the mitochondrial respiratory chain are located on the mitochondrial genome that is inherited maternally. The remainder of these components is encoded by the nuclear genome. These defects of oxidative phosphorylation may affect multiple organs and tissues.

Neuromuscular disease is the best recognized part of this complex phenotype. Kidney disease is now recognized as a common component, as well. Tubulointerstitial disease may be seen on kidney biopsy, and progression to kidney failure may occur. Glomerular involvement, manifest as proteinuria and glomerulosclerosis, can also develop. Changes in proximal tubule activity are the most common renal phenotype. Patients may have several defects in proximal tubule transport, including the Fanconi syndrome. Some patients may also have acidosis, hypophosphatemic rickets, hypercalciuria, glycosuria, and tubular proteinuria. Decreased urine concentrating ability is common.

GLOBAL CONSIDERATIONS

The disorders discussed above are all seen worldwide. In addition, a previously unrecognized epidemic of kidney disease is leading to very high rates of kidney failure in and near the western coast of Central America. This mesoamerican nephropathy is particularly common in Nicaragua and El Salvador. Mesoamerican nephropathy patients do not have significant proteinuria, suggesting that this is a disease of the kidney tubules and interstitium. The cause is unknown, but some have suggested that a combination of toxic environmental factors and heat stress underlie the development of this kidney disease, which has a striking male predominance. However, the fact that in many families, a large fraction of the men are affected with kidney disease has suggested that a strong genetic component is involved, as well.