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.
Scheme of the primary cilium and cystic kidney disease proteins. Left: a scheme of the primary cilium. Primary cilia share a “9+0” organization of microtubule doublets. Proteins are transported into the cilium by motor protein kinesin 2 and transported out of the cilium by dynein. The cilium is connected to the basal body through the transition zone. Middle: topology of ADPKD and ARPKD proteins polycystin 1, polycystin 2, and FPC are shown. Localization of disease proteins in the cilium, the transition zone and the basal body are color coded. Right: potential disease mechanisms due to cilium mediated signaling events.
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.
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.
Photograph showing a kidney from a patient with autosomal dominant polycystic kidney disease. The kidney has been cut open to expose the parenchyma and internal aspects of cysts.
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 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 Autosomal Dominant Polycystic Kidney Disease
No specific treatment to prevent cyst growth or the decline of renal function has been approved by U.S. Food and Drug Administration. Blood pressure control to a target of 140/90 mmHg is recommended according to the guidelines from the eighth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VIII report) for reducing cardiovascular complications in ADPKD and renal disease progression. More rigorous blood pressure control does not equal greater clinical benefits. Maintaining a target systolic blood pressure to 110 mmHg in patients with moderate or advanced disease may increase the risk of renal disease progression by reducing renal blood flow. Lipid-soluble antibiotics against common gram-negative enteric organisms include trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol, and are preferred for cyst infection because most renal cysts are not connected to glomerular filtration and antibiotics that are capable to penetrate the cyst walls are likely to be more effective. Treatment often requires 4–6 weeks. The treatment of kidney stones in ADPKD includes standard measures such as analgesics for pain relief, and hydration to ensure adequate urine flow. Management of chronic flank, back, or abdominal pain due to renal enlargement may include both pharmacologic (non-narcotic and narcotic analgesics) and non-pharmacological (transcutaneous electrical nerve stimulation, acupuncture, and biofeedback). Occasionally surgical decompression of cysts may be necessary. More than half of ADPKD patients eventually require peritoneal dialysis, hemodialysis, or kidney transplantation. Peritoneal dialysis may not be suitable for some patients with massively enlarged polycystic kidneys due to the small intraabdominal space for efficient peritoneal exchange of fluid and solutes and increased chance of abdominal hernia and back pain. Patients with very large polycystic kidneys and recurrent renal cyst infection may require pretransplant nephrectomy or bilateral nephrectomy to accommodate the allograft and reduce the pain.
Specific treatment strategies to ADPKD have focused on slowing renal disease progression and lowering cardiovascular risk. For the latter, the main approach is to control blood pressure by inhibiting the renin-angiotensin-aldosterone system. The HALT PKD trial was set to evaluate the impact of intensive blockade of the renin-angiotensin-aldosterone system, and levels of blood pressure control on progressive renal disease. This trial found that rigorous blood-pressure control could slow cyst growth. Most approaches target the slowing of renal disease progression by inhibiting cell proliferation and fluid secretion. Several clinical trials have been conducted targeting cell proliferation: sirolimus and everolimus, inhibitors of the mammalian target of rapamycin (mTOR) pathway; OPC31260 and tolvaptan, which inhibits cyclic adenosine monophosphate (cAMP) pathways by antagonizing the activation of vasopressin V2 receptor (V2R) in collecting ducts and reduces cell proliferation by decreasing renal cAMP levels; and somatostatin analogues, which reduces cAMP levels by binding to several G-protein coupled receptors. The TAMPO and ALADIN trials showed that V2R antagonists and somatostatin analogues (octreotide-LAR groups) respectively slowed the decline of renal function. Some side effects, such as liver function impairment, polydipsia, and diarrhea, have been observed for tolvaptan and cholecystitis for octreotide-LAR. A recent report also showed that tolvaptan reduces renal pain. DIPAK, a small multi-center European study, showed that nerve block may be used to relieve pain in ADPKD patients suffering with refractory chronic pain. A combination of different growth inhibitors may enhance efficacy and reduce side effects.
Additional preclinical studies in animal models include the use of inhibitors to nonreceptor tyrosine kinase Src, B-raf, cycline-dependent kinase (CDK), transcription factors STAT3 and STAT6 (pyrimethamine and leflunomide), purinergic receptors, hepatocyte growth factor receptor, glucosylceramide, and agonists to peroxisome proliferator-activated receptor-gamma (PPARγ) receptors (thiazolidodinediones). Recently, several microRNAs have been identified that mediate disease progression, which may prove to be a new therapeutic target. Food restriction in mouse models of the disease was reported to reduce cyst area, kidney fibrosis, inflammation, and injury. Branched chain amino acids appear to enhance cyst development in a mouse model.