Abstract
The discovery of the genes responsible for many hereditary cystic kidney diseases has led to the characterization of their protein products. Most of these proteins localize to the primary cilium and have led to a cascade of scientific discoveries and advancements unraveling the molecular pathogenesis of cystogenesis. These exciting developments brought to light common biologic pathways that different hereditary cystic disorders share, and identified potential targets for therapeutic interventions.
Keywords
ADPKD, ARPKD, tuberous sclerosis complex, VHL, hereditary, cystic disease
Significant advances have been made in understanding the genetic and molecular pathogenesis of inherited cystic disorders of the kidney. Many of the genes and their respective proteins have been identified ( Table 40.1 ). Final common pathways regarding the formation and development of cysts are being elucidated. Most kidney cysts develop because of abnormal function of the primary cilium that resides in all epithelial cells. Recently developed, molecularly targeted therapies offer hope for improved outcome or cure of these disorders.
| Disease | Frequency | Chromosome | Gene Locus | Protein | Function |
|---|---|---|---|---|---|
| ADPKD | 1 : 1000 | 16p13.3 | PKD1 | Polycystin 1, which colocalizes with polycystin 2 in the primary cilium | Regulates intracellular cAMP, mTOR, planar polarity |
| 1 : 15,000 | 4q21.2 | PKD2 | Polycystin 2, which colocalizes with polycystin 1 in the primary cilium and ER | Regulates intracellular Ca levels through ER Ca release, activates Ca channels | |
| ARPKD | 1 : 20,000 | 6q24.2 | PKHD | Fibrocystin or polyductin, located throughout the primary cilium | Serves as receptor to maintain intracellular cAMP levels |
| VHL | 1 : 36,000 | 3p25 | VHL | VHL, located at the base of the primary cilium | Inhibits HIF-1α and cell turnover, maintains planar polarity, allows ciliogenesis |
| TSC | 1 : 6000 | 9q34.3 | TSC1 | Hamartin | Interacts with tuberin to suppress mTOR activity |
| 16p13.3 | TSC2 | Tuberin | Interacts with hamartin to suppress mTOR activity |
Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, occurring in 1 of 400 to 1000 live births. ADPKD affects all ethnic groups equally, and it has been reported worldwide. It accounts for approximately 5% of the end-stage kidney disease (ESKD) population in the United States and 10% of those under 60 years of age. ADPKD is a systemic disorder that affects almost every organ resulting in significant extrarenal manifestations; however, its hallmark is the gradual and massive cystic enlargement of the kidneys, ultimately resulting in kidney failure.
Pathogenesis
At least three genes have been implicated in the pathogenesis of ADPKD. Approximately 85% of patients with ADPKD have mutations in the PKD1 gene, close to 15% of ADPKD patients have mutations in the PKD2 gene, and approximately 1% of patients are found to have mutations in the GANAB gene. Although mutations in PKD1 and PKD2 lead to the same phenotype, patients with PKD2 mutations have milder disease with fewer kidney cysts, later onset of hypertension, and less ESKD than their counterparts with PKD1 mutations (median age of onset of ESKD 74 vs. 54 years, respectively). Given the milder phenotype associated with PKD2 , when surveillance autopsies are performed, the relative frequency of PKD2 increases, accounting for up to 27% of all ADPKD cases. GANAB mutation cases are still relatively rarely reported; however, they appear to have a milder phenotype than PKD1 with hepatic cystic disease predominating.
PKD1 is located on the short arm of chromosome 16 (16p13.3) and codes for polycystin-1 (PC1), an integral membrane protein made up of 4304 amino acids. PC1 has a large extracellular N-terminal, 11 transmembrane regions, and a short intracellular C-terminal. PC1 is located in the primary cilium, focal adhesions, tight junctions, desmosomes, and adherens junctions. PC1 plays an important role in cell-cell interactions and cell-matrix interactions. PKD2 is located on the long arm of chromosome 4 (4q12.2) and encodes for polycystin-2 (PC2), a 968 amino acid protein with a short cytoplasmic N-terminal, six transmembrane regions, and a short cytoplasmic C-terminal. It localizes to the endoplasmic reticulum, plasma membrane, primary cilium, centrosome, and mitotic spindles in dividing cells. PC2 belongs to the family of voltage-activated calcium channels (e.g., transient receptor potential polycystin-2 [TRPP-2]) and is involved in intracellular calcium regulation through several pathways. PC1 and PC2 are colocalized in the primary cilium of renal epithelial cells, which functions as a mechanosensor. Primary cilia create transmembrane calcium currents in the presence of stretch or luminal flow. PC1 and PC2 contribute to ciliary function, and the physical interaction between PC1 and PC2 is required for a membrane calcium channel to operate properly. Normal polycystin function increases intracellular calcium, which initiates a signaling cascade leading to vesicle fusion and a change in gene transcription. The magnitude of these changes contributing to the PKD epithelial phenotype has recently been challenged because the reservoir of calcium released from primary ciliary stimulation is relatively low.
Each polycystin affects cell proliferation, differentiation, and fluid secretion through G protein or JAK-STAT-mediated signaling pathways. The interaction of PC1 ligand on the basolateral surface with adenylate cyclase and the G protein–coupled response of adenylate cyclase to binding of vasopressin to the vasopressin V 2 receptor produce similar results. Both result in increased intracellular concentrations of cyclic adenosine monophosphate (cAMP) and ultimately in chloride secretion across the luminal membrane. This chloride-rich fluid secretion is a critical component of cystogenesis, enabling expansion of cysts even after they detach from their parent nephron. The accumulation of cyst fluid, rich in chloride and sodium, relies on the active luminal excretion of chloride primarily through the cystic fibrosis transmembrane conductor regulator (CFTR) ( Fig. 40.1 ).
ADPKD cystic disease is focal, with less than 5% of all nephrons becoming cystic. It is thought that each kidney cyst is derived from a single, clonal hyperproliferative epithelial cell that has genetically transformed. The clonal cystic epithelia proliferate because of an additional somatic mutation in the PKD1 or PKD2 gene, indicating that a “second hit” is involved in cyst growth and development. Epithelial cell proliferation, fluid secretion, and alterations in extracellular matrix ultimately result in focal out-pouching from the parent nephron. Most cysts detach from the parent nephron when cyst size exceeds 2 cm and continue to secrete fluid autonomously, resulting in cyst and kidney enlargement, and ultimately progressive loss of kidney function.
Diagnosis
Kidney imaging by ultrasound remains the primary method for diagnosing ADPKD. The characteristic findings include enlarged kidneys and the presence of multiple cysts throughout the kidney parenchyma ( Fig. 40.2 ). Unified diagnostic ultrasonographic criteria for at-risk individuals independent of genotype were developed by . In individuals aged 15 to 39, the presence of at least three (unilateral or bilateral) kidney cysts is sufficient to establish a diagnosis of ADPKD. In those individuals 40 to 59 years of age, two cysts in each kidney are required, and in those older than 60, in whom acquired cystic disease is common, four or more cysts in each kidney are required for diagnosis. For patients with no family history, the diagnostic criteria are more stringent with at least five cysts bilaterally by the age of 30 and a phenotype consistent with ADPKD required (see later).
When disease status must be determined with certainty, as when an at-risk family member is being evaluated as a potential kidney donor or for family-planning purposes, then initial computed tomography (CT) or magnetic resonance imaging (MRI) should be pursued. Genetic testing should also be considered in young individuals under the age of 40 if imaging is negative. Mutation screening with direct sequencing of the PKD1 or PKD2 genes is commercially available. Both the high cost of the test and its ability to detect mutations in only up to 85% of individuals restrict its use. After a genetic diagnosis is confirmed in a patient, which often requires a diagnosis in other affected members, other at-risk family members can be screened at a reduced cost by performing targeted exon-specific sequencing of the identified mutation. Current mutation detection rates are up to 86% and 95% for PKD1 and PKD2 genes, respectively.
Kidney Manifestations and Complications
Kidney enlargement is a universal feature of ADPKD, and individuals with multiple cysts in small kidneys should be screened for other cystic diseases. Kidney function among ADPKD patients remains normal for decades despite significant cyst expansion and kidney enlargement. After kidney function becomes impaired, progression is typically universal and rapid, with an average decline in glomerular filtration rate (GFR) of 4.0 to 5.0 mL/min/year. There are a number of clinical and genetic predictors for progression to ESKD in ADPKD, such as male sex, PKD1 genotype, early age onset of hypertension, and the presence of detectable proteinuria. Total kidney volume incorporates all of the aforementioned risk factors and is the strongest predictor of future GFR loss. Significant progression of cyst growth and kidney enlargement precedes the loss of kidney function by decades in ADPKD. In the Consortium for Radiologic Imaging in the Study of Polycystic Kidney Disease (CRISP), a large multicenter study of 241 ADPKD patients with intact kidney function, patients were followed prospectively with serial MRI of their kidneys and demonstrated a 5.2%/year increase in kidney volume. Cysts accounted for the increase in total kidney volume seen, and kidney volume increased at a continuous rate resulting in an overall increase of approximately 55% over 8 years. PKD2 patients had smaller kidney volumes at baseline (694 ± 221 vs. 986 ± 204 mL) and lower age-adjusted cyst number per kidney when compared with PKD1 patients but demonstrated similar rates of growth (4.9 ± 2.3% vs. 5.2 ± 1.6%/year), indicating that the rate of cyst formation and cyst number rather than the rate of cyst expansion differs between the two genotypes. More recently, data from the CRISP study showed that height-adjusted total kidney volume (HtTKV) of greater than 600 mL/m accurately predicted progression to CKD stage 3 within 8 years. For each 100 mL/m change in HtTKV, there was a 48% relative risk of reaching CKD stage 3. Therefore total kidney volume is a good predictive biomarker for the development of future CKD, with potential application for risk stratification in clinical practice. Patients can now be classified into risk classes (1A to 1E) based on age, sex, serum creatinine, and measured HtTKV. Patients in class 1A and 1B are at a low risk for loss of kidney function, and patients in class 1C to 1E are at a high risk for kidney function loss and would benefit from aggressive monitoring with regard to blood pressure and diet and potentially from participating in clinical trials. TKV can be measured by ultrasound; however, ultrasound measurements are less precise, and TKV measurements are inaccurate when used over short periods of time. US measurements use the ellipsoid formula where maximum length, width, and depth are determined. This approach typically overestimates the TKV by close to 11%. Because of its lack of precision, ultrasound cannot be used to measure short-term disease progression, but single measurements can be used for risk stratification. Similar to MRI, ultrasound measured HtTKV of greater than 650 mL/m or simply a kidney length over 16.5 cm predicts the development of CKD stage 3 within 8 years.
Hematuria, whether gross or microscopic, occurs in about 35% to 50% of patients and often precedes loss of kidney function. It is associated with increased kidney size and with worse kidney outcomes. Hematuria can be precipitated by an acute event such as trauma, heavy exertion, cyst rupture, lower urinary tract infection, pyelonephritis, cyst infection, or nephrolithiasis. Therefore ADPKD patients are typically advised to avoid heavy and high-impact exercise. Cyst hemorrhage occurs more commonly as kidneys enlarge and may be associated with hematuria and fever. However, localized pain is often the only presenting complaint. The diagnosis of a cyst hemorrhage is based on clinical evaluation and can be difficult to differentiate from kidney cyst infection. CT scan occasionally can be helpful in locating hemorrhagic cysts. The management for uncomplicated cyst hemorrhage and hematuria is supportive and includes fluid resuscitation, rest, pain control, and often withholding antihypertensive medications until the acute episode has resolved.
Lower urinary tract infections are common among ADPKD patients, as in the general population, with coliforms being the most common pathogens. The treatment is the same as in the general population. Pyelonephritis and kidney cyst infections can occur and may be challenging to differentiate. Patients with cyst infection commonly present with fever, abdominal pain, and, often, elevated C-reactive protein. Typically, blood cultures identify the offending pathogen more frequently than urine cultures. Most important, treatment of cyst infections requires a prolonged 4-week course of antibiotics that adequately penetrate into the cyst, such as quinolones, vancomycin, chloramphenicol, or trimethoprim-sulfamethoxazole. Recent reports have suggested that positron emission tomography with fluorodeoxyglucose (FDG-PET) may be a promising diagnostic tool for detecting infected cysts in challenging cases.
The incidence of nephrolithiasis is about 5 to 10 times higher among patients with ADPKD compared with the general population. About 25% of those afflicted with kidney stones are symptomatic. Increased urinary stasis and metabolic disturbances, including hypocitraturia, low urinary pH, and abnormal renal transport of ammonium, account for the high incidence of nephrolithiasis. The most common stone type in ADPKD is uric acid, responsible for approximately 50% of all stones, followed by calcium oxalate. Nephrolithiasis should be suspected in any ADPKD patient with acute flank pain. Diagnosis by imaging is difficult given the radiolucent nature of the stones and the presence of calcified cyst walls. Noncontrast CT remains the imaging modality of choice for detecting nephrolithiasis. The medical management of nephrolithiasis in ADPKD is similar to that in non-ADPKD patients. Noninvasive or minimally invasive interventions such as extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy have been performed on ADPKD patients; however, long-term studies regarding safety in this patient population are lacking.
Patients with ADPKD commonly complain of increased thirst, polyuria, nocturia, and urinary frequency. A decrease in urinary concentrating ability is one of the earliest manifestations of ADPKD. It is initially mild and worsens with increasing age and declining kidney function. The urinary concentrating defect is closely related to the severity of anatomic deformities induced by the cysts, independent of age and GFR. Approximately 60% of affected children demonstrated a decreased response to desmopressin, possibly because of disruption of tubular architecture and alterations in principal cell function.
Proteinuria is typically mild in ADPKD with an average of 260 mg of protein excretion per day, and only 18% of ADPKD adults have detectable proteinuria on dipstick or greater than 300 mg/day of protein excretion. Although the level of proteinuria is low-grade in ADPKD, the presence of proteinuria and albuminuria is associated with increased TKV and more rapid decline in kidney function.
Pain is the most common symptom in ADPKD and can be acute or chronic. Acute pain episodes are usually related to cyst rupture or hemorrhage, cyst or parenchymal infection, or nephrolithiasis. Chronic pain, on the other hand, is typically related to the massive enlargement of the kidneys and liver and their increased weight. The site of pain can be in the lower back as increased lumbar lordosis has been observed in ADPKD patients. Pain can also result from the stretching of the renal capsule or pedicle. Pain management can be challenging but should include nonpharmacologic as well as pharmacologic interventions.
Hypertension is a common and early manifestation of ADPKD affecting more than 60% of patients before any detectable decline in kidney function. Hypertension is the cause for diagnosis of ADPKD in approximately 30% of cases, with the average age of onset being 29 years. Studies show that hypertension occurs earlier and tends to be more severe among PKD1 versus PKD2 patients. Hypertension is also associated with a greater rate of kidney enlargement (6.2%/year vs. 4.5%/year), suggesting a relationship between cyst expansion and elevations in blood pressure. Hypertension is associated with worse kidney outcomes and increased cardiovascular morbidity and mortality. ADPKD kidneys have an attenuated vasculature with angiographic evidence of intrarenal arteriolar tapering. MRI-based measurements demonstrate a reduction of renal blood flow that correlates inversely with kidney volume and occurs before loss of kidney function. These findings suggest that renal ischemia induced by cyst expansion plays a role in the etiology of hypertension, with intrarenal activation of the renin-angiotensin-aldosterone system (RAAS). Data from the HALT-PKD trial showed that in young patients (15 to 49 years) with preserved kidney function, treatment with inhibitors of the RAAS with a goal blood pressure of <110/75 resulted in a 14.2% slower increase in TKV over 5 years, reduced urinary albumin excretion, and a greater decline in left ventricular mass index. The overall rate of decline in estimated glomerular filtration rate (eGFR) in the strict and the standard blood pressure group was similar overall but slower in the lower blood pressure group during the chronic phase of the 5-year study. The overall lack of difference in eGFR decline was due to the more rapid decline in eGFR in the strict blood pressure group during the first four months of the trial. Importantly when class 1A and 1B patients (those unlikely to progress) were excluded from the analysis, then significant benefits in change in TKV and slope of eGFR were found in the low BP control group.
Kidney transplantation remains a viable option for patients approaching ESKD. ADPKD transplant recipients tend to survive longer than those transplanted for other kidney pathologies. Native polycystic kidneys do not have to be removed before transplantation unless chronic infections are present or their large size interferes with nutritional intake or quality of life.
Extrarenal Manifestations
Polycystic Liver Disease
Liver cysts are the most common extrarenal manifestation in ADPKD. MRI shows presence of liver cysts in more than 80% of patients by the age of 30 ( Fig. 40.3 ), with equal sex representation. The liver cyst burden, however, is greater in women than in men. Previous estrogen or progesterone exposure, through birth-control pills, hormone replacement therapy, or pregnancy, is associated with significant polycystic liver disease. Liver function is preserved even in the presence of massive liver cystic disease, and standard biochemical tests are normal except for mild elevation in the serum concentration of alkaline phosphatase. Isolated autosomal dominant polycystic liver disease (ADPLD) without kidney cysts exists. ADPLD is a distinct disease genetically unrelated to ADPKD and instead linked to mutations in two genes: PRKCSH (protein kinase C substrate 80K-H) located on chromosome 19 and SEC 63 located on chromosome 6.
