Autosomal Dominant Polycystic Kidney Disease

Stefan Somlo

Arlene B. Chapman

INTRODUCTION

Autosomal dominant polycystic kidney disease (ADPKD; MIM 173990) is the most common hereditary renal disease occurring in 1:400 to 1:1000 individuals. It accounts for over 90% of all hereditary renal cystic diseases (Table 16.1). ADPKD is characterized by the presence of bilateral renal cysts that gradually grow and expand over time, resulting in significantly increased total kidney volume, progressive renal injury, and ultimately, end-stage renal disease (ESRD), usually in the sixth decade of life.

Other Mendelian diseases with varying degrees of fibrocystic involvement of the kidney are relatively rare. Autosomal recessive polycystic kidney disease (ARPKD; MIM 606702) occurs in 1:25,000; autosomal dominant tuberous sclerosis complex (TSC; MIM 191100 and 613254) occurs in 1:10,000; autosomal dominant medullary cystic disease or UMOD (MIM 174000) occurs in 1:35,000; and autosomal recessive familial juvenile nephronophthisis (NPHP; MIM 256100 and 602088) occurs in 1:40,000. In addition to the Mendelian diseases described previously, a variety of hereditary syndromes, such as Bardet-Biedl syndrome (BBS; MIM 209900) and Meckel Gruber syndrome (MKS; MIM 249000), result in a constellation of clinical manifestations that include renal cysts and are collectively termed ciliopathies (Table 16.1). In terms of clinical disease burden, however, all of the hereditary ciliopathies combined account for less than 1% of all renal cystic diseases.

This chapter will focus primarily on the single most common renal cystic disease, ADPKD. Current understanding of the epidemiology, clinical characteristics, and the pathology of ADPKD will be elucidated, and the appropriate approaches to the diagnosis and management of ADPKD will be provided. An overview of the genetics and the molecular pathways involving the polycystins is provided. Finally, a review of molecularly targeted therapeutic interventional trials will be presented to establish the potential future management for ADPKD individuals.

EPIDEMIOLOGY

Worldwide, ADPKD occurs between 1:400 and 1:1000 live births in all ethnicities when including ascertainment by autopsy.¹,²,³ Epidemiologic studies suggest that fewer than half of those with the disease are diagnosed during their life, with a majority of diagnoses occurring on autopsy after death from other causes.¹ Although not specifically evaluated in those studies, it is plausible that these individuals had a milder manifestation of disease. ADPKD has been estimated to be present in up to 600,000 individuals in the United States of America, and 12.5 million people worldwide (www .pkdcure.org). The disease accounts for about 6% of all patients on hemodialysis.⁴ The incidence of ADPKD varies by genotype. PKD1 occurs in approximately 1:700 live births and PKD2 occurs in 1:15,000 live births. Reports from Japan, Denmark, the United States, Europe, India, Saudi Arabia, and Turkey show similar incidence rates, with no racial or ethnic predilection.⁵,⁶,⁷,⁸,⁹ Patient and renal outcomes differ by PKD genotype. ADPKD resulting from mutations in PKD1 result in earlier mean age of onset of hypertension (29 versus 41 years of age), ESRD (55 versus 74 years of age), and death (68 versus 79 years of age) when compared to ADPKD due to PKD2 mutations.¹⁰,¹¹,¹²

Current worldwide yearly incidence rates for ESRD due to ADPKD are 7.5 and 6.1 per million population for men and women, respectively. Gender differences with regard to disease progression and severity have been reported, with women having a more favorable renal outcome than men.¹⁰,¹³ However, when gender differences and genotype are considered together, little or no differences in the age of onset of renal failure are found in PKD1 individuals. Importantly, significant differences in survival are found between men and women with PKD2 mutations (67.3 versus 71.0 years). In addition, previous age-adjusted sex ratios of the incidence of ESRD, which were greater in men than in women (1.4 to 1.6), are now beginning to reach parity in various countries, including Denmark and the United States.

TABLE 16.1 The Spectrum of Inherited Human Diseases with Kidney Cysts

Disorder	MIM	Frequency	Gene	Chromosome	Protein	Length (bp)	Protein size (aa)	Exon #	SNP #
Hereditary Renal Cystic Diseases
ADPKD	601313	1:700	*PKD1*	16p13.3	Polycystin 1	14138	4303	46	592
		1:15,000	*PKD2*	4q22.1	Polycystin 2	5056	968	15	62
ARPKD	606702	1:25,000	*PKHD1*	6p12.2	Polyductin/fibrocystin	16282	4074	67	356
TSC	191100	1:10,000	*TSCI*	9q34.13	Hamartin	8604	1164	23	52
	613254		*TSC2*	16p13.3	Tuberin	6156	1807	42	136
GCKD	137920	Not available	*HNF-1β*	17cen-q21.3	TCF2 protein	2977	557	9
MCD/MCKD	174000	1:50,000	*MCKD1*	1q21
			*MCKD2 (UMOD)*	16p12.3	Uromodulin	2315	640	11	47
NPHP	256100	1:100,000	*NPHP1*	2q13	Nephrocystin-1	2752	732	20	50
	602088		*NPHP2/INVS*	9q31	Inversin	2968	895	17	79
			*NPHP3*	3q22.1	Nephrocystin-3	4362	1330	27	103
			*NPHP4*	1p36.22	Nephroretinin	4994	1426	30	84
			*NPHP5/IQCB1*	3q13.33	Nephrocystin-5	2594	598	15	36
			*NPHP6/CEP290*	12q21.32	Nephrocystin-6	7948	2479	54	63
			*NPHP7/GLIS2*	16p13.3	Nephrocystin-7	4469	524	6	42
			*NPHP8/RPGRIP1L*	16q12.2	Nephrocystin-8	5936	1235	27	99
			*NPHP9/NEK8*	17q11.1	Nephrocystin-9	2858	692	15	47
VHL	193300	1:53,000	*VHL*	3p25.3	von Hippel-Lindau	3737	213	3	36
Ciliopathy Syndromes
BBS	209900	1:16,000	*BBS1*	11q13	BBS1	3423	593	17	59
			*BBS2*	16q21	BBS2	2814	721	17	59
			*ARL6 (BBS3)*	3q11.2	ADP-ribosylation factor-like protein 6	1518	186	9	9
			BBS4	15q22.3-q23	BBS4	2490	519	16	51
			*BBS5*	2q31.1	BBS5	3475	341	6	21
			*MKKS (BBS6)*	20p12	McKusick-Kaufman/BBS6	2539	570	6	37
			*BBS7*	4q27	BBS7	3752	715	19	34
			*TTC8 (BBS8)*	14q31.3	Tetratricopeptide repeat domain 8	2183	505	15	36
			*BBS9*	7p14	BBS9	3899	847	23	78
			*BBS10*	12q21.2	BBS10	3595	723	2	50
			*TRIM32*	9q33.1	Tripartite motif-containing protein 32	3677	653	2	44
			*BBS12*	4q27	BBS12	3244	710	2	66
			*MKS1*	17q22	MKS1	1748	520	18	29
			*CEP290*	12q21.32	Centrosomal protein of 290 kDa	7948	2479	54	63
JBTS	213300	1:100,000	*INPP5E*	9q34.3	72 kDa inositol polyphosphate 5-phosphatase	3394	644	10	57
			*TMEM216*	11q13.1	Transmembrane protein 216	1955	145	5	8
			*AHI1*	6q23.3	Jouberin	213792	2340	668	46
			*NPHP1*	2q13	Nephrocystin-1	2752	732	20	50
			*CEP290*	12q21.32	Centrosomal protein of 290 kDa	7948	2479	54	63
			*TMEM67*	8q22.1	Meckelin	4651	995	28	60
			*RPGRIP1L*	16q12.2	RPGRIP 1-like protein	5936	1235	27	99
			*ARL13B*	3q11.1	ADP-ribosylation factor-like protein 13B	3264	321	11	35
			*CC2D2A*	4p15.32	Coiled-coil and C2 domaincontaining protein 2A	5175	1620	38	50
			*OFD1*	Xp22	Lys-63-specific deubiquitinase BRCC36	3611	1012	23	49
MKS	249000	7:10,000	*MKS1*	17q22	MKS1	1748	520	18	29
			*TMEM216*	11q13.1	Transmembrane protein 216	1955	145	5	8
			*TMEM67*	8q22.1	Meckelin	4651	995	28	60
			*CEP290*	12q21.32	Centrosomal protein of 290 kDa	7948	2479	54	63
			*RPGRIP1L*	16q12.2	ADP-ribosylation factor-like protein 13B	5936	1235	27	99
			CC2D2A	4p15.32	Coiled-coil and C2 domaincontaining protein 2A	5175	1620	38	50
OFD	311200	1:50,000	*OFD1*	Xp22	Oral-facial-digital syndrome 1	3611	1012	23	49
SLS	266900	1:250,000	*NPHP1*	2q13	Nephrocystin-1	2752	732	20	50
	606996		*NPHP4*	1p36.22	Nephrocystin-4	4994	1426	30	84
	609254		*NPHP5/IQCB1*	3q13.33	IQ calmodulin-binding motif-containing protein 1	2594	598	15	36
			*CEP290*	12q21.32	Centrosomal protein of 290 kDa	7948	2479	54	63
			*SDCCAG8*	1q43	Serologically defined colon cancer antigen 8	2567	713	18	53
Usher	276900	1:20,000	*CDH23*	10q22.1	Cadherin-23	11079	3357	68	131
			*MYO7A*	11q13.5	Myosin VIIA	7462	2215	49	75
	276901	*PCDH15*	10q21.1	Protocadherin-15	6845	1955	35	172
			*USH1C*	11p14.3	Harmonin	2237	552	27	60
			*USH1G*	17q25.1	Usher syndrome type1G	3561	461	3	31
			*USH2A*	1q41	Usherin	6320	1546	72	472
			*GPR98*	5q13	VLGR1b	19338	6306	90	209
			*USH3A*	3q25	Clarin-1	2359	232	3	17
MIM, Mendelian Inheritance in Man; ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; TSC, tuberous sclerosis complex; GCKD, glomerulocystic kidney disease; MCD/MCKD, medullary cystic disease/medullary cystic kidney disease; NPHP, nephronophthisis; VHL, von-Hippel Lindau disease; BBS, Bardet-Biedl syndrome; JBTS, Joubert syndrome; MKS, Meckel Gruber syndrome; OFD, orofacial digital syndrome; SLS, Senior-Loken syndrome; SNP, single nucleotide polymorphism; ADP, adenosine diphosphate.

African American ADPKD patients have been reported to have a more aggressive renal course than their non-African American counterparts.¹⁴,¹⁵,¹⁶ However, these reports are limited due to the small number of patients and the presence of other diseases affecting renal function, including the sickle cell disease or trait. Importantly, the relative incidence of ESRD due to ADPKD per million population in African Americans is lower than their non-African American counterparts.⁴,¹⁷,¹⁸ Whether this relates to earlier mortality in African Americans or improved renal survival has not yet been determined.

During the past 3 decades, the average age of onset of ESRD, the incidence and prevalence rates of ADPKD in ESRD, and the survival rates of ADPKD in ESRD have increased. Incidence rates of ADPKD patients entering ESRD have increased significantly from 1990 to 2010 in the United States (35%), Japan (30%), and Denmark (33%).⁵,¹⁷,¹⁹ The average age of onset of ESRD has increased in the United States (4.5 years), Denmark (5.1 years), and Japan (4.6 years). Importantly, the use and the number of antihypertensive agents, specifically inhibitors of the renin-angiotensin-aldosterone system (RAAS) are associated with decreased patient mortality and an increased age of onset of ESRD.²⁰,²¹ Taken together, these data suggest that patients are now more often surviving to start renal replacement therapy, and improved patient care has extended both renal and patient survival with a positive impact on patient mortality for those receiving renal replacement therapy.

DIAGNOSIS OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Although symptoms in ADPKD individuals can present at a young age, a diagnosis of ADPKD is confirmed either with radiographic imaging or genetic testing. Before undertaking a diagnostic evaluation, counseling should be done to educate the family about the risk for inheritance. The mode of presentation for diagnostic screening has not changed over the last half century, with approximately 40% of individuals with a positive family history presenting asymptomatically.¹³,²² The remaining patients present with clinical complications such as new onset hypertension, gross hematuria, acute flank pain, or fevers. The average age of presentation for diagnosis has also remained unchanged for the last 4 decades. With a number of potential beneficial therapies becoming available and evidence for improved mortality due to standard medical care, an earlier presentation for screening of at risk individuals will most likely occur.

The risk for discrimination in terms of insurability and employment has been reduced, but not eliminated, by the passage into law of the Genetic Information Nondiscrimination Act (GINA).²³,²⁴ GINA prohibits insurers from canceling, denying, refusing to renew, or changing the terms or premiums of coverage based on genetic information. It also prohibits employers from making hiring, firing, promotion, and other employment-related decisions based on genetic factors. Genetic information is defined as information about an individual’s genetic tests, the genetic tests of family members, or occurrence of a disease in family members of the individual. GINA, however, applies only to individuals who are asymptomatic, does not prohibit underwriting based on information about current health status, and does not apply to life insurance, disability insurance, or long-term care insurance.

Ultrasound imaging is the initial imaging modality of choice for a diagnosis of ADPKD (Fig. 16.1). Ultrasound is cost-efficient as compared to magnetic resonance imaging (MRI) or computed tomography (CT) and is not associated with the radiation exposure that occurs with CT imaging. The vast majority of affected ADPKD patients can be diagnosed by ultrasound imaging alone. Since the initial ultrasound criteria for a diagnosis of ADPKD were developed in 1994,²⁵ the imaging resolution for detection of small cysts with ultrasound, CT, and MRI have vastly improved.²⁶,²⁷ The limit of detection of cysts using CT and MRI is now as low as 1 mm in diameter as compared to 0.5 to 1 cm with ultrasound.²⁸ Importantly, and relevant to the value of diagnostic imaging in ADPKD, simple renal cysts >1 cm in diameter remain relatively rare in childhood, occurring in <0.1% in the general population.

MR- and CT-based imaging studies of healthy young adults without a family history of ADPKD show that simple renal cysts of diameters as small as 1 mm are relatively common, even in young adults, occurring in 11 out of 35 or 28% in 18- to 29-year-olds and 97 out of 190 or 51% in 30- to 44-year-olds.²⁶ Therefore, if Ravine criteria using cyst number alone is used with CT or MRI in individuals between the ages of 18 and 45 years of age, more than one third would erroneously qualify for a diagnosis of ADPKD. However, if only those with cysts >1 cm in diameter are considered, the size of the cyst commonly seen in ADPKD individuals and detectable by ultrasonography, the number of incorrectly diagnosed individuals would remain <1%. Therefore, in at-risk individuals, sensitivity and specificity for a correct diagnosis of ADPKD using ultrasound remains intact and a single renal cyst in an at-risk child from a family with AD-PKD is sufficient to make a diagnosis (Table 16.2).²⁹

An age-based renal cyst number is required for a diagnosis of ADPKD, given that simple renal cysts are present with increasing frequency as age increases in the general population. Ultrasound still carries high sensitivity and specificity for the majority of PKD1 individuals over the age of 30 years.³⁰,³¹ At age 30, a negative ultrasound indicates a less than 5% likelihood of having ADPKD in individuals from PKD1 families. Negative ultrasound imaging is also informative at earlier ages in at-risk individuals from PKD1 families, with a negative ultrasound in an at-risk 20-year-old conferring a less than 10% chance of carrying the disease. Additional experience with screening PKD2 individuals provides a more accurate estimate of the relatively high falsenegative rates when screening at-risk individuals under the age of 40.³² Although the specificity and positive predictive value of sonographic criteria is very high in PKD1 individuals, their sensitivity and negative predictive value are low when applied to PKD2 in the 15 to 29 age group (69.5 and 78%, respectively). This is particularly a problem when evaluating potential young related kidney transplant donors, where the exclusion of ADPKD is important.

FIGURE 16.1 A radiographic appearance of hereditary renal cystic disorders. The top panels show ultrasonographic, longitudinal axis images of (A) autosomal dominant polycystic kidney disease (ADPKD), (B) autosomal recessive polycystic kidney disease ( ARPKD), (C) familial juvenile nephronophthisis (NPHP), (D) glomerular cystic kidney disease (GCKD), (E) medullary cystic kidney disease (MCKD), and (F) tuberous sclerosis complex (TSC). The bottom panels show the same sequence of renal cystic disorders using either magnetic resonance imaging (MRI) or computed tomographic (CT) imaging: (G) a coronal MRI of early stage ADPKD, (H) an axial CT image of ARPKD, (I) a coronal MRI of NPHP, (J) an axial CT image of GCKD, (K) an axial CT image of MCKD, and (L) a coronal MRI of TSC.

TABLE 16.2 Diagnostic Criteria for Autosomal Dominant Polycystic Kidney Disease

Age		PKD1	PKD2	Unknown ADPKD Gene Type
Diagnosis
	30-39 years	>3 cysts^a
		PPV = 100%	PPV = 100%	PPV = 100%
		SEN = 96.6%	SEN = 94.9%	SEN = 95.5%
	40-59 years	>2 cysts in each kidney
		PPV = 100%	PPV = 100%	PPV = 100%
		SEN = 92.6%	SEN = 88.8%	SEN = 90%
Exclusion
	30-39 years	<1 cyst
		NPV = 100%	NPV = 96.8%	NPV = 98.3%
		SPEC = 96%	SPEC = 93.8%	SPEC = 94.8%
	40-59 years	<1 cyst
		NPV = 100%	NPV = 100%	NPV = 100%
		SPEC = 93.9%	SPEC = 93.7%	SPEC = 94.8%
^a Unilateral or bilateral.
All values presented are mean estimates.
ADPKD, autosomal polycystic kidney disease; PPV, positive predictive value; SEN, sensitivity; SPEC, specificity; NPV, negative predictive value.
Derived from Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20(1):205-212.

Based on this experience, Pei and colleagues³³ are now able to provide a unified age-based criteria for a diagnosis of ADPKD using ultrasound imaging for both PKD1 and PKD2 individuals (Table 16.2). This modification from the original Ravine criteria increases the age from 30 to 40 years for screening purposes. The presence of at least three (unilateral or bilateral) renal cysts and two cysts in each kidney are sufficient for a diagnosis of both at-risk individuals and those without a family history of ADPKD aged 15 to 39 years and 40 to 59 years, respectively. The requirement of three or more cysts (unilateral or bilateral) has a positive predictive value of 100% in the younger age group and minimizes false-positive diagnoses, because 2.1% and 0.7% of unaffected healthy individuals younger than 30 years have one and two renal cysts, respectively. In those 30 to 39 years old, both the original (two cysts in each kidney) and the revised (three cysts, unilateral or bilateral) criteria have a positive predictive value of 100%. Finally, for at-risk individuals aged greater than 60 years, four or more cysts in each kidney are required. Even with these criteria in place, there are still exceptions where ultrasound screening is not sufficient, usually when either a family history for ADPKD is absent and the clinical presentation is atypical, or when clinical suspicion for a positive diagnosis is high and evidence for renal cystic disease by ultrasound is lacking.

Although a minimum number of renal cysts are required for a diagnosis of ADPKD, other renal cystic diseases may also meet the requisite cyst number criteria to qualify for a diagnosis of ADPKD (Fig. 16.1). Additionally, given that approximately 15% of ADPKD individuals develop polycystic kidney disease (PKD) spontaneously and have unaffected biologic parents, other features of the clinical presentation are important to consider beyond simply the number of renal cysts identified. For example, the distribution and size of cysts can be informative. Cysts occurring predominantly in the medullary space with relatively small size are found in medullary cystic disease and familial juvenile nephronophthisis in the setting of normal or small kidney size and can be used to distinguish these from ADPKD. Angiomyolipomas are typically present in the kidneys of patients with tuberous sclerosis complex. Glomerular cystic disease is associated with relatively small widely distributed discrete cysts found predominantly in the cortex in the setting of normal kidney size.

In contrast to many other hereditary renal cystic diseases, ADPKD is characterized by significant renal enlargement in the setting of normal kidney function. Although renal enlargement is a feature of ARPKD, particularly in those diagnosed in utero or at birth, significant renal insufficiency usually accompanies this feature. The cysts in ARPKD tend to be diffuse, small, and relatively homogeneous and are more commonly described as fusiform and ectactic dilatations rather than discrete macrocysts. Significant renal enlargement is not present in other hereditary kidney diseases including von Hippel Lindau disease, nephronophthisis,

and medullary cystic disease. Renal enlargement with significant renal cystic burden in the setting of normal kidney function, often with early onset, can be seen in specific individuals who have contiguous gene deletion mutations involving both the PKD1 and TSC2 genes.³⁴ This contiguous gene syndrome usually requires further genetic testing for accurate diagnosis. In addition to the diagnostic value of kidney enlargement in the setting of normal kidney function in ADPKD, the presence of radiographically visible liver cystic disease, when present, is also a unique and diagnostically useful feature of ADPKD. No other hereditary renal cystic disease is accompanied by polycystic liver disease with the exception of some instances of familial juvenile nephronophthisis. Importantly, familial instances of liver cystic disease indistinguishable from that seen in ADPKD but lacking kidney cysts is a genetically distinct disorder.³⁵

Genetic testing may be required to confirm or exclude a diagnosis of ADPKD. Genetic testing is reserved for patients with renal cystic disease without a family history and with an uncertain presentation of ADPKD, or those with a negative ultrasound who are at risk for ADPKD but who need a confirmatory diagnosis for the purposes of living related kidney donation, family planning, or for occupational safety. Direct sequencing of the PKD1 and PKD2 genes is the most reliable approach to a genetic diagnosis.³⁶,³⁷,³⁸ A curated database of PKD1 and PKD2 mutations is available at http://pkdb.mayo .edu/. Mutation detection is successful in up to 85% of cases in research laboratories. Destructive mutations (i.e., those predicted to result in truncated proteins due to premature termination codons, aberrant splicing, or insertion-deletions resulting in frame shifting) are readily identifiable as pathogenic. The same is not true for mutations due to nonsynonymous amino acid substitutions, which may account for up to 30% of mutations in PKD1 and a significantly lower percentage of PKD2. The pathogenicity of missense sequence variations often need to be confirmed with segregation studies in other affected family members before a diagnosis can be confirmed. A genetic diagnosis is further complicated by the lack of commonly recurring mutations that have been identified in other diseases such as cystic fibrosis. As a result, most families have private mutations requiring the relatively expensive whole gene sequencing approach for detection that nonetheless yields a mutation detection rate (highest detection rate, 85%) lower than the rate of cyst detection by age-appropriate ultrasound (lowest detection rate, 99%). As a result, this approach is reserved in the clinical setting for a limited group of patients meeting the previous criteria.

PATHOLOGY OF POLYCYSTIC KIDNEY DISEASE

The kidneys of patients with polycystic disease gradually enlarge and attain an enormous size due to the growth of hundreds of cysts. Kidneys measuring 40 ×25 ×20 cm and weighing 7 to 8 kg have been reported. Usually, these greatly enlarged kidneys are seen in patients with ESRD undergoing
nephrectomy or at autopsy. These end-stage kidneys contain hundreds of fluid-filled cysts of widely differing sizes. The cyst walls can be thin and transparent, but calcification of cyst walls is also common.³⁹ The renal capsule may be thickened around infected cysts, and the kidney may be attached to adjacent abdominal organs such as the spleen and the adrenal glands by fibrous tissue.

Cut sections demonstrate cysts throughout the renal parenchyma. Islands of normal-appearing renal parenchyma can usually be found only in kidneys from young, nonazotemic patients. The cysts vary in size from 1 mm to 10 cm or more in diameter. Cysts in ADPKD arise from all segments of the nephron, and some cysts (˜11%) retain the morphologic characteristics of proximal or distal tubules or collecting ducts. However, most (84%) are lined by a single layer of poorly differentiated columnar or cuboidal epithelium.⁴⁰,⁴¹ Approximately 5% of cysts are lined by a markedly hyperplastic epithelium, forming polyps and microadenomas.⁴⁰,⁴² This hyperproliferative epithelium typically has no signs of dysplasia or premalignant features. The cysts are surrounded by a fibrous stroma, which may contain bundles of smooth musclelike cells, likely transformed myofibroblasts. Inflammatory interstitial infiltrates are seen, and in advanced cases, the renal interstitium is replaced by fibrosis. Marked arteriosclerosis and arteriolosclerosis are found in nephrectomy specimens, evidence that ischemic injury and damage from hypertension contribute to tubular atrophy and glomerulosclerosis.⁴³

Microdissection studies of human kidneys suggest that only 1% to 2% of nephrons are cystic.⁴⁰ These studies also have shown that cysts begin as focal dilatations of tubular segments.⁴⁴ When these dilatations exceed approximately 2 mm in diameter, they typically disconnect from the parent tubule; at least 73% of the cysts have no tubular openings when evaluated by scanning electron microscopy.⁴⁰ The cysts lining epithelial cells are joined together by junctional complexes like those seen in normal proximal tubules or by tight junctions typical of the distal renal epithelium.⁴¹ Only a few microvilli are seen on the luminal surface and a few mitochondria in the cytoplasm. Some cells have prominent cilia, and different types of cells are found in some cysts. Occasional infoldings of the plasma membranes may be found on the basal surface. The basement membrane of most cysts is strikingly abnormal. There is pronounced splitting, duplication, thickening, and lamination of the basal lamina.

The osmolality of cyst fluids is similar to that of plasma, but sodium and nonsodium osmolyte concentrations vary significantly.⁴⁵,⁴⁶,⁴⁷ Sodium concentrations can vary between 3 and 207 mEq per liter, but often are either less than 60 mEq per liter or more than 75 mEq per liter.⁴⁶ Therefore, a distinction was made between low sodium and high sodium cysts. The high sodium cysts have sodium concentrations similar to plasma and therefore are also called nongradient cysts, whereas the low sodium cysts are gradient cysts because they are able to maintain steep concentration gradients not only for sodium but for protons, potassium, chloride, phosphates, and other ions.⁴⁸ Morphologically, the gradient cysts have long tight junctions (zonulae occludens depth >500 m), making them impermeable to ions, whereas the nongradient cysts have short tight junctions (<500 m), making them leaky for solutes and water.⁴⁶ These characteristics suggested that gradient cysts were derived from collecting ducts and nongradient cysts from proximal tubules. However, most nongradient cysts are lined by a poorly differentiated epithelium with few microvilli and few mitochondria, which does not resemble the proximal tubular epithelium.⁴⁶

More recent studies have assessed the distribution of aquaporin-1 and -2 in ADPKD cysts. In normal kidneys, aquaporin-1 is expressed in proximal tubules and thin descending limbs of the Henle loop, whereas aquaporin-2 is expressed on the apical surfaces of the collecting duct epithelia. In ADPKD kidneys, approximately 30% of cysts stain positive for aquaporin-1, another 30% are positive for aquaporin-2, and the rest are negative for both aquaporin-1 and -2.⁴⁹,⁵⁰ The aquaporin-1-positive cysts presumably are derived from proximal tubules or thin descending limbs, the aquaporin-2-positive cysts are from collecting ducts, and the negative cysts are from nephron segments that do not express these water channels (i.e., the ascending limb of the Henle loop and distal convoluted tubules). These results also imply that the expression of water channels is not a prerequisite for cyst expansion. Moreover, the aquaporins appear to retain their segment-specific expression in ADPKD even though the morphologic characteristics of proximal and distal tubules are lost.

In addition to electrolytes and water, cyst fluids also contain amino acids, glucose, urea; idiogenic osmoles such as sorbitol, betaine, and glycerophosphorylcholine; and proteins, such as β₂ -microglobulin, erythropoietin, renin, and albumin.⁴⁷,⁴⁸ Cytokines, specifically interleukin (IL)-1 β, IL-2, and tumor necrosis factor (TNF)-α, growth factors (epidermal growth factor [EGF], hepatocyte growth factor, endothelins), and a nonpolar lipid cyst activating factor, are present in cyst fluids as well and likely play a significant role in the pathophysiology of ADPKD.⁵¹,⁵²,⁵³,⁵⁴,⁵⁵,⁵⁶

Therefore, the cysts of polycystic kidneys are not simply impermeable cul-de-sacs that collect and store urine from more proximal nephron segments. They are complex structures that proliferate and undergo apoptosis; that synthesize or transport various proteins, hormones, and cytokines; and that actively secrete chloride and water. Under certain conditions, they also may be able to absorb solutes and water.⁴⁵ Most cysts are permeable to small solutes, but some are highly impermeable. Although most cysts are lined by morphologically undifferentiated epithelium, the differential expression of water channels is maintained.

CLINICAL CHARACTERISTICS OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Although ADPKD derives its name from the kidney, it is a systemic disorder with extrarenal manifestations that are unique to ADPKD.³,⁵⁷,⁵⁸ Renal manifestations of ADPKD are
the most common and include the presence of renal cysts, renal enlargement, a decreased renal concentrating ability, polyuria, nocturia, and increased thirst.⁵⁹,⁶⁰ In addition, renal complications of ADPKD include flank or abdominal pain, gross hematuria, hypertension, urinary tract infections, and nephrolithiasis.¹³,⁶¹,⁶² Extrarenal manifestations are common in ADPKD and involve the cardiovascular, gastrointestinal, male and female reproductive systems, and the thyroid, subarachnoid, pericardial, and bronchial spaces.⁶³,⁶⁴,⁶⁵,⁶⁶,⁶⁷

Although ADPKD is a hereditary renal disease, patients are relatively oligosymptomatic until the second or third decade of life. Renal complications are the most common and occur with increasing frequency with age. Pain is the most common complication, followed by hypertension and gross hematuria. The age-dependent presentation of these manifestations relate closely to kidney size or total kidney volume.⁶² By the third decade of life, less than 10% of all ADPKD patients are complication free, even though the mean age of diagnosis of ADPKD is 27 years.¹³ Patient-centered outcome reporting demonstrates that thirst, pain, and urinary frequency are the most common patient concerns.⁶⁸ However, close attention to other renal complications is important, given their contribution to progressive renal insufficiency and ESRD. Not surprisingly, renal complications are associated with poorer renal and patient outcomes.

Pain is the most common clinical manifestation of ADPKD and is responsible for the majority of presentations for symptomatic diagnosis.⁶⁹,⁷⁰ Pre-ESRD patients completing quality of life questionnaires demonstrate lower scores on the physical component summary suggesting that symptoms of discomfort significantly impact their quality of life. Focus groups determining the most common patient-reported outcomes find that pain along with thirst and polyuria are the most important. Pain can be managed effectively in most patients, but in a minority, chronic pain limits individuals’ ability to function, resulting in sleep deprivation, fatigue, anxiety, and a decreased quality of life.⁷¹ Acute and chronic pain in ADPKD is due to different causes. Acute pain syndromes in ADPKD are most often associated with cyst rupture, hemorrhage, renal infections, or nephrolithiasis. Chronic pain is a more complex and less defined problem. ADPKD patients report pain located in the back (71%), abdomen (61%), head (49%), chest (30%), and legs (27%).⁷² Renal and nonrenal sources of pain not related to cystic disease should be considered including diverticulitis, ovarian cyst rupture, aortic or iliac aneurysms, or incarcerated hernias.

Chronic pain management related to polycystic kidneys requires a staged approach beginning with nonpharmacologic interventions including ice, heat, whirlpool, massage, and physical therapy as well as exercises to improve vertebral and abdominal wall support. When these approaches are not successful, other therapies including intermittent transcutaneous electrical nerve stimulation (TENS) unit and nonopioid analgesics, such as acetaminophen, can improve the level of pain in polycystic patients. There is less objective information regarding the benefits of other treatments including short- and long-term opioid medications, tramadol (Ultram), clonidine, gabapentin, or pregabalin. Nontraditional complementary medical approaches such as acupuncture may be helpful, although this may involve a placebo effect. Surgical approaches to pain in ADPKD patients are reserved for those who have systematically attempted all nonmedical and medical therapies over a reasonable period of time. The least invasive approach is percutaneous cyst aspiration with alcohol injection, typically done in patients with symptoms that can be matched locally to candidate cysts identified using CT or MRI. This can be done in interventional radiology suites as an outpatient procedure. Multiple cyst fenestrations or deroofing procedures (Rovsing procedures) can be done in more severe and complicated cases. Prospective studies report an immediate improvement in 85% to 90% of individuals with close to two thirds maintaining a benefit up to 2 years after treatment.⁷³,⁷⁴,⁷⁵,⁷⁶ More recently, renal denervation procedures both abdominally and thoracoscopically with and without nephropexy have demonstrated early short-term pain relief.⁷⁷,⁷⁸ Whether there are long-term benefits resulting from these interventions is not yet clear. Finally, partial or full nephrectomy or volume reducing procedures, including transcatheter arterial embolization, have been used with success in small numbers of patients with intractable pain.

Hypertension

Hypertension is common in ADPKD and, unlike in other tubulointerstitial diseases, it occurs in the majority of patients prior to the loss of kidney function.⁷⁹,⁸⁰,⁸¹ The average age of onset is 29 years, and men are more often hypertensive than women early in the course of disease.¹¹,⁸⁰ Evidence suggests that carotid and left and right ventricular structure are abnormal in asymptomatic ADPKD patients early in the course of disease prior to the development of hypertension. This is manifest by increases in carotid intimal wall thickness, reduced end-diastolic relaxation, decreased aortic relaxation, increased left ventricular mass, and left ventricular hypertrophy.⁸²,⁸³,⁸⁴ Hypertension is common in children with ADPKD, affecting 10% to 25% of individuals,⁸⁵,⁸⁶,⁸⁷ and it is associated with evidence of end-organ damage including increased left ventricular mass index and left ventricular hypertrophy. Whether primary cardiovascular abnormalities or increased systemic blood pressure are the primary hemodynamic abnormality to develop in ADPKD and how they relate to each other is unclear. A recent study suggested that an early intervention in ADPKD, particularly with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, may decrease the occurrence of left ventricular hypertrophy and has the potential to decrease cardiovascular mortality.⁸⁸

Total kidney volume (TKV) is greater in hypertensive ADPKD adults and children with normal kidney function when compared to the respective normotensive ADPKD controls.⁸⁹,⁹⁰,⁹¹ The increased cyst burden found in hypertensive ADPKD individuals is associated with evidence of systemic activation of the RAAS. Vascular imaging and MR-based quantification of renal blood flow demonstrate attenuated renal vasculature and reduced renal blood flow,
both of which occur early and are associated with hypertension and increased TKV.⁹²,⁹³ Activation of the RAAS in ADPKD is most likely due to increased intrarenal ischemia secondary to cyst formation and expansion. Distortion of the renal vasculature due to increased cyst burden results in decreased renal nitric oxide production, increased reactive oxygen species formation, and further activation of the intrarenal RAAS.⁹⁴ Currently two large randomized clinical trials are under way to determine the impact of inhibition of the RAAS and the value of rigorous blood pressure control in disease progression in ADPKD.⁹⁵ Results of these trials will be available in 2014.

Gross Hematuria

Gross hematuria is a common initial clinical presentation in ADPKD, often presenting prior to the onset of hypertension. Although not prospectively established, gross hematuria tends to associate with rapid cyst expansion, increased physical activity, and cyst wall calcifications. Gross hematuria is significantly associated with increased kidney size and a poorer renal prognosis.⁶²,⁹⁶,⁹⁷ Gross hematuria may or may not be associated with renal pain. In patients with gross hematuria who are asymptomatic, cyst rupture into the urinary collecting system is the most likely cause. Renal imaging is encouraged to rule out other treatable causes of gross hematuria. In patients in whom symptoms develop, localized pain, fever, and dysuria are common. When these clinical signs and symptoms occur, it is important to rule out cyst infection, nephrolithiasis, pyelonephritis, or lower urinary tract infections.

Gross hematuria secondary to cyst rupture is typically self-limited and usually lasts 2 to 5 days. Increased hydration with oral fluid intake and bed rest with close monitoring of blood pressure is indicated given the increased risk for acute reversible kidney injury in the setting of antihypertensive medication intake, particularly angiotensin-receptor blocking agents and angiotensin-converting enzyme inhibitors.⁹⁸ Often, it is advised to temporarily discontinue these agents until the episode of gross hematuria resolves. It is important to monitor blood pressure closely with home blood pressure monitoring devices during this time.

Urinary Tract Infections

Urinary tract infections are common in ADPKD and occur more often in women as compared to men.⁹⁹ Unlike hypertension and gross hematuria, it is not well established whether urinary tract infections are associated with progressive renal injury. Given that lower urinary tract infections are relatively common in the general population, their occurrence in ADPKD may or may not be disease related. Differentiation between lower and upper urinary tract infections can be difficult, further complicating the discovery of any link between urinary tract infections and disease severity. Upper urinary tract infections in ADPKD may be due to cyst infections, nephrolithiasis, or pyelonephritis and require careful evaluation.¹⁰⁰,¹⁰¹ Therapy for cyst infections requires different antibiotic treatment than those recommended to treat pyelonephritis in the general population. Antibiotics that provide adequate cyst fluid concentrations are necessary.¹⁰² In addition, a more prolonged course of therapy is needed to ensure successful eradication of the infection. Current recommendations for the treatment of cyst infections include a 2-week course of an oral quinolone or possibly trimethoprim-sulfamethoxazole.

The diagnosis of a cyst infection is often difficult. Clinical presentations vary ranging from local tenderness, fever, leukocytosis, and leukocyturia with positive urine cultures to diffuse abdominal discomfort or pain, absence of a fever, and negative urine cultures.¹⁰³ Importantly, blood cultures may more often provide evidence of the infecting organism than urine cultures given that many infected cysts do not directly communicate with the urinary collecting system. Occasionally, cyst infections do not respond to appropriate oral antibiotic therapy. Typically, this occurs in larger cysts (> 5 cm in diameter) or when intracystic antibiotic levels are inadequate. It may be necessary to administer parenteral antibiotics, conduct imaging studies to rule out other causes of fever and pain (including nephrolithiasis), and to consider percutaneous cyst aspiration to obtain cultures or to decompress the large infected space.¹⁰⁴ In rare circumstances, frank pyonephritis may develop associated with sever malaise, sepsis, and shock and may necessitate partial or total nephrectomy.

Nephrolithiasis

Kidney stones are tenfold more common in ADPKD patients than the general population, occurring in approximately 25% of affected individuals.¹⁰⁵ Symptomatic nephrolithiasis typically occurs later than other renal complications in ADPKD.⁹⁶ Nephrolithiasis associates with increased TKV in ADPKD patients with normal kidney function. All types of kidney stones can occur in ADPKD; however, urate nephrolithiasis is more common than other types of kidney stones.¹⁰⁶ ADPKD patients develop hypocitraturia, even prior to a loss of renal function, and this may contribute to the increased frequency of urate nephrolithiasis. Whether the hypocitraturia associated with ADPKD is due to abnormalities in renal ammonia generation or other tubular defects is unknown. Of note, urinary biochemical parameters in ADPKD patients uniquely demonstrate normal urinary calcium excretion with increased oxaluria. Patients with nephrolithiasis typically present with unilateral flank pain, with or without radiation, and may have micro- (or rarely, macro-) hematuria. Those with nephrolithiasis diagnosed incidentally during renal imaging more commonly report lower unilateral back pain. Importantly, fevers and chills may occur in the setting of nephrolithiasis. This constellation of signs and symptoms overlap significantly with cyst infections and cyst hemorrhage. An evaluation of nephrolithiasis almost always requires renal imaging—most often, noncontrast CT imaging.¹⁰⁷ Ultrasound has a reduced sensitivity for the detection of kidney stones as compared to CT imaging
in ADPKD individuals. Excretory urography, abdominal flat plate X-rays, and ultrasound can all be used; however, the localization and detection of renal stones is achieved best with CT imaging. The differentiation of renal cyst wall calcification and nephrolithiasis is important and can be easily done when CT imaging is performed. Cyst wall calcifications are more common in ADPKD patients who demonstrate nephrolithiasis than those who do not.

The approach to the management of nephrolithiasis in ADPKD patients should involve a biochemical analysis of the urine and stone using crystallography if possible. Estimates of daily fluid intake and dietary intake of stone-forming elements should be established. Both of these evaluations can be determined from a single 24-hour urine collection. Urinary biochemical analysis should include calcium, urate, oxalate, citrate, and pH.¹⁰⁸ For the majority of stones formed in ADPKD, increases in fluid intake are the cornerstone of therapy. A minimum of 3 L per day of fluid intake should be established using home monitoring coupled with monthly 24-hour urine collections. The addition of bicarbonate or citrate is also helpful for those patients with urate nephrolithiasis to decrease urinary acidification and to increase potential stone dissolution. Dietary education is also helpful with regard to dietary intake of urate, calcium, and oxalate. For patients with calcium oxalate stones, the addition of thiazide diuretics will help to reduce urinary calcium excretion and, coupled with increased fluid intake to greater than 3 L per day, will reduce the concentration of urinary calcium and inhibit initial stone formation.

The most complicated stone in ADPKD patients is the struvite stone, or staghorn calculus. These stones are a constant nidus for infection, which can recur shortly after each treatment course and must be removed to avoid complications. These stones are a nidus for infection, which recurs after each treatment course, and must be removed to avoid complications. Collaboration with the urologic specialists is essential for the management of these patients. Depending of the size of the stone and its location, retrograde lithotripsy, extracorporeal shock wave lithotripsy (EWAL) therapy, or percutaneous stone removal may be necessary.

EXTRARENAL MANIFESTATIONS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Polycystic Liver Disease

Liver cyst formation is the most common extrarenal manifestation in ADPKD. Polycystic liver disease is due to the presence of multiple scattered cysts of biliary origin in the liver parenchyma. Among the hereditary renal cystic disorders, it is only found in ADPKD and, when present, is a useful adjunct in securing the diagnosis. In individuals with kidney cysts and no family history of ADPKD, the presence of liver cystic disease provides confirmation of the clinical diagnosis. Liver cystic disease occurs in over 85% of PKD1 patients by the age of 30.¹⁰⁹ An MRI analysis performed as part of the Consortium for the Radiographic Imaging Studies of Polycystic Kidney Disease (CRISP) study demonstrated that the prevalence of liver cysts increases with age, occurring in 58%, 85%, and 94% of affected individuals age 15 to 24, 25 to 34, and 35 to 46 years, respectively. The severity of cystic liver disease appears to parallel the severity of cystic kidney disease.¹¹⁰,¹¹¹ Liver cystic disease varies from a few cysts to massive cystic liver enlargement. Importantly, liver parenchyma and liver function are normal even in the setting of massive polycystic liver disease, and portal hypertension does not occur. Biochemically, the only liver function abnormalities found are mild elevations in the alkaline phosphatase and bilirubin. In contrast to renal cystic disease, polycystic liver disease occurs earlier and is more likely to be severe in women than in men and is influenced dramatically by estrogen exposure.¹¹⁰ Liver cysts develop within specific segments of the liver, and there is no predictable segment sparing.

The signs and symptoms of polycystic liver disease include increased abdominal girth, increased clothing size, shortness of breath, early satiety, abdominal pain, and umbilical herniation. Morphologic studies of liver cysts demonstrate that they originate from biliary microhamartomas that arise from biliary ductules and peribiliary glands. As in the kidney, as liver cysts expand and enlarge, they become detached from their biliary tree of origin.¹¹² Similarly to polycystic kidney disease, cyst expansion is the result of multiple effects of proliferation of cyst-lining epithelia, fluid secretion, remodeling of the extracellular matrix, and neovascularization.¹¹² The genetic and molecular signaling mechanisms found in renal cystic epithelia have also been found in liver cystic disease in ADPKD, suggesting that the underlying disease biology in both organs are closely related.

Isolated Polycystic Liver Disease

Isolated autosomal dominant polycystic liver disease (ADPLD; MIM 177060, 608648) is an autosomal-dominant familial disease with significant genetic heterogeneity.³⁵,¹¹³ It is relatively rare, with an estimated incidence of < 0.01% of the population. This may be related to the low rate of clinical symptoms; autopsy studies suggest a rate of occurrence that is only slightly lower than that of ADPKD.¹¹⁴ Although isolated ADPLD was reported as early as 1906,¹¹⁵ it was not until 2003 that linkage analysis in eight Finnish families confirmed that isolated ADPLD is a disease genetically distinct from polycystic kidney disease. Subsequent gene discovery studies in patient families showed that ADPLD is genetically heterogeneous, with a subset of affected families having heterozygous mutations in PRKCSH or SEC63 in the setting of clinically indistinguishable clinical presentations.¹¹⁶,¹¹⁷,¹¹⁸ Further genetic heterogeneity is suggested by the finding that only approximately 30% of AD-PLD families have mutations in either of these two genes.¹¹⁹ As a result, DNA testing in ADPLD patients has limited use because the mutated genes responsible for ADPLD have not been identified for the majority of families.

The natural history of ADPLD is relatively oligosymptomatic, characterized by associated symptoms in less than 30% of individuals. Those with symptomatic ADPLD complain of abdominal distention, fullness, discomfort, early satiety, and dyspnea and back pain. Individuals with ADPLD also demonstrate mild elevations in serum alkaline phosphatase as well as total bilirubin associated with lower total cholesterol and triglyceride levels. As in ADPKD, ADPLD women show a tendency toward significantly more liver cystic burden than men. As compared to unrelated and related unaffected individuals, mitral leaflet abnormalities may be more common, and other vascular malformations including intracranial aneurysms, carotid artery dissections, and ectatic cavernous arteries have been seen.³⁵ The differential diagnosis of ADPLD includes simple liver cysts and liver cysts resulting from other diseases, including ADPKD. Because simple liver cysts are common in the general population and occur with increasing frequency with increasing age, at least four liver cysts visible by ultrasonography are required for the diagnosis of ADPLD in individuals over the age of 40.

Intracranial Aneurysms and Other Vascular Abnormalities

The frequency of intracranial aneurysms (ICAs) is increased in ADPKD. A recent meta-analysis of 645 ADPKD patients with ICA demonstrated a 6.6-fold increased likelihood of an ICA developing compared to the general population.¹²⁰ This represents a frequency of 5.8% in selected ADPKD populations (as compared to 2.8% in the general population) and a 12% frequency in ADPKD patients with a positive family history of an ICA. ICAs tend to cluster in a small number of ADPKD families, and a positive family history of ICA is the only established risk factor associated with ICA in ADPKD. Gender, age, smoking exposures, hypertension, and race do not contribute to the risk of ICA formation in ADPKD. Mutations in the PKD1 gene tend to be closer to the 5’ end of the gene in families with intracranial aneurysms¹²¹ and a common PKD1 mutation has been reported in individuals with a variety of vascular malformations including ICA,¹²² but the genetic basis of ICA beyond the tendency to cluster in certain families is not well understood.

As compared to the general population, ICAs are more often found in the anterior circulation (84%) and rupture at an earlier age in ADPKD, but they do not differ in size at the time of rupture. As with all ICAs, the risk of rupture increases significantly once size reaches 10 mm in diameter. Given the serious consequences of an ICA rupture with permanent morbidity and mortality in excess of 40%, preventative screening and management are important aspects to patient care. Given that aneurysms are relatively rare, selective screening should be considered. Multiple studies of asymptomatic ADPKD patients demonstrate that only a positive family history associates with an ICA.¹²³,¹²⁴ Repeat screening in individuals following an initial negative screen provided a very low yield of 2.4% in 76 individuals over 10 years.²⁰ Two longitudinal imaging studies of ADPKD individuals with documented small intact ICAs demonstrated a low frequency (8 out of 65) of increases in diameter over 243 patient years with the occurrence of six de novo aneurysms.¹²⁵,¹²⁶ Taken together, these data suggest that the presence of ICAs in AD-PKD patients is reflective of an initial expansion at the time of formation, perhaps with a higher risk of rupture. If the initial screening does not show vascular abnormalities, further imaging is not required unless individuals are symptomatic. Specific subgroups of ADPKD patients in addition to those with a positive family history of ICA, such as those considering organ donation or receipt, commercial pilots, or those with considerable personal burden due to concern about their status should undergo an initial screening for ICA.

Potential imaging modalities to assess the intracerebral vasculature include CT angiography, four vessel arteriography, or MRI. All modalities have excellent resolution, accuracy, and reliability. CTs and angiographies are associated with increased radiation exposure and potential complications. Therefore, MR angiography is the imaging modality of choice for screening. MRs with and without gadolinium can be used to clearly outline the cerebral vasculature. The management of ICAs in ADPKD patients relate primarily to the size of the ICA but also depend on location and whether they are asymptomatic. Typically, ICAs less than 5 mm in diameter are at low risk of rupture. In symptomatic individuals or those with ICAs greater than 7 mm, either surgical ablation or coil ablation or thrombosis can be used, depending on the size and location of the ICA. Complications related to surgical intervention are low (< 1%), but when they occur, they have significant morbidity, particularly with procedures performed in the posterior circulation of the circle of Willis. Therefore, patients with ICAs are advised to carefully review the risks of rupture and complications of treatment before moving forward with surgical or endovascular interventions.

Fertility in Autosomal Dominant Polycystic Kidney Disease

Women with ADPKD demonstrate fertility rates similar to the general population. However, an increased rate of ectopic pregnancy¹²⁷ has been reported that is potentially associated with abnormalities in fallopian tube function or ciliary motility. Importantly, seminal vesicle cysts are common in men and can be detected by transrectal ultrasonography in up to 40% of male ADPKD patients.¹²⁸ Abnormal sperm motility occurs in the majority of men with ADPKD, and although this has not been shown to directly relate to fertility, it may play a role in the increased occurrence of azoospermia reported in men with ADPKD.¹²⁹ Although women with ADPKD demonstrate a normal ability to become pregnant, the course of pregnancy is associated with increased maternal and fetal complications. In general, the likelihood of a successful pregnancy in ADPKD is similar to the general population,¹²⁷,¹³⁰ but there are subgroups of patients, such as those with preexisting hypertension or with established renal insufficiency, who are at an increased risk for fetal loss.

Premature delivery, small for gestational age babies, and congenital abnormalities occur in a small percent of offspring
born to women with ADPKD, typically those older than 30 years or with preexisting hypertension.¹²⁷ In a large series of 605 pregnancies in 235 women with ADPKD, only 2 individuals had serum creatinine concentrations greater than 1.2 mg per deciliter prior to becoming pregnant. This is in large part due to the typically delayed occurrence of renal insufficiency in the fourth to sixth decades of life in ADPKD individuals. Given that renal function is usually intact in ADPKD individuals during their reproductive years, the typical complications of polyhydramnios and preterm labor that are associated with pregnancy in women with established renal insufficiency are not typical features of pregnancy management in ADPKD. Maternal complications occurred in 35% of women with ADPKD who become pregnant, including newonset hypertension, worsening hypertension, preeclampsia, and acute kidney injury. These complications tend to be relatively mild and resulted in uncomplicated pregnancies in the majority of women with ADPKD.

In women with ADPKD who are planning a pregnancy, proactive management before and during pregnancy is critical. For women with hypertension planning to become pregnant, all inhibitors of the RAAS should be stopped prior to pregnancy given the untoward effects on the fetus even with first trimester exposure to this class of drugs. Once pregnant, women with ADPKD should be seen by a high-risk obstetrician and a nephrologist beginning in the middle of the second trimester, particularly if prepregnancy renal function is not normal. Monthly screening for the development of new or worsening hypertension should be conducted. Patients should also check their blood pressure in their home environment on a regular basis. Patients should have their urine reviewed for the presence of new or increased proteinuria, which is a potential sign for the development of preeclampsia. Blood pressure management during pregnancy should include using antihypertensive therapies approved for use in pregnancy including aldomet, hydralazine, clonidine, labetalol, or a dihydropyridine. Immediately postdelivery, women with ADPKD should be monitored closely for signs of worsening hypertension and should have their level of kidney function and blood pressure established approximately 6 weeks after delivery. Longitudinal studies of risk factors for the progression to renal failure have suggested that pregnancy number (particularly for those with more than three pregnancies) is an independent risk factor for the development of ESRD in ADPKD.¹³¹ This association is weak compared to other risk factors such as the presence of hypertension or total kidney volume. The association with pregnancy number or use of estrogen/progesterone agents use is much stronger for liver cyst burden.¹³²

THE PKD GENES AND THEIR PROTEIN PRODUCTS

The evolving understanding of the pathogenesis of polycystic kidney diseases has been punctuated by several critical discoveries. The most fundamental of these advances came with the identification of the genes and the respective protein products that are mutated in families with these diseases.¹¹⁶,¹¹⁷,¹¹⁸,¹³³,¹³⁴,¹³⁵,¹³⁶,¹³⁷ At the time of their discovery, the genes for ADPKD (and ARPKD) were completely novel and did not readily fit into in any known biologic pathways. The initial clues regarding their putative roles had to come from the predicted structure of the respective protein products and the knowledge that their functions are expected to intersect at the level of clinical human disease phenotype manifested as the dysregulated nephron tubule structure. This section will review the current state of knowledge regarding the protein products of the various genes associated with human polycystic kidney and liver disease.

PKD1 and Polycystin-1

PKD1 is located on chromosome 16p13.3.¹³³,¹³⁴,¹³⁵,¹³⁸ The structure of the gene locus is complicated by the fact that the 5’ two-thirds of the gene is duplicated multiple times with very high sequence fidelity in pseudogenes located on more proximal regions of chromosome 16.¹³⁹,¹⁴⁰,¹⁴¹,¹⁴² The need to resolve sequence variants occurring in the PKD1 gene itself as opposed to its homologs for purposes of mutation detection has complicated genetic testing in ADPKD, although current sequence-based technologies are able to address this complication. The protein encoded by PKD1 is called PC-1. PC-1 is a large, low abundance, polytopic integral membrane protein with complex domain structure suggestive of receptor function that undergoes multiple proteolytic cleavage processes (Fig. 16.2). This constellation of features coupled with the absence of direct biochemical and cell biologic assays for its function has made deciphering the mechanisms of ADPKD challenging despite the successful identification of the genes almost 2 decades ago.

Human PC1 is comprised of 4302 amino acids with a 3074 amino acid extracellular NH₂ -terminus, 11 transmembrane domains, and a 198 amino acid cytosolic COOH- terminus (Fig. 16.2).¹⁴³ The extracellular NH₂ -terminal domain contains a number of protein motifs including leucine-rich repeats, a WSC homology domain, C-type lectin domain, a low density lipoprotein (LDL)-A related domain, 16 immunoglobinlike PKD repeats,¹³⁴,¹⁴⁴,¹⁴⁵ a receptor egg jelly (REJ) module,¹⁴⁶ and a G-protein-coupled receptor (GPCR) proteolytic site (GPS).¹⁴⁷ The Ig-like polycystic kidney disease (PKD) domains occupy 40% of the extracellular portion of PC1 and contain a distinct β-sandwich fold structure¹⁴⁸ that is resistant to unfolding under mechanical force.¹⁴⁹,¹⁵⁰,¹⁵¹ The stability of these PKD domains is altered by naturally occurring mutations in PKD patients.¹⁵² The REJ module is comprised of four fibronectin type III βsheet domains.¹⁵³ The first intracellular loop contains a highly conserved polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain that may be involved in protein interactions.¹⁵⁴ The extracellular loop between the sixth and seventh transmembrane domains contains a highly conserved domain that is common to both PC-1 and PC-2 family members and is not found in any other protein families.¹⁵⁵ The region of the last six transmembrane domains of PC1 share sequence similarity with
PC-2 but lack critical residues suggesting that PC1 does not have the channel activity associated with PC-2 (see the following). The COOH terminus of PC1 contains a coiled coil domain that is necessary for interaction with PC-2.¹⁵⁶,¹⁵⁷,¹⁵⁸ In addition to the repeated partial PKD1 sequences on chromosome 16, there are four homologous protein products in the PKD1 gene family: PKD1L1, PKD1L2, PKD1L3, and PKDREJ. A complex of PKD1L3 protein with the PKD2 homolog, PKD2L1, has been assigned chemosensory function in sour taste and pH sensation,¹⁵⁹,¹⁶⁰ although studies with Pkd1L3 knockout mice have called this into question.¹⁶¹ PKD1L1, but not PKD1, has been implicated in left-right axis determination in mammals.¹⁶²

FIGURE 16.2 The protein products of the autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2. The schematic drawing highlights the predicted domain structure of polycystin-1 (PC-1) and polycystin-2 (PC-2). PC-1 and PC-2 interact via coiled coil domains in their respective cytoplasmic carboxy (COOH)-termini to form a predicted receptor-channel complex; the most likely stoichiometry is three PC-2 molecules (only one is shown) and one PC-1 molecule. The extensive extracellular NH₂-terminal domain of PC-1 is cleaved at the G-protein-coupled receptor proteolytic site (GPS) in the endoplasmic reticulum (ER) but remains noncovalently associated with the intramembranous COOH-terminal PC-1 fragment. Additional putative cleavage sites are indicated by arrows. See the text for further discussion of the structural features of both proteins. PKD, polycystic kidney disease; LDL-A, low density lipoprotein-A; REJ, receptor egg jelly; PLAT, polycystin-1, lipoxygenase, alpha-toxin; TRP, transient receptor potential. (See Color Plate.)

Several functional cleavage processes have been defined for PC1. The best characterized of these is the autoproteolytic cleavage within the sequence HL↓T³⁰⁴⁹ at the GPS in a process that requires an intact REJ module.¹⁶³,¹⁶⁴ The GPS cleavage process occurs early in the secretory pathway, most likely in the endoplasmic reticulum (ER), and requires N-glycan attachment.¹⁶⁴ The resultant extracellular NH₂ -terminal fragment and the intramembranous COOH-terminal fragment remain noncovalently associated with each other.¹⁶³ Although the GPS site is conserved in all PC1 homologs within and across species, at least two homologs, PKDREJ and the sea urchin protein SuREJ2, do not undergo GPS cleavage.¹⁶⁵,¹⁶⁶ Experimental evidence for the functional importance of GPS cleavage in PC-1 comes from findings that pathogenic patient mutations in the REJ abrogate GPS cleavage, that cleavage deficient PC-1 does not support tubulogenesis and STAT1 activation in a cell culture assay, and that a GPS cleavage mutant knockin functions as a hypomorphic allele in mice.¹⁶³,¹⁶⁷ GPS cleavage appears to promote cell surface expression of PC-1.¹⁶⁸ Cleaved PC-1 has been identified in urinary exosome-like vesicles, raising the possibility of a signaling function for shed polycystins.¹⁶⁹ Additional cleavage products of PC-1 have been identified, although these are less well understood than the GPS cleavage. P100, a second intramembranous cleavage product of PC-1 encompassing the last six transmembrane domains, has been shown to diminish store-operated calcium entry by altering the translocation of the ER calcium sensor protein STIM1 to the cell periphery.¹⁷⁰ Two cleavages liberating different fragments of the cytoplasmic tail of PC-1 have also been identified. The first yields a 35 kDa fragment that translocates to the nucleus following cleavage step that is dependent on the presence of functional PC-2.¹⁷¹,¹⁷² This fragment is released by gamma-secretase-mediated cleavage and regulates the Wnt and C/EBP homologous protein (CHOP) pathways by binding to respective transcription factors (TCF) and CHOP, thereby disrupting their interaction with a common transcriptional coactivator p300.¹⁷³,¹⁷⁴ The second proposed COOH terminal cleavage product is a 15 kDa fragment that interacts with the transcriptional activator STAT6 and the coactivator p100 in a process that is enhanced by the cessation of flow-induced mechanical stimuli.¹⁷⁵ Inhibition of STAT6 in a Pkd1 mouse model results in the slowing of cyst growth.¹⁷⁶

PKD2 and Polycystin-2

PKD2 encodes PC2, a 968 amino acid integral membrane protein with six transmembrane spans and intracellular NH₂ and COOH termini (Fig. 16.2).¹³⁵,¹⁷⁷,¹⁷⁸ It is a member of the transient receptor potential (TRP) family of cation channels and is also known as TRPP2.¹⁷⁹,¹⁸⁰,¹⁸¹,¹⁸² Two mammalian homologs of PKD2, PKD2L1 (TRPP3) and PKD2L2 (TRPP5), have been identified. The TRP channel family is comprised of
28 different gene products, which function in diverse, mostly sensory, cellular processes including sensation of pain, temperature (hot and cold), taste, pressure, and vision.¹⁸³ The last five transmembrane spans of PC-2 have the greatest structural similarity with other TRP channels, with the region between the fifth and sixth transmembrane domains comprising the ion selectivity pore. An RVxP motif in the NH₂ terminus of PC-2 is necessary for its localization in cilia, and PC-2 can traffic to cilia independently of PC-1 (see the following).¹⁸⁴ Phosphorylation at serine 812 in the COOH terminus of PC-2 affects the channel properties¹⁸⁵ and trafficking¹⁸⁶,¹⁸⁷ of the protein. The subcellular immunolocalization of PC-2 has been controversial. There is general consensus that PC-2 is abundantly expressed in the ER¹⁷⁷,¹⁷⁹,¹⁸⁸ and the primary cilium.¹⁸⁹,¹⁹⁰ COOH truncated forms of PC-2 readily traffic to the plasma membrane,¹⁷⁷,¹⁸⁴ and it has been suggested that coassembly with PC-1 is required for trafficking of full-length PC-2 to the generalized plasma membrane.¹⁸⁰ PC-2 has also been reported associated with centrosomes¹⁹¹ and the mitotic spindles of dividing cells.¹⁹²

The cellular mechanisms for trafficking PC-2 to the cilium and the somatic plasma membrane are divergent.¹⁹³ Trafficking begins with a coat protein complex II (COPII)-dependent process that delivers PC-2 from the ER to the cis side of the Golgi. From there, the bulk of PC-2 is returned to the ER in a process dependent on a 34 amino acid retrieval signal in the COOH terminus of PC-2. A minority of PC-2 enters a vesicular transport process directly from the cis part of the Golgi that delivers the protein to the cilium in a process that depends on Rab8a as well as the RVxP motif. If PC-2 is also to be delivered to the somatic plasma membrane (e.g., by truncation of the COOH terminus retrieval signal), this process traverses the Golgi in the conventional manner of other integral membrane and secreted proteins. PC-2, like PC-1 and the ARPKD (PKHD1) gene product fibrocystin, is a prominent component in urinary exosomeslike vesicles that are produced by the multivesicular body sorting pathway.¹⁶⁹ The PKD-related proteins and the exosomes that contain them may play a role in novel urinary signaling pathways in the kidney.

The COOH terminus of PC-2 contains EF hand¹³⁵,¹⁹⁴,¹⁹⁵ and coiled domains¹⁵⁶,¹⁵⁷,¹⁵⁸,¹⁹⁵,¹⁹⁶ and has been the subject of several biophysical and biochemical studies. The EF hand binds calcium¹⁹⁴ and may have a role in modulating channel activation and inhibition. The coiled coil domain is responsible for homo- and hetero-multimerization of PC-2 with itself and with PC-1, respectively. The structural data are most consistent with a complex consisting of three PC-2 molecules and one PC-1 molecule interacting through their respective coiled coil domains.¹⁵⁷,¹⁹⁷ Critical residues in both proteins that weaken these interactions have been identified and should prove useful in modulating activity of the polycystins in experimental systems.¹⁵⁸,¹⁹⁶ In addition to interacting with each other, PC-2 and to a lesser but still significant extent, PC-1, have acquired an extensive list of interacting proteins primarily associated with their respective COOH termini.⁵⁸ Although many of these interactions have shown functional effects in a variety of biologic systems, a direct role in the pathogenesis of ADPKD is lacking in most of them. This may in fact highlight the likelihood that PC-1 and PC-2 serve additional cellular and tissue functions that may not be directly related to their role in PKD. Identifying the roles specific to ADPKD remains a challenge especially in light of the fact that those roles might be subsumed by the minute fraction of each protein that appears in the primary cilium (see the following).

The Genes for Autosomal Dominant Polycystic Liver Disease

The two known genes for ADPLD, PRKCSH¹¹⁶,¹¹⁷ and SEC63,¹¹⁸ respectively encode the noncatalytic beta subunit of glucosidase II (GIIβ)¹⁹⁸,¹⁹⁹ and SEC63p. These proteins work at the level of the ER to ensure the proper biogenesis of integral membrane and secreted proteins (Fig. 16.3). As such, their client proteins include up to one-third of the cellular proteome. GII is an ER luminal enzyme involved in glucose trimming of N-glycan moieties in the calnexincalreticulin cycle. GII activity is necessary for proper folding and quality control of proteins passing through the ER translocon.²⁰⁰

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