Cystic Diseases of the Kidneys: From Bench to Bedside

Role of cilia in cystic kidney disease

The primary cilium is a ubiquitous organelle involved in chemosensation, signal transduction, and cell growth. Primary cilia are arranged in a 9+0 axoneme (versus 9+2 axoneme in motile cilia) which warp orientation in reaction to fluid flow. Research on cilia conducted through the ORPK mouse (model system with intraflagellar transport (IFT) protein localized in the cilia) demonstrated an association between shortened/absent cilia and autosomal recessive polycystic kidney disease (ARPKD).[11,12] In the kidneys, the cilium’s unique position as a projection into the lumen of the duct from epithelial cells allows for its principal function to sense the locale and provide control over proliferation and differentiation. The signaling process is still poorly understood; however, proposed models suggest an interaction between luminal flow and paracrine signaling.[13] Kidney function depends on flow through nephrons, this flow is sensed by the primary cilia of the nephrons and deflected by the fluid passing to increase intracellular calcium. Normally, this increase causes regulation of a calcium-dependent channel. However, disruption of cilia formation is proposed to result in both defects in the channel and ultimately, polycystic kidney disease (PKD). Similar mechanistic disruptions occur on extrarenal systems: pulmonary hypoplasia or bronchiectasis, hypogonadism, intellectual disability, congenital heart defects, skeletal malformations and visual disturbances are all associated with ciliopathies.[1,2,12,13]

Genes involved in cystic kidney diseases have been shown to encode proteins involved in cilia formation/function [Figure 1].[5,14,15] Models using non-biased forward genetic screening for cystic kidney mutations in non-human models found defects in cilia associated with abnormal cytogenesis [Supplement A].[6,7] Mutations in the hi409, hi221, and hi3417 genes disrupt the creation of portions of the IFT particle required for cilia formation.[16] In conclusion, the overarching cause of PKD involves mutations in ciliary genes, and specific gene targets are possible options for therapy in human diseases involving kidney cyst formation. A summary of pathophysiologic and imaging characteristics used to confirm the diagnosis of cystic kidney diseases is summarized in Table 2.

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Figure 1

Representation of the ciliary structure and associated renal cystic proteasome. Each associated pathology shows overlap as the depicted protein products are all involved in the homeostatic function of the cilium. Abbreviations: BBS, Bardet–Biedl syndrome; NPHP, Nephronophthisis; OFD1, Oral-facial-digital syndrome 1; PC, Polycystin; PC1/PC3, Prohormone convertase ½

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The signaling pathway connecting cilia to cell proliferation is largely unknown; polycystin-1 and polycystin-2 have been implicated in numerous pathways including JAK-STAT, Wnt, β-catenin, protein kinase C, cAMP, G-protein, and Ca²⁺ signaling pathways.[17] IFT genes have been implicated in hedgehog signaling, and the lack of cilia is reported to activate β-catenin signaling.[18] Analyzing mutant phenotypes suggests that cilia link extracellular signals to intracellular events such as cell proliferation. Further research will be paramount in dissecting the signaling network of cilia’s role in coordinated cellular responses.

Hepatorenal fibrocystic disease

Hepatorenal fibrocystic diseases are monogenic disorders characterized by fibrocystic abnormalities of the kidney and dysgenesis of the portobiliary tract. Clinical presentation is variable and includes oligohydramnios, enlarged kidneys, hypertension, and Potter sequence.

Development of hepatic bile ducts starts at gestational age (GA) six to eight weeks, initiating from the contact of primitive epithelial cells with portal vein mesenchyme.[19,20] A ductal plate begins differentiation from unknown developmental signals around GA 13–17 weeks where any interruption can lead to malformation. Dysregulated proliferation leads to dilated ductule and the initial hepatic lesions, subsequent liver damage, and inflammation can cause fibrosis and cirrhosis. This pattern is seen in a variety of fibrocystic syndromes including Meckel–Gruber syndrome (MKS), Renal–Hepatic–Pancreatic Dysplasia or Ivemark’s syndrome (RHPD), and Jeune Syndrome (JATD1–5).[21]

Meckel–Gruber syndrome (MKS) is a rare congenital and lethal autosomal recessive condition characterized by the triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. MKS has variable expressivity and allelism similar to other ciliopathies such as Joubert syndrome, which attributes to its rare diagnosis.[22] Asphyxiating thoracic dystrophy, or Jeune syndrome, is one of several ciliopathies associated with skeletal disorders. In addition to changes in the hedgehog signaling pathway, genes associated with “skeletal ciliopathies” continue to be discovered, but the conditions can have mutations in the dynein motor (e.g., DYNC2H1), intraflagellar transport complexes (e.g., IFT80), and the basal body (e.g., NEK1).[22] A more comprehensive list of causes for hepatorenal fibrocystic diseases can be found in Table 3.

Polycystic kidney diseases

Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is another hereditary cause of CKD, with an estimated incidence of 1 in 20,000 live births.[23] Neonates typically present with history of oligohydramnios, enlarged kidneys, respiratory insufficiency secondary to pulmonary hypoplasia, and perinatal death in approximately 30% of affected newborns.

ARPKD is caused by mutations in PKHD1, a large ~500-kb gene with a complex splicing pattern located on chromosome 6p21.1-p12.[45] The product of PKHD1, fibrocystin/polyductin (FPC), is a single membrane spanning protein with multiple isoforms expressed predominantly in the kidneys (collecting ducts and thick ascending loops of Henle), liver (in bile duct epithelia), and pancreas.[46] In renal tubular and biliary epithelial cells, FPC localizes to apical membranes, which are the primary cilia/basal body.[47] The function of FPC remains unclear, yet the role for the primary cilium in renal tubular architecture has led aforementioned disorders to be categorized as ciliopathies. Through its interactions with the ADPKD protein polycystin-2, FPC forms a common signaling pathway with polycystin-1.[48]

Numerous groups have attempted to categorize sequence variations based on the likelihood of pathogenicity, many of which are catalogued in the ARPKD mutation database.[49,50] However, because many patients have novel PKHD1 variants, interpretation of genetic testing results can be challenging. Genetic modifiers likely play a significant role in disease expression as illustrated by significant phenotypic variability in family subsets; for example, in a study of 126 unrelated families, 20 siblings showed widely discordant phenotypes (perinatal death in one sibling and survival into childhood in the other).[24]

Nephronophthisis

Nephronophthisis (NPHP) is an autosomal recessive kidney disease, typically causing ESRD within the first three decades of life.[51] Traditionally diagnosed clinically through onset of insidious chronic renal failure (CRF) followed by histological confirmation, advancements in molecular diagnostics have provided insight into the underlying mechanisms of NPHP.[22] NPHP genes encode proteins expressed ubiquitously in centrosomes and primary cilia. NPHP is, therefore, considered to be a ciliopathy, consistent with the fact that extrarenal manifestations occur in around 20% of cases. Reviewing clinical and histological features of the disease highlights the multiple ciliopathic syndromes associated with NPHP.[22]

With more than 25 mutated genes now affiliated with NPHP, reviewing genetic causes provides mechanistic insights into the pathogenesis of NPHP.[22] A number of these genetic mutations appear to be associated with the centrosome/basal body/primary cilium [Table 4]. Two studies, one which identified nine NPHP genes, and another identifying 25 genes, found similar prevalence of mutations in NPHP1, a large homozygous deletion, accounting for ~20% of NPHP.[22,25,27] The remaining known mutations accounted for approximately 1% of all NPHP cases which suggest that up to two-thirds of cases remain unsolved.[25] Genotypic mutations in NPHP may lead to a wide spectrum of phenotypes including isolated NPHP, NPHP with additional features (Senior–Løken syndrome and Joubert syndrome), and lethal neonatal forms (Meckel–Gruber syndrome).

Autosomal dominant tubulointerstitial kidney disease

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) contains a group of diseases that affect tubules of the kidney and can lead to CKD. Uniquely, this disease is associated with elevated uric acid concentrations in the blood, leading to gout in as early as teenage years for several of its associated subtypes.[59] These types include uromodulin kidney disease (ADTKD-UMOD), renin mutation (ADTKD-REN), or mucin-1 mutation (ADTKD-MUC1) subtype. The UMOD subtype has a mutation in uromodulin, also called Tamm–Horsfall protein, which is a protein made in the kidney that is associated with gout when elevated.[59] The subtype with mucin-1 mutations differs from both the UMOD and REN subtypes because it is the only type to not be associated with increased risk of gout, but rather an insidious, gradually progressive kidney disease that presents in the sixth decade of life.[59]

Hepatocyte nuclear factor-1beta–associated kidney disease

Hepatocyte nuclear factor-1beta (HNF1β)–associated kidney disease is a newly recognized disease with multisystem phenotypical expression and renal cysts as a common presentation. It is closely associated with maturity onset diabetes of the young. Decline in renal function along with renal cysts prior to the onset of diabetes is often noticed. HNF1β transcription factor is involved in the development of ureteric bud giving ureter, renal pelvis, collecting ducts and mesenchyme, pancreas, liver and brain. Any mutation can lead to a wide variety of phenotypical expressions and developmental renal abnormalities, such as renal cysts preceding diabetes, hyperechogenic kidneys with slightly enhanced or normal kidney size on ultrasound, hypoplastic glomerulocystic kidney disease, hyperuricemia or hypomagnesemia.

Ciliopathy-associated cystic kidney diseases

Tuberous Sclerosis: Tuberous sclerosis complex (TSC, OMIM: 19100) is a multisystemic neurocutaneous condition with autosomal dominant inheritance, characterized by renal cysts, hamartomas across multiple organs, skin, central nervous system, heart, lungs, and kidney.[54] The condition affects 1 in 6,000–10,000 individuals and can affect both sexes and all ethnic groups equally.[55] TSC occurs due to the deletion, rearrangement, or inactivation mutations of tumor suppressor genes, TSC1 or TSC2, leading to abnormal proteins hamartin and tuberin, codified in the loci 9p34 and 16p13, respectively.[29,60,61,62-68] In countries where genetic analysis is scarce, establishing TSC remains a clinical diagnosis.[69] Renal manifestations include angiomyolipoma (AML), hemorrhage, CKD, anemia, and hypertension often diagnosed through radiological findings (MRI, CT, Ultrasound) or needle biopsy if without definitive imaging.[70,71]

Zellweger Syndrome: The Zellweger spectrum disorders (ZSDs) are a heterogeneous group of autosomal recessive disorders characterized by a defect in peroxisome formation and are caused by mutations in one of 13 PEX genes.[29,60] Defects in peroxisome formation are associated with ZSD patients accumulating very long chain fatty acids (VLCFAs), phytanic- and pristanic acid, C27-bile acid intermediates and pipecolic acid in plasma, and deficiency of plasmalogens in erythrocytes.[61,69,62-68] Clinically, ZSDs are highly heterogeneous, but the core features are liver and adrenocortical dysfunction, developmental delay, hearing and vision impairment, and other neurological abnormalities.

Von Hippel–Lindau: Von Hippel–Lindau (VHL) disease (MIM #193300) occurs as the result of germline mutations in the VHL tumor suppressor gene, located on chromosome 3p25–26.[70] Patients with VHL disease are at risk of developing visceral cysts and tumors throughout the body including simple cysts, hemangioblastomas (HBs) of the retina and central nervous system, clear cell renal cell carcinomas (RCCs), pheochromocytomas, pancreatic neuroendocrine tumors (PNETs), pancreatic serous cystadenomas, and endolymphatic sac tumors (ELSTs).[71,72] VHL gene is composed of three exons coding for two isoforms of the protein pVH, which form part of a multiprotein complex including elongin B, elongin C, and Cullin 2 (CUL2) responsible for ubiquitination and degradation of the a subunits of hypoxia-inducible factors (HIFs) 1 and 2.[73] VHL is almost completely penetrative: Most individuals with mutations in VHL tumor suppressor gene have VHL disease–related symptoms by the age of 65.[74] The estimated incidence of sporadic mutations in VHL disease is 1 in 36,000 live births with no known parental age affect.

Genetic counseling

Prenatal and pre-implantation genetic testing plans should be highly considered for families with high-risk pregnancies that are predisposed to pathogenic gene mutations for cystic diseases.[75,76] The families should be referred to a genetic counselor who will review family history and clinical findings to provide pre-implantation, prenatal, and postnatal genetic testing options. Genetic testing may involve the use of targeted next-generation sequencing (NGS); however, the specific testing options provided may vary based on the history of ciliopathy present, renal findings, and other inconsistencies present.

For autosomal dominant ciliopathies (ADPKD, HNF1B, BORSD, VHL), assuming one parent has the proband, all offspring have a 50% chance of inheriting the pathogenic gene mutation, increasing to 75% if both parents are afflicted. Assessing parental predisposition can be done on a macroscale with MRI or CT scan (ADPKD) or microscale with genetic testing of both parents for the proband.[30] However, these tests are imperfect as parents may have mosaicism of the gene or a proband may form from de novo mutations in utero, both resulting in minimal positive pretest probability.

In contrast, in autosomal recessive ciliopathies (isolated/syndromic nephronophthisis, ARPKD, BBS, Zellweger), both parents are carriers of the gene mutation or one carrier parent and one afflicted parent. Siblings of the proband have a 25% chance of inheriting both genotypes resulting in pathology, 50% chance of becoming a carrier, and a 25% chance of not being a carrier. Siblings of the proband’s parents are at 50% risk of being carriers of the pathogenic gene mutation. For high-risk pregnancies (>25% chance of autosomal recessive ciliopathy), if mutant genes have been identified in the family member, prenatal testing is available.[76] For low-risk pregnancies (no family history of ARPKD, but enlarged cystic kidneys on prenatal ultrasound), there are multiple testing options including karyotyping or array with fetal ultrasonography, molecular genetic testing, and renal ultrasound (ARPKD) of both parents assessing predisposition. De novo mutations in the proband can also affect success of risk assessment with genetic testing.[32]

As many ciliopathies are rare and not completely understood, simple Mendelian inheritance patterns cannot always be attributed to the transmittance of these pathologies; rather, oligogenic inheritance plays a role. For example, MKS has both variable expressivity and allelism similar to other ciliopathies such as Joubert syndrome. In addition to making the distinction when diagnosing these pathologies difficult, the overlapping allelism leaves the possibility of effect modifiers to play a role in each disease’s manifestation. Similarly, NPHP is still not entirely understood despite the number of identified mutations having grown from 9 to 25 in just a couple of years. Thus, despite NPHP being considered an autosomal recessive disease, this disease along with other ciliopathies may have additional interactions which play a role in the resulting genotypic heterogeneity. With the varying severity of clinical presentations resulting from mutations of different subtypes in the CEP290 gene ranging from isolated nephronophthisis to the lethal MKS phenotype, more research is needed to further understand how different factors play a role in the development of these pathologies.[30–32,76]

Currently, the decision of who should receive and the type of testing is controversial in current guidelines. This is complicated by the fact that there are more than 100 genes associated with cystic kidney diseases, as listed by Park et al. [Supplement A].[10] Thus, the decision should be made by the family members after the genetic counselor has extensively discussed the possible cons and benefits of genetic testing.

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The authors received no financial support for the research, authorship, and/or publication of this article.

Conflicts of interest

The authors declare that there is no conflicts of interest.