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Review Article
33 (
2
); 83-92
doi:
10.4103/ijn.ijn_318_21

Cystic Diseases of the Kidneys: From Bench to Bedside

Department of Pediatric Nephrology, Akron Children’s Hospital, Akron, Ohio, USA
Department of Nephrology, Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, USA
College of Medicine, Northeast Ohio Medical University, Rootstown, USA
Department of Nephrology, Akron Children’s Hospital, Akron, USA
Faculty of Science, McMaster University, Hamilton, ON, Canada
College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, USA
Kidney and Renal Transplant Institute, Medanta, The Medicity Hospital, Gurugram, Haryana, India
Both are co-first authors
Address for correspondence: Dr. Rupesh Raina, Department of Nephrology, Cleveland Clinic Akron General and Akron Children’s Hospital, Akron, Ohio, Faculty Staff at Case Western Reserve University, School of Medicine Cleveland Ohio, USA. E-mail: rraina@akronchildrens.org
Licence
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Disclaimer:
This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet–Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel–Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.

Keywords

Bardet–Biedl syndrome
ciliopathy
genetic counseling
Joubert syndrome
kidney disease
nephronophthisis
polycystic kidney disease
renal cystic disease
tuberous sclerosis
Von Hippel–Lindau
Zellweger spectrum disorders

Introduction

Renal cystic disease encompasses a wide range of hereditary, non-hereditary, and acquired pathologies that demand a multidisciplinary approach to treatment. This may accompany extrarenal abnormalities or be a part of a well-defined syndrome. In 1964, Potter and Osathanondh pioneered a classification system based on microdissections of cystic kidneys, and hypothesized the mechanisms of cyst formation by localizing the cysts to specific segments of the nephrons.[1] Newly elucidated genetic and pathophysiologic concepts further refined the classification in 1969.[2] Ongoing research continue to clarify clinicopathologic correlations in the more recent classifications [Table 1].[3]

Table 1 Classification of cystic kidney diseases[1,3-10]
Classification of Cystic Kidney Diseases
Genetic
 Ciliopathy associated Autosomal dominant polycystic kidney disease (ADPKD)
Autosomal recessive polycystic kidney disease (ARPKD)
Nephronophthisis-related isolated syndrome
 Bardet–Biedl syndrome
 Joubert syndrome
 Meckel–Gruber syndrome
Phakomatoses associated Tuberous sclerosis
Von Hippel–Lindau syndrome
Cystic Dysplasia associated Multicystic dysplastic kidney (MCDK)
Posterior urethral valve (PUV) Reflux nephropathy
Hypodysplastic kidneys
Autosomal dominant tubulointerstitial kidney disease (ADTKD) ADTKD-uromodulin kidney disease (ADTKD-UMOD)
ADTKD-renin mutation (ADTKD-REN)
ADTKD-mucin-1 mutation (ADTKD-MUC1)
Hepatocyte nuclear factor-1beta (HNF1β)–associated kidney disease
Miscellaneous Acquired cystic kidney disease
Glycogen storage disease
Leukemia or lymphoma
Nephroblastomatosis
Pyelonephritis

Cysts form in the kidney through a myriad of unspecified mechanisms where the consensus considers cysts secondary to obstructive, degenerative, or neoplastic mechanisms. Recent data provides compelling evidence that inherited cystic disease is linked to alterations in different genes involved in the formation and function of both the cilia of the embryonic node and cilia in epithelial renal tubes.[4] Inherited causes that result in the cystic kidney disease phenotype as well as ciliopathy-associated (related to the structure/function of the primary cilia complex) cystic kidney diseases will be further examined.

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.

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
Table 2 Pathophysiologic and imaging characteristics of renal cystic diseases[18,1032]
Pathophysiologic and Imaging Characteristics of Renal Cystic Diseases
Disease type Pathophysiologic Characteristics Image Findings
Acquired cystic kidney disease Hyperplasia of tubular epithelium due to↑mitogenic growth factors and activation of proto-oncogenes with↑fluid secretion Bilateral small kidneys with multiple cysts, ↑risk of intracystic hemorrhage, and development of renal cell carcinomas
Medullary sponge kidney Disruption of the embryonic interface between the developing ureteral bud and the metanephric blastema during embryogenesis Medullary nephrocalcinosis and cysts, paint-like appearance at urography, multiple renal calculi
Multicystic dysplastic kidney Abnormal metanephric-mesenchymal differentiation in the setting of urinary tract obstruction during embryogenesis Non-reniform, non-functional kidney with multiple peripheral cysts and central solid components
Localized renal cystic disease Acquired maldevelopmental origin is hypothesized Conglomerate mass of multiple simple cysts of various sizes, separated by enhancing or atrophic renal tissue without definite capsule
Autosomal dominant polycystic kidney disease Dysregulation function of renal cilium with↑proliferation of renal tubular epithelium and↑fluid secretion Bilateral enlarged kidneys with multiple expansile cysts
Autosomal Recessive polycystic kidney disease Altered molecular and cellular pathways causing abnormal cellular proliferation, fluid secretion and alterations in extracellular matrix. Bilaterally enlarged echogenic kidneys.
Hepatocyte nuclear factor -1beta–associated kidney disease HNF1β mutations leads to abnormal nephron development and affects many genes involved in the pathogenesis of renal cystic disease Hyperechogenic kidneys with normal or slightly enhanced size
Medullary cystic kidney disease Ciliary dysfunction postulated to be secondary to altered interaction of MCKD1 or MCKD2 protein with nephrocystin Multiple cysts at the corticomedullary junction and in medulla
Von Hippel–Lindau disease Upregulation of HIF with resultant↑in downstream effectors. Dysregulation of ciliary assembly and mechanosensory function of renal cilium Multiple, variably sized cysts in kidneys; multiple interspersed cystic solid renal cell carcinomas
Tuberous sclerosis complex Uncontrolled activation of mTOR and downstream effectors. Defects in ciliary function and epithelial cells polarity. Multiple bilateral renal cysts intermixed with multiple angiomyolipomas

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.

Table 3 Causes of hepatorenal fibrocystic diseases [18,1033]
Fibrocystic Disease Gene and Protein Renal Impairment Hepatic Association Extra-hepatorenal Implications
Autosomal dominant polycystic kidney disease PKD (Polycystin-1)PKD2 (Polycystin-2) Cysts over whole nephron Nodular hepatomegaly, hepatic cysts, pancreatic cysts Hypertension, retinal dysplasia, aneurysm
Autosomal recessive polycystic kidney disease PKHD1 (Fibrocystin) Cysts towards collecting ducts Congenital hepatic fibrosis, portal hypertension Hypoplastic lung, splenomegaly, hypersplenism, cholangitis
Bardet–Biedl syndrome BBS1-21 (BBSome) Structural impairment, cyst formation, urinary tract malformation Non-alcoholic steatohepatitis Retinal dystrophy, obesity, polydactyly, hypogonadism, mental retardation
Joubert syndrome AHI1, CPLANE1, CC2D2A, CEP290, CSPP1, INPP5E, KIAA0586, MKS1, NPHP1, RPGRIP1L, TCTN2, TMEM67, TMEM216 Cystic dysplasia Congenital hepatic fibrosis Muscle control (ataxia), coloboma, polydactyly, encephalocele
Zellweger syndrome PEX1 (Pex1p) Cortical microcysts Fibrosis, cirrhosis, hepatomegaly Craniofacial abnormality, hypomyelination, chondrodysplasia
Von Hippel–Lindau VHL (pVHL) Clear cell RCC Tumor PNET, pancreatic cysts, pheochromocytoma, hemangioblastoma, ovarian cysts
Jeune syndrome Several implicated genes Cystic dysplasia Fibrosis Skeletal dysplasia (small thorax), pancreatic cysts, retinal abnormality
Nephronophthisis NPHP1–18 Hyperechogenic kidneys, reduced size, and corticomedullar cysts Congenital hepatic fibrosis Tapetoretinal degeneration, ocular motor apraxia, and cone-shaped epiphysis

Abbreviations: AML, angiomyolipoma; PNET, pancreatic neuroendocrine tumors; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma

Polycystic kidney diseases

Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD, OMIM: 618061) is the most common hereditary kidney disease worldwide, characterized by bilateral kidney enlargement with numerous cysts and a variable rate of chronic kidney disease (CKD) progression. Common comorbidities include hypertension, nephrolithiasis, urinary tract infections (UTIs), and extrarenal complications.[8] Since the approval of tolvaptan, the first treatment for patients with high risk of progressive ADPKD, emphasis on risk assessment of ADPKD progression has become clinically significant.[34,35]

In clinically ascertained samples, mutations in PKD1 and PKD2 are responsible for 60%–78% and 15%–26% of ADPKD, respectively (A8, A9). Additionally, about 10%–15% of patients with apparent ADPKD have no identifiable PKD1 or PKD2 mutation; however, whole-exome sequencing studies have identified additional genes (i.e., GANAB, DNAJB11) mutated in a small proportion of patients (<1%).[9,36] Both genic and allelic heterogeneity contribute to phenotype severity in ADPKD. Mutations in PKD1 lead to a more severe phenotype with larger kidneys, earlier onset of end-stage renal disease (ESRD), hemorrhage into cysts, and gross hematuria when compared to mutations in PKD2. Protein-truncating mutations caused by nonsense, frameshift, or canonical splice-site mutations, lead to a more severe disease than non-truncating mutation (i.e., in-frame insertion and deletions (indels), missense mutations, and atypical splicing mutations).[37]

The study of intrafamilial kidney disease discordance provides an opportunity to delineate genetic and environmental modifiers impacting the predictability of kidney disease progression in ADPKD. One potential explanation for intrafamilial disease discordance is compound heterozygosity or digenic inheritance of an additional mutation in a cystogenic gene, including PKD1 and PKD2.[38] Mosaicism, in which two populations of cells with different genotypes exist in the same person, can lead to intrafamilial kidney disease discordance.[39] While mosaicism can lead to intrafamilial kidney disease discordance, its prevalence in ADPKD remains poorly defined.[40]

Mutations in additional disease modifiers, including COL4A1 and HNF1B have been described and could create intrafamilial variations under heterozygous conditions.[41] Genetic variants may modify the kidney disease severity of ADPKD, exemplified by DKK3, and a polygenic component with numerous genetic variants causing accumulation of small microaggressions contributing to disease progression.[42] Comorbidities including obesity, diabetes, vascular disease, acute kidney injury, and environmental factors such as cigarette smoking, diet, and water intake could also contribute to intrafamilial kidney disease discordance in ADPKD.[43,44]

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).

Table 4 Primary NPHP genetic mutations[27]
Gene Locus Protein Location Function Disorder
NPHPI 2q12.3 Nephrocystin-l Adherens, focal adhesion, transition zone Cellular scaffolding and cell-cell adhesion/signalling NPHP, SLSN, JBTS
NPHP2/lNVS 9q21-22 Inversin Inversin compartment Wnt pathway for cell polarity iNPHP, SLSN, Situs Inversus, cHeart Defects
NPHP3 3q22.1 Nephrocystin-3 Inversin compartment, axoneme Wnt inhibitor NPHP, RP, Situs inversus, MKS, SLSN
NPHP4 Ip36.31 Nephrocystin-4 Transition Zone Wnt inhibitor, Hippo pathway jNPHP, RP, OMA, SLSN
NPHP5/lQCB1 3q13.33 Nephrocystin5/1Q Motif Bl Transition Zone, centrosome RPGR Complex jNPHP, RP, LCA
NPHP6/CEP290 12q21.32 Nephrocystin6/CEP 290 Transition Zone, centrosome ATF4/CREB 2 regulation, cAMPdependent cyst, DDR NPHP, RP, LCA, JBTA, MKS
NPHP7/GLlS2 16p13.3 Nephrocystin7/GLl S-2 Nucleus Hh Regulation NPHP
NPHP8/RPGRlPIL 16q12.2 Nephrocystin9/RPGRlP1-like Transition Zone Shh Signalling jNPHP, JBTS, MKS, RP, LCA, COACH
NPHP9/NEK8 17q11.1 Nephrocystin9/NlMA-related kinase 8 Basal Body DDR Signaling jNPHP, RP, SLSN, BBS
NPHPI0/SDC CAG8 Iq43q44 Nephrocystin10/Serologically defined colon cancer antigen Transition Zone Cellular structure and centrosome migration NPHP, JBTS, MKS, COACH

NPHP, Nephronophthisis; INVS, Inversin; SLSN, Senior Loken Syndrome; JBTS, Joubert Syndrome; cHeart Defects, congenital heart defects; RP, retinitis pigmentosa; MKS, Meckel Gruber Syndrome; jNPNP, Juvenile Nephronophthisis; OMA, oculomotor apraxia; LCA, Leber’s congenital amaurosis; COACH, COACH syndrome

Bardet–Biedl Syndrome

Bardet–Biedl syndrome (BBS; MIM 209900) is a genetic disorder characterized by defects in multiple organ systems, and the estimated prevalence ranges from 1 in 160,000 in northern European populations to as high as 1 in 13,500 in Kuwait and Newfoundland.[26,52,53] BBS is a disorder of locus and allelic heterogeneity. It is typically inherited in an autosomal recessive fashion, under which model mutations in 14 loci (BBS1–12, MKS1, centrosomal protein 290 kDa/nephronophthisis 6 [CEP290/NPHP6]) have been identified.[54,55]

Joubert syndrome

Joubert syndrome (JS) and disorders (JSRD, OMIM: 213300) are a genetically heterogenous group of congenital disorders that affect brain development and other organs such as the eye, kidney, or lungs.[56] Other names referring to Joubert syndrome in the past include COACH syndrome, cerebellar ocular renal syndrome, and Cogan type oculomotor apraxia. The latter being characterized by impairment of voluntary horizontal eye movements. Multi-organ symptoms manifest as retinal dystrophy, NPHP, and retinal cystic dysplasia with renal involvement are accounted for in 25%-30% of patients with JSRD. Incidence rates of JSRD range between 1 in 80,000–100,000 in neonatal populations; however, these rates tend to range at the lower estimate of the confidence interval (CI) due to the continual discovery of more causative genes.[56] JSRD was first described in isolated groups with high rates of consanguinity, including French–Canadian, Arab, and Ashkenazi Jewish populations. The genetic causes of cerebellar-ocular-renal syndrome can be largely attributed to mutations in JBTS5, caused by mutation in the CEP290 gene, also called NPHP6, on chromosome 12q21; JBTS3, caused by mutation in the AHI1 gene on chromosome 6q23; JBTS6 caused by mutation in the TMEM67 gene on chromosome 8q21; JBTS4 caused by mutation in the NPHP1 gene on chromosome 2q13.[27,57,58]

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.[3032,76]

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.

Conclusion

In conclusion, ciliopathies are an emerging conceptual framework to tie in the clinically relevant renal cystic diseases with the emerging cellular research into ciliopathies. By combining animal models (particularly mouse) with clinically oriented research, new insights can further the molecular basis of understanding the cystic kidney diseases and provide a novel understanding into the role of cilia in pathologic manifestations. The quintessential example is the creation of double knockout mice lacking Pkd genes and Kif3a or Ift20, which reduced the burden of polycystic kidney disease.

Financial support and sponsorship

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.

Acknowledgements

We would like to thank Dr Shweta Deshpande for creating and refining the tables for this review.

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Supplement A

Supplement A: Genes associated with cystic kidney diseases[10]
Cystic diseases Associated Gene (s)
ADPKD GANAB
PKD1
PKD2
MUC1
UMOD
Alport syndrome COL4A3
COL4A4
COL4A5
ARPKD PKHD1
Branchio-oto-renal dysplasia syndrome EYA1
Cilia-associated cystic genes CYS1
DYNC2H1
IFT140
IFT172
IFT80
WDR34
WDR35
WDR60
Cilia-associated cystic genes, phenotype resembling ADPKD IFT88
ER candidate gene (polycystic liver) ATF6B
ATXN3
CAPN2
EDEM3
HSP90AA1
HSPA6
HYOU1
NGLY1
PARK2
SEC24B
SEC24C
SEC24D
SEC31A
SEC31B
SEC61A1
SEC61A2
SEC62
TXNDC5
UBE4B
UGGT1
UGGT2
WFS1
Familial hyperproteinemia, high blood pressure REN
Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps COL4A1
Joubert syndrome INPP5E
KIAA0586
AHI1
ARL13B
C5ORF42
CC2D2A
CEP120
CSPP1
TCTN2
TMEM216
Joubert syndrome/MKS MKS1
RPGRIP1L
Karyomegalic interstitial nephritis FAN1
Neonatal diabetes, hypothyroid, and cystic kidney disease GLIS3
NPHP CEP164
GLIS2
INVS
IQCB1
NEK8
NPHP3
NPHP4
SDCCAG8
TTC21B
WDR19
NPHP/Joubert syndrome/MKS TMEM67
NPHP/MKS CEP290
OFD OFD1
Optic nerve coloboma, renal hypoplasia PAX2
Polycystic kidney and liver diseases XBP1
Polycystic kidney disease AVP
AVPR2
NEK1
Polycystic kidney disease with hyperinsulinemic, hypoglycemia PMM2
Polycystic liver disease ALG8
LRP5
PRKCSH
SEC61B
SEC63
Renal cysts and diabetes syndrome HNF1B
Tuberous sclerosis complex TSC1
TSC2
Von Hippel-Lindau syndrome VHL
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