The non-motile primary cilium, a specialized organelle found in nucleated mammalian cells, plays an important role in human biology due to its pleiotropic effects. This microtubule-based structure, projecting from the apical cell surface, has diverse functions as a signaling hub to direct intracellular physiologic responses to the external environment, promote cellular proliferation and differentiation, and determine cell polarity. Though only 20 years have passed since the relationship between dysfunctional cilia and cystic kidneys in mammals was first described, research has identified hundreds of cilia-associated genes and provided a better understanding of how the proteins they encode, as part of the primary ciliary apparatus, leads to human disease.

It is not surprising that disrupted function of such a ubiquitous and evolutionarily conserved organelle can have myriad clinical manifestations affecting one or more organ systems; as a group, there are currently more than specific 35 genetic ciliopathies identified in humans, many in which kidney involvement can significantly influence overall patient prognosis. This is particularly relevant for pediatric nephrologists, who encounter a wide range of cilia-associated kidney disease and must provide appropriate anticipatory guidance to patients and families. As a group, the renal ciliopathies are an important cause of kidney disease in the pediatric population.

In a recent review published in AJKD, McConnachie et al provide a succinct review of the normal biology of primary cilia and their constituent proteins, and describe the pathophysiology and clinical manifestations of several hereditary kidney diseases known to have a genetic basis in this important organelle. Children with renal ciliopathies collectively make up 5-9% of the pediatric CKD population and up to 12% of the pediatric ESKD population. With the exception of autosomal dominant polycystic kidney disease (ADPKD), the majority of renal ciliopathies presenting during childhood have an autosomal recessive inheritance pattern. Several of these conditions have concurrent hepatobiliary disease due to dysfunction of primary cilia extending from cholangiocytes into the bile duct lumen. Liver involvement may present any time from birth into adulthood, stemming from biliary dysgenesis, and may manifest as recurrent episodes of bacterial cholangitis, portal hypertension, splenomegaly, and/or hypersplenism.

The key structural components of the primary cilium based around the central axoneme. This nonmotile cilium has 9 outer microtubule doublets but no central doublet. Ciliary components, receptors, and signaling proteins are trafficked in anterograde and retrograde directions on the axoneme by intraflagellar transport (IFT) complexes, IFTA and IFTB, which engage dynein II and kinesins (blue box), respectively. The BBSome complex assists traffic at the base of the cilium and then cooperates with IFTs. The cilium grows out of the mother centriole within the basal body and the base of the cilium is segregated from the cytoplasm by the transition zone, defined by the presence of Y-linkers. The primary cilium is erected in quiescent cells and disassembled before cell division. Abbreviation: KIF, Kinesion family members. Created with BioRender.com. Figure 1 from McConnachie et al, AJKD © The Authors

One of the more challenging clinical scenarios for the pediatric nephrologist is that of the severe, prenatal presentation of a renal ciliopathy. This commonly presents prenatally with enlarged, echogenic kidneys with diminished corticomedullary differentiation and a variable degree of oligohydramnios. Smaller discrete cysts may be present bilaterally, but macrocysts (> 10 mm) are rare. As the pregnancy continues beyond the first trimester, when amniotic fluid production is most dependent on fetal urine, the severity of oligohydramnios becomes more apparent. In the most severe cases, Potter sequence can develop from a lack of amniotic fluid and lead to pulmonary hypoplasia, typical Potter facies (flattened nose, recessed chin, posteriorly rotated and flattened ears), and limb deformities as a result of fetal compression (e.g. talipes equinovarus, hip dislocation). The overwhelming majority of these cases is caused by autosomal recessive polycystic kidney disease (ARPKD), from biallelic recessive PKHD1 mutations; however in rare situations dominant or recessive mutations in PKD1, PKD2, and other ciliary genes can produce phenocopies with an ARPKD-like presentation.

Counseling expectant families in this situation is a collaborative effort by the pediatric nephrologist, maternal-fetal medicine specialist, and neonatologist. Genetic counseling should be pursued, including completing a three-generation family pedigree and considering renal ultrasound of the parents to screen for asymptomatic, autosomal dominant ciliopathies such as ADPKD and HNF1b–related kidney disease. Following serial fetal ultrasonography to monitor kidney size and amniotic fluid volumes is important, as postnatal survival with a prenatal diagnosis of a renal ciliopathy is largely dependent on the degree of pulmonary hypoplasia. In the case of ARPKD specifically, a 30-40% mortality rate in the neonatal period has been reported; however recent data show the 1- and 5-year survival rates for those infants who make it through this critical period exceeds 85%. Postnatal management should be discussed in detail with families, including preferences for aggressiveness of neonatal resuscitation, medical management, and respiratory support. A joint decision between the parents and care providers should be made ahead of delivery on whether dialysis will be offered.

Unlike children who first present with renal ciliopathies in the perinatal period, infants and older children have improved survival with renal replacement therapy once end-stage kidney disease (ESKD) is reached. Prognosis after kidney transplantation is excellent due to a lack of disease recurrence. However, children with hepatobiliary involvement or who have a genetic syndrome associated with diffuse ciliary dysfunction may have a higher risk of morbidity and mortality independent of their kidney disease. For example, about 40% of children with ARPKD have severe kidney and hepatobiliary disease, the latter leading to complications such as bacterial ascending cholangitis, portal hypertension, esophageal or gastric varices, hypersplenism, and gastrointestinal bleeding events. Similar liver involvement can be seen with other renal ciliopathies. Children with nephronophthisis may have isolated kidney disease, which is commonly insidious in onset but in nearly all cases progresses to ESKD by late adolescence. However, mutations in nephronophthisis-related genes are associated with extrarenal disease in 10-20% of children, which may be diagnosed even before kidney involvement becomes apparent.

For the pediatric nephrologist, the renal ciliopathies have a wide phenotypic spectrum that present unique diagnostic and management challenges. In addition to the inherent challenges of genotype-phenotype correlation with these disorders and morbidity and mortality risk from CKD and ESKD, quality of life and survival also depend upon age of presentation and coexisting extra-renal disease. While we have a better understanding of disease mechanisms related to abnormal ciliary protein function, treatment of children with renal ciliopathies remains limited to conservative treatment strategies to slow CKD progression and mitigate its complications. Further research is needed to develop specific therapies that address these disorders, as well as study therapies already being used in adult patients (e.g. vasopressin antagonists in ADPKD) to determine their safety and efficacy in childhood-onset disease.

– Post prepared by Brian Stotter, AJKDBlog Guest Contributor. Follow him @StotterMD.

To view McConnachie et al (Open Access), please visit AJKD.org.

Title: Ciliopathies and the Kidney: A Review
Authors: Dominique J. McConnachie, Jennifer L. Stow, and Andrew J. Mallett
DOI: 10.1053/j.ajkd.2020.08.012

Review articles cover clinical, translational, or basic science topics of interest to practitioners. Reviews published in the last two years are freely available.