Here we describe the current knowledge about the ciliary kinase NEK8, highlighting what we know and what we don't know about its regulation, substrates and potential functions. We also review the literature about the pathological consequences of different NEK8 variants in patients of nephronophthisis, renal-hepatic-pancreatic dysplasia and autosomal dominant polycystic kidney disease, three different types of ciliopathies. NEK8 belongs to the NIMA family of serine/threonine protein kinases. Like its closest relative, NEK9, it contains a protein kinase and an RCC1 domain, but lacks the C-terminal region that is key for NEK9's regulation as a G2/M kinase. Importantly, NEK8 localizes to cilia as part of a multimeric protein complex that assembles in a fibrillar fashion at the proximal half of this signaling organelle, defining what is known as the INV compartment. NEK8 and its INV compartment partners inversin, ANKS6 and NPHP3 are necessary for left-right determination and the correct development of different organs such as the kidney, the heart and the liver. But the kinase substrates, regulatory mechanism and activating cues and thus the molecular basis of NEK8 important physiological roles remain elusive. We present the current findings regarding NEK8 and also highlight what we miss in order to progress towards the understanding of the kinase and the function of the INV complex at the cilia.

Background: Noninfectious complications of peritoneal dialysis (PD) are common in infants. Mechanical dysfunctions with abdominal compartment syndrome, hydrothorax with respiratory failure, and medication-induced chyloperitoneum are rare during PD. In this case report, we aim to present several life-threatening events and the timely management of a PD infant. Case Presentation: This male infant is a case of infantile nephronophthisis, NPHP3/renal-hepatic-pancreatic dysplasia type 1, with end-stage kidney disease, and he received PD therapy at 4 months of age. Because of the young age with low body weight and hepatosplenomegaly with a limited abdominal cavity, intra-abdominal pressure-associated noninfectious complications frequently occurred. Acute respiratory failure with abdominal dullness was detected at 5 months of age. Abdominal compartment syndrome caused by PD catheter outflow obstruction from omental wrapping was diagnosed via laparoscopic revision surgery. Hyperkalemia, decreased PD drainage volume, and sudden respiratory distress occurred at 10 months old. Hydrothorax due to pleuroperitoneal communication was confirmed by scintigraphy. After thoracoscopic diaphragmatic bleb repair and plication surgery were performed, no recurrence of hydrothorax was observed. Calcium channel blocker-induced chyloperitoneum was observed at 13 months of age. Chylous ascites disappeared after tapering off the calcium channel blocker in 3 days. After the patient grew up with a larger peritoneal cavity, no more pressure-associated complications of PD occurred. Conclusions: The key to successful treatment of rare and life-threatening noninfectious complications of PD in young infants lies in early detection and timely intervention. A limited abdominal cavity is not a contraindication for PD therapy, especially in very young infants with low body weight, because hemodialysis is not a choice of long-term dialysis modality.

Primary cilia (PC) are microtubule-based organelles that function as cellular antennae to sense and transduce extracellular signals. Nephronophthisis 3 (NPHP3) is localized in the inversin compartment of PC. Mutations in NPHP3 are associated with renal-hepatic-pancreatic dysplasia. In this study, we investigated whether vinblastine (VBL), a microtubule destabilizer, induces anticancer drug resistance through NPHP3-associated PC formation in HeLa human cervical cancer cells. A considerable increase in PC frequency was observed in HeLa cells under serum-deprived (SD) conditions, which led to the inhibition of VBL-induced cell death. VBL-resistant cells were established by repetitive treatments with VBL and showed an increase in PC frequency. NPHP3 expression was also increased by VBL treatment under serum starvation as well as in VBL-resistant cells. NPHP3 expression and PC-associated resistance were positively correlated with apoptosis-antagonizing transcription factor (AATF) and negatively correlated with inhibition of NPHP3. In addition, AATF-mediated NPHP3 expression is associated with PC formation via the regulation of intraflagellar transport protein 88 (IFT88). VBL resistance ability was reduced by treating with ciliobrevin A, a well-known ciliogenesis inhibitor. Collectively, cancer cell survival following VBL treatment is regulated by PC formation via AATF-mediated expression of IFT88 and NPHP3. Our data suggest that the activation of AATF and IFT88 could be a novel regulator to induce anticancer drug resistance through NPHP3-associated PC formation.

Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data. An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients. With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival. These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

Renal-hepatic-pancreatic dysplasia type 1 (RHPD1) is a rare sporadic and autosomal recessive disorder with unknown incidence. RHPD1 is caused by biallelic pathogenic variants in NPHP3, which encode nephrocystin, an important component of the ciliary protein complex. In this case report, we describe a male newborn who was confirmed by ultrasound to have renal enlargement with multiple cysts, pancreatic enlargement with cysts, and increased liver echogenicity, leading to the clinical diagnosis of RHPD. In addition, a compound heterozygous pathogenic variant, namely, NPHP3 c.1761G > A (p. W587*) and the c.69delC (p. Gly24Ala24*11) variant, was detected by WES. The patient was clinically and genetically diagnosed with RHPD1. At 34 h of life, the infant died of respiratory insufficiency. This is the first published case of RHPD1 in China. This study broadens the known range of RHPD1 due to NPHP3 pathogenic variants.