BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited cystic disease characterized by bilateral renal cyst formation and congenital liver fibrosis. Cardiovascular disorders such as noncompaction of ventricular myocardium (NVM) have not been reported with ARPKD.
METHODS: A 5-month-old girl was examined after presenting with a fever and turbid urine for one day and was diagnosed as urinary tract infection. Urinary ultrasound showed multiple round, small cysts varying in size in both kidneys. Genetic testing revealed two heterozygous mutations and one exon deletion in the polycystic kidney and hepatic disease 1 gene, indicating a diagnosis of ARPKD. During hospitalization, she was found to have chronic heart failure after respiratory tract infection, with an ejection fraction of 29% and fraction shortening of 13%. When the patient was 15 months old, it was found that she had prominent trabeculations and deep intertrabecular recesses with the appearance of blood flow from the ventricular cavity into the intertrabecular recesses by echocardiography. The noncompaction myocardium was 0.716 cm and compaction myocardium was 0.221 cm (N/C = 3.27), indicating a diagnosis of NVM. Liver and kidney function remained normal during four-year follow-up.
CONCLUSIONS: This is the first report of NVM in a patient with ARPKD. It is unsure if the coexistence of NVM and ARPKD is a coincidence or they are different manifestations of ciliary dysfunction in the heart and kidneys.

Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the polycystic kidney and hepatic disease-1 (PKHD1) gene and is an important inherited cause of chronic kidney disease in children. The most typical presentations in neonates are massively enlarged kidneys with variable echogenicity, multiple small cysts, and congenital hepatic fibrosis. Potter sequence with pulmonary hypoplasia can present due to oligohydramnios. Severe pulmonary hypoplasia can lead to respiratory insufficiency and perinatal death. Some affected children can develop end-stage renal disease in early childhood or adolescence. Here, we report the clinical presentations, management, and renal outcomes of three neonatal cases of ARPKD from our center.

Autosomal recessive polycystic kidney disease (ARPKD) is often associated with hepatobiliary disease in the form of hepatic fibrosis and/or Caroli disease. Combined liver-kidney transplantation (CLKT) is a transplant modality of choice in children with both end-stage renal disease (ESRD) and severe hepatic disease. However, there is no consensus on whether children with ARPKD-associated ESRD without severe hepatic disease can be treated with isolated kidney transplantation (KT) without the need for CLKT. We retrospectively studied the efficacy of isolated KT in children with ARPKD without severe hepatic disease, and followed the course of hepatic disease post KT. This is a single-center study of three children with ARPKD and ESRD who underwent isolated KT. None of them had severe hepatic disease at the time of KT. All children were clinically diagnosed with ARPKD in the immediate postnatal period. All had hepatic fibrosis of varying degrees and two had intrahepatic biliary duct (IHBD) dilatation. None had gastrointestinal (GI) bleed, portal hypertension or cholangitis. Two children had preemptive KT. Pre-transplant unilateral or bilateral native nephrectomy were performed for two children, and one underwent unilateral native nephrectomy at the time of KT. The median creatinine clearance at a median post-KT follow-up of 24 months was 60.3 mL/min/1.73 m2. The two-year graft and patient survival were both 100%. Post KT, all three patients continued to demonstrate evidence of hepatic fibrosis and IHBD on sonogram; however, none of them were either evaluated for or required liver transplantation given normal synthetic liver function and absence of portal hypertension or other severe hepatobiliary disease. There were no adverse events observed such as cholangitis, GI bleed, or multiorgan failure. Hence, an excellent short-term graft and patient survival was demonstrated in this study of children with ARPKD and mild to moderate hepatic disease who received isolated KT. Long-term follow-up and larger studies are important to assess the efficacy of isolated KT in this subset of children with ARPKD.

Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment.

Priapism is a urologic emergency requiring prompt management. There are three types of priapism: stuttering (intermittent), non-ischemic (high-flow/arterial), and ischemic (low-flow/veno-occlusive). Here, we present the first case of an infant with recurrent non-ischemic priapism as the first sign of severe hypertension. An 11-month-old infant was admitted to the hospital for high-flow priapism. On admission, he was found to have severe hypertension that required a combination of five antihypertensive drugs; abdominal ultrasound showed polycystic kidneys, splenomegaly, and a parenchymal liver lesion. The priapism resolved spontaneously and did not recur again after the initiation of antihypertensive treatment. Genetic analysis confirmed autosomal recessive polycystic kidney disease (ARPKD). We found no other explanation for the priapism, such as genital trauma, hematologic disease, or anything else. Decreased nitric oxide (NO) bioavailability seen in patients with hypertension seems to be the principal mechanism of hypertension causing priapism. This hypothesis is supported by animal models of genetically modified mice lacking nitric oxide synthase. The same mechanism is thought to be the genesis of priapism and other complications, such as pulmonary hypertension, in patients with sickle cell disease. We present a case of severe hypertension-associated priapism in a child with unrecognized ARPKD. The endothelial dysfunction with decreased NO bioavailability seen in patients with hypertension may be the principal pathogenic mechanism.

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD.

Objective: Variants of the polycystic kidney and hepatic disease 1 (PKHD1) gene are associated with autosomal recessive polycystic kidney disease (ARPKD). This study aimed to identify the genetic causes in a Chinese pedigree with ARPKD and design a minigene construct of the PKHD1 gene to investigate the impact of its variants on splicing. Methods: Umbilical cord samples from the proband and peripheral blood samples from his parents were collected, and genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatic analysis was used to identify potential genetic causes, and Sanger sequencing confirmed the existence of variants within the pedigree. A minigene assay was performed to validate the effects of an intronic variant on mRNA splicing. Results: Two variants, c.9455del (p.N3152Tfs*10) and c.2408-13C>G, were identified in the PKHD1 gene (NM_138694.4) by WES; the latter has not been previously reported. In silico analysis predicted that this intronic variant is potentially pathogenic. Bioinformatic splice prediction tools revealed that the variant is likely to strongly impact splice site function. An in vitro minigene assay revealed that c.2408-13C>G can cause aberrant splicing, resulting in the retention of 12 bp of intron 23. Conclusion: A novel pathogenic variant of PKHD1, c.2408-13C>G, was found in a fetus with ARPKD, which enriches the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and the diagnosis of ARPKD. Minigenes are optimal to determine whether intron variants can cause aberrant splicing.

Autosomal recessive polycystic kidney disease (ARPKD) is a significant cause of morbidity and mortality in infants and children. In severe cases bilateral nephrectomies are considered but may be associated with significant neurological complications and life-threatening hypotension.
We describe a case of a 17 months old boy with genetically confirmed ARPKD who underwent sequential bilateral nephrectomies at the age of 4 and 10 months. Following the second nephrectomy the boy was started on continuous cycling peritoneal dialysis with blood pressure on the lower range. At the age of 12 months after a few days of poor feeding at home the boy experienced a severe episode of hypotension and coma of Glasgow Come Scale of three. Brain magnetic-resonance imaging (MRI) showed signs of hemorrhage, cytotoxic cerebral edema and diffuse cerebral atrophy. During the subsequent 72 h he developed seizures requiring anti-epileptic drug therapy, gradually regained consciousness but remained significantly hypotensive after discontinuation of vasopressors. Thus, he received high doses of sodium chloride orally and intraperitoneally as well as midodrine hydrochloride. His ultrafiltration (UF) was targeted to keep him in mild-to-moderate fluid overload. After two months of stable condition the patient started to develop hypertension requiring four antihypertensive medications. After optimizing peritoneal dialysis to avoid fluid overload and discontinuation of sodium chloride the antihypertensives were discontinued, but hyponatremia with hypotensive episodes reoccurred. Sodium chloride was reintroduced resulting in recurrent salt-dependent hypertension.
Our case report illustrates an unusual course of blood pressure changes following bilateral nephrectomies in an infant with ARPKD and the particular importance of tight regulation of sodium chloride supplementation. The case adds to the scarce literature about clinical sequences of bilateral nephrectomies in infants, and as well highlights the challenge of managing blood pressure in these patients. Further research on the mechanisms and management of blood pressure control is clearly needed.

Systemic and portal hypertension, liver fibrosis, and hepatomegaly are manifestations associated with autosomal recessive polycystic kidney disease (ARPKD), which is caused by malfunctions of fibrocystin/polyductin (FPC). The goal is to understand how liver pathology occurs and to devise therapeutic strategies to treat it. We injected 5-day-old Pkhd1del3-4/del3-4 mice for 1 mo with the cystic fibrosis transmembrane conductance regulator (CFTR) modulator VX-809 designed to rescue processing and trafficking of CFTR folding mutants. We used immunostaining and immunofluorescence techniques to evaluate liver pathology. We assessed protein expression via Western blotting. We detected abnormal biliary ducts consistent with ductal plate abnormalities, as well as a greatly increased proliferation of cholangiocytes in the Pkhd1del3-4/del3-4 mice. CFTR was present in the apical membrane of cholangiocytes and increased in the Pkhd1del3-4/del3-4 mice, consistent with a role for apically located CFTR in enlarged bile ducts. Interestingly, we also found CFTR in the primary cilium, in association with polycystin (PC2). Localization of CFTR and PC2 and overall length of the cilia were increased in the Pkhd1del3-4/del3-4 mice. In addition, several of the heat shock proteins; 27, 70, and 90 were upregulated, suggesting that global changes in protein processing and trafficking had occurred. We found that a deficit of FPC leads to bile duct abnormalities, enhanced cholangiocyte proliferation, and misregulation of heat shock proteins, which all returned toward wild type (WT) values following VX-809 treatment. These data suggest that CFTR correctors can be useful as therapeutics for ARPKD. Given that these drugs are already approved for use in humans, they can be fast-tracked for clinical use.NEW & NOTEWORTHY ARPKD is a multiorgan genetic disorder resulting in newborn morbidity and mortality. There is a critical need for new therapies to treat this disease. We show that persistent cholangiocytes proliferation occurs in a mouse model of ARPKD along with mislocalized CFTR and misregulated heat shock proteins. We found that VX-809, a CFTR modulator, inhibits proliferation and limits bile duct malformation. The data provide a therapeutic pathway for strategies to treat ADPKD.

(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for ARPKD have yet to be found. Antisense oligonucleotides (ASOs) are short special oligonucleotides which function to regulate gene expression and alter mRNA splicing. Several ASOs have been approved by the FDA for the treatment of genetic disorders, and many are progressing at present. We designed ASOs to verify whether ASOs mediate the correction of splicing further to treat ARPKD arising from splicing defects and explored them as a potential treatment option. (2) Methods: We screened 38 children with polycystic kidney disease for gene detection using whole-exome sequencing (WES) and targeted next-generation sequencing. Their clinical information was investigated and followed up. The PKHD1 variants were summarized and analyzed, and association analysis was carried out to analyze the relationship between genotype and phenotype. Various bioinformatics tools were used to predict pathogenicity. Hybrid minigene analysis was performed as part of the functional splicing analysis. Moreover, the de novo protein synthesis inhibitor cycloheximide was selected to verify the degraded pathway of abnormal pre-mRNAs. ASOs were designed to rescue aberrant splicing, and this was verified. (3) Results: Of the 11 patients with PKHD1 variants, all of them exhibited variable levels of complications of the liver and kidneys. We found that patients with truncating variants and variants in certain regions had a more severe phenotype. Two splicing variants of the PKHD1 genotypes were studied via the hybrid minigene assay: variants c.2141-3T>C and c.11174+5G>A. These cause aberrant splicing, and their strong pathogenicity was confirmed. We demonstrated that the abnormal pre-mRNAs produced from the variants escaped from the NMD pathway with the use of the de novo protein synthesis inhibitor cycloheximide. Moreover, we found that the splicing defects were rescued by using ASOs, which efficiently induced the exclusion of pseudoexons. (4) Conclusion: Patients with truncating variants and variants in certain regions had a more severe phenotype. ASOs are a potential drug for treating ARPKD patients harboring splicing mutations of the PKHD1 gene by correcting the splicing defects and increasing the expression of the normal PKHD1 gene.