Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Spontaneous renal cyst hemorrhage is one of the clinical emergencies in peritoneal dialysis (PD) patients and is potentially life-threatening. The main complaints are sudden low back pain, paleness, and hypotensive shock with or without vomiting or fever. In contrast to inherited polycystic kidney disease, acquired cystic kidney disease (ACKD) secondary to chronic kidney disease is easily overlooked or delayed in clinical diagnosis and treatment, leading to severe clinical outcomes. We report three patients with spontaneous hemorrhage of ACKD in the peritoneal dialysis center at Peking University First Hospital. The common features are as follows, long history of dialysis, mild to severe low back pain, decrease in hemoglobulin, negative PD solutions, diagnosis established through computed tomography (CT), and continuing PD during treatment of ACKD hemorrhage. Treatments vary from conservative to unilaterally selective renal artery embolization. In this study, ACKD morbidity was investigated in PD patients. A total of 316 patients who had an abdominal ultrasound, CT, or magnetic resonance imaging (MRI) in the past 1 year were enrolled. Among them, 103 cases (32.9%) met the diagnostic criteria of ACKD. The morbidity rates were 27.5%, 37.8%, 43.8%, 59.1%, and 88.6%, when the dialysis history ranged from ≤3, >3 & ≤5, >5 & ≤7, >7 & ≤9, >9 years, respectively, showing a increasing trend. Most ACKD hemorrhages could be healed and got an acceptable prognosis after treatment, including rest, blood transfusion, selective renal artery embolization, or nephrectomy. We summarize the risk factors, including a long history of dialysis, anticoagulation or antiplatelet, and inflammation or stones of the urinary system, but with no difference in initial kidney diseases and gender. ACKD hemorrhage mainly includes intracapsular hemorrhage, cyst rupture, and spontaneous retroperitoneal hemorrhage. In addition, we also recommend an adaptive process for spontaneous kidney hemorrhage of diagnosis and treatment in peritoneal dialysis patients. The significance of these cases lies in the fact that patients with ACKD are potentially associated with complications such as cyst hemorrhage and malignancy. Thus, peritoneal dialysis physicians should place great importance on the surveillance of ACKD.

Acquired cystic disease associated renal cell carcinomas (ACD-RCC) are rare and their molecular and histopathological characteristics are still being explored. We therefore investigated the clinicopathologic and molecular characteristics of 31 tumors. The patients were predominantly male (n = 30), with tumors mainly left-sided (n = 17), unifocal (n = 19), and unilateral (n = 29) and a mean tumor size of 25 mm (range, 3-65 mm). Microscopically, several histologic patterns were present, including pure classic sieve-like (n = 4), and varied proportions of mixed classic sieve-like with papillary (n = 23), tubulocystic (n = 9), compact tubular (n = 4) and solid (n = 1) patterns. Calcium-oxalate crystals were seen in all tumors. Molecular analysis of 9 tumors using next generation sequencing showed alterations in SMARCB1 in 3 tumors (1 with frameshift deletion and 2 with copy number loss in chromosome 22 involving SMARCB1 region), however, INI1 stain was retained in all. Nonrecurrent genetic alterations in SETD2, NF1, NOTCH4, BRCA2 and CANT1 genes were also seen. Additionally, MTOR p.Pro351Ser was identified in one tumor. Copy number analysis showed gains in chromosome 16 (n = 5), 17 (n = 2) and 8 (n = 2) as well as loss in chromosome 22 (n = 2). In summary, ACD-RCC is a recognized subtype of kidney tumors, with several histological architectural patterns. Our molecular data identifies genetic alterations in chromatin modifying genes (SMARCB1 and SETD2), which may suggest a role of such genes in ACD-RCC development.

BACKGROUND: This study aimed to assess the feasibility, safety, and efficacy of an endoscopic parapelvic renal cyst (PRC) incision using flexible ureterorenoscopy (fURS).
METHODS: We retrospectively reviewed data concerning 16 patients in whom PRC incisions had been performed using fURS between January 2016 and January 2022. Two patients were excluded from the study owing to a lack of follow-up information. The cysts of all the patients were evaluated preoperatively by computed tomography. The patients\' age, gender, cyst size, presenting symptoms, postoperative complications, and pre- and post-treatment visual analogue scale (VAS) scores were evaluated. Surgical success was defined as a reduction of more than half of the cyst size in the sixth postoperative month.
RESULTS: A total of 14 patients were included in this study. The patients\' mean age was 52.6 ± 8.8 years, and the mean cyst size was 69.1 ± 15.5 mm. Twelve (85.7%) patients presented with flank pain. Clavien-Dindo grade 1 complications were observed in two patients (14.3%), and grade 2 complications were observed in one (7.1%). The median VAS scores were significantly lower after treatment than before in patients who presented with flank pain (2 (1-2.8) vs 8 (7-8), respectively; p = 0.002). Surgical success rate was detected in 11 patients (78.6%) six months after the treatment.
CONCLUSIONS: Endoscopic incision of the PRC is a feasible treatment modality with high success rates and low complication rates. However, multicentre studies with larger populations and longer follow-ups are needed to evaluate the lasting effects.

Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 (Car2) significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in Tsc1 KO mice. In these studies, we contrasted the ontogeny of cyst burden in Tsc1/Car2 dKO mice vs. Tsc1/Foxi1 dKO mice. Compared to Tsc1 KO, the Tsc1/Car2 dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in Tsc1/Car2 dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to Tsc1/Foxi1 dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of Foxi1 and kidney-collecting duct-specific H+-ATPase subunits in 110-day-old Tsc1/Car2 dKO mice. We conclude that Car2 inactivation temporarily decreases the kidney cyst burden in Tsc1 KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.

Standard ultrasound (US) finds wide use in renal diseases as a screening procedure, but it is not always able to characterize lesions, especially in differential diagnosis between benign and malignant lesions. In contrast, contrast-enhanced ultrasonography (CEUS) is appropriate in differentiating between solid and cystic lesions as well as between tumors and pseudotumors. We show the case of a nephropathic patient who showed a complex, large, growing renal mass, characterized through a CEUS. This seventy-five-year-old diabetic heart patient showed a 6 cm-complex and plurisected cyst on ultrasound of left kidney. Laboratory data showed the presence of stage IIIb chronic renal failure with GFR 30 ml/min, creatinine 2.33 mg/dl, azotemia 88 mg/dl. The patient performed abdominal CT without contrast medium, showing at the level of the left upper pole, a roundish formation with the dimensions of approximately 70x53x50 mm. At the semiannual checkup, the nephrology examination showed a slight rise in creatinine and, therefore, after six months, it was decided to perform a CT scan without contrast medium again. CT showed a slight increase in the size of the mass located at the left kidney (74x56x57 mm). Given the increased size of the left mass, albeit modest, a CEUS was performed to reach a diriment diagnosis. CEUS concluded for complex cystic formation with presence of intraluminal solid-corpuscular material, with thrombotic-hemorrhagic etiology, in progressive phase of organization, classifiable as Bosniak type II cyst. CEUS in the kidneys is a cost-effective and valuable imaging technique; it is accurate in the characterization of indeterminate lesions and complex cysts.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient\'s electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing.
METHODS: A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS.
CONCLUSIONS: This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

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